Hospitalization rates among dialysis patients during Hurricane Katrina.
Dialysis centers struggled to maintain continuity of care for dialysis patients during and immediately following Hurricane Katrina's landfall on the US Gulf Coast in August 2005. However, the impact on patient health and service use is unclear. The impact of Hurricane Katrina on hospitalization rates among dialysis patients was estimated. Data from the United States Renal Data System were used to identify patients receiving dialysis from January 1, 2001 through August 29, 2005 at clinics that experienced service disruptions during Hurricane Katrina. A repeated events duration model was used with a time-varying Hurricane Katrina indicator to estimate trends in hospitalization rates. Trends were estimated separately by cause: surgical hospitalizations, medical, non-renal-related hospitalizations, and renal-related hospitalizations. The rate ratio for all-cause hospitalization associated with the time-varying Hurricane Katrina indicator was 1.16 (95% CI, 1.05-1.29; P = .004). The ratios for cause-specific hospitalization were: surgery, 0.84 (95% CI, 0.68-1.04; P = .11); renal-related admissions, 2.53 (95% CI, 2.09-3.06); P < .001), and medical non-renal related, 1.04 (95% CI, 0.89-1.20; P = .63). The estimated number of excess renal-related hospital admissions attributable to Katrina was 140, representing approximately three percent of dialysis patients at the affected clinics. Hospitalization rates among dialysis patients increased in the month following the Hurricane Katrina landfall, suggesting that providers and patients were not adequately prepared for large-scale disasters.


Mycobacterium tuberculosis persistence mutants identified by screening in isoniazid-treated mice.
Tuberculosis (TB) is notoriously difficult to cure, requiring administration of multiple antibiotics for 6 mo or longer. Conventional anti-TB drugs inhibit biosynthetic processes involved in cell growth and division, such as DNA replication, RNA transcription, protein translation, and cell wall biogenesis. Although highly effective against bacteria cultured in vitro under optimal growth conditions, these antibiotics are less effective against bacteria grown in vivo in the tissues of a mammalian host. The factors that contribute to the antibiotic tolerance of bacteria grown in vivo are unknown, although altered metabolism and sluggish growth are hypothesized to play a role. To address this question, we identified mutations in Mycobacterium tuberculosis that impaired or enhanced persistence in mice treated with isoniazid (INH), a front-line anti-TB drug. Disruption of cydC, encoding a putative ATP-binding cassette transporter subunit, accelerated bacterial clearance in INH-treated mice without affecting growth or survival in untreated mice. Conversely, transposon insertions within the rv0096-rv0101 gene cluster attenuated bacterial growth and survival in untreated mice but paradoxically prevented INH-mediated killing of bacteria in treated mice. These contrasting phenotypes were dependent on the interaction of the bacteria with the tissue environment because both mutants responded normally to INH when grown in macrophages ex vivo or in axenic cultures in vitro. Our findings have important implications because persistence-impairing mutations would be missed by conventional genetic screens to identify candidate drug targets. Conversely, persistence-enhancing mutations would be missed by standard diagnostic methods, which are performed on bacteria grown in vitro, to detect drug resistance.


The challenge of finding a cure for HIV infection.
Although combination therapy for HIV infection represents a triumph for modern medicine, chronic suppressive therapy is required to contain persistent infection in reservoirs such as latently infected CD4+ lymphocytes and cells of the macrophage-monocyte lineage. Despite its success, chronic suppressive therapy is limited by its cost, the requirement of lifelong adherence, and the unknown effects of long-term treatment. This review discusses our current understanding of suppressive antiretroviral therapy, the latent viral reservoir, and the needs for and challenges of attacking this reservoir to achieve a cure.


The neural bases of directed and spontaneous mental state attributions to group agents.
In daily life, perceivers often need to predict and interpret the behavior of group agents, such as corporations and governments. Although research has investigated how perceivers reason about individual members of particular groups, less is known about how perceivers reason about group agents themselves. The present studies investigate how perceivers understand group agents by investigating the extent to which understanding the 'mind' of the group as a whole shares important properties and processes with understanding the minds of individuals. Experiment 1 demonstrates that perceivers are sometimes willing to attribute a mental state to a group as a whole even when they are not willing to attribute that mental state to any of the individual members of the group, suggesting that perceivers can reason about the beliefs and desires of group agents over and above those of their individual members. Experiment 2 demonstrates that the degree of activation in brain regions associated with attributing mental states to individuals--i.e., brain regions associated with mentalizing or theory-of-mind, including the medial prefrontal cortex (MPFC), temporo-parietal junction (TPJ), and precuneus--does not distinguish individual from group targets, either when reading statements about those targets' mental states (directed) or when attributing mental states implicitly in order to predict their behavior (spontaneous). Together, these results help to illuminate the processes that support understanding group agents themselves.


Facial resurfacing for nonmelanoma skin cancer prophylaxis.
To determine the effect of facial skin resurfacing for treatment of actinic keratoses (AKs) and prophylaxis against new primary basal and squamous cell carcinomas in individuals with previous nonmelanoma skin cancer (NMSC) or severe photodamage. Randomized, prospective 5-year trial. Dermatology and otolaryngology clinics of a Veterans Affairs hospital. Thirty-four patients with a history of facial or scalp AKs or basal or squamous cell carcinoma were enrolled. Five of 7 eligible patients who declined study-related treatment were used as controls. Twenty-seven patients were randomized to 3 treatment arms; 3 patients were discontinued from the study. Carbon dioxide laser resurfacing, 30% trichloroacetic acid peel, or 5% fluorouracil cream applied twice daily for 3 weeks. Reduction in the number of AKs was measured 3 months after treatment. The incidence of new NMSC in treated areas was assessed between January 1, 2001, and June 30, 2005. Times from baseline to diagnosis of first skin cancer were compared between the treatment and control groups. Treatment with fluorouracil, trichloroacetic acid, or carbon dioxide laser resulted in an 83% to 92% reduction in AKs (P< or =.03), a lower incidence of NMSC compared with the control group (P<.001), and a trend toward longer time to development of new skin cancer compared with the control group (P=.07). However, no significant differences were noted among the treatment groups. All 3 modalities demonstrated benefit for AK reduction and skin cancer prophylaxis compared with controls and warrant further study in a larger trial.


Salt, sodium channels, and SGK1.
The hormone aldosterone increases extracellular fluid volume and blood pressure by activating epithelial Na+ channels (ENaCs). Serum- and glucocorticoid-induced kinase 1 (SGK1) is an aldosterone-stimulated signaling molecule that enhances distal nephron Na+ transport, in part by preventing the internalization of ENaCs from the plasma membrane. In this issue of the JCI, Zhang et al. demonstrate that SGK1 enhances transcription of the alpha subunit of ENaC by preventing histone methylation, providing an additional mechanism by which SGK1 increases ENaC-mediated Na+ transport in the distal nephron (see the related article beginning on page 773).


Effect of sensor location on controller performance in a wastewater treatment plant.
Complete mixing is hard to achieve in large bioreactors in wastewater treatment plants. This often leads to a non-uniform distribution of components such as dissolved oxygen and, hence, the process rates depend on them. Furthermore, when these components are used as input for a controller, the location of the sensor can potentially affect the control action. In this contribution, the effect of sensor location and the choice of setpoint on the controller performance were examined for a non-homogeneously mixed pilot bioreactor described by a compartmental model. The impacts on effluent quality and aeration cost were evaluated. It was shown that a dissolved oxygen controller with a fixed setpoint performs differently as a function of the location of the sensor. When placed in a poorly mixed location, the controller increases the aeration intensity to its maximum capacity leading to higher aeration costs. When placed just above the aerated zone, the controller decreases the aeration rate resulting in lower dissolved oxygen concentrations in the remainder of the system, compromising effluent quality. In addition to the location of the sensor, the selection of an appropriate setpoint also impacts controller behavior. This suggests that mixing behavior of bioreactors should be better quantified for proper sensor location and controller design.


Differences in the profile, treatment, and prognosis of patients with cardiogenic shock by myocardial infarction classification: A report from NCDR.
Cardiogenic shock is a deadly complication of an acute myocardial infarction (MI). We sought to characterize differences in patient features, treatments, and outcomes of cardiogenic shock by MI classification: ST-segment-elevation MI (STEMI) versus non-ST-segment elevation MI (NSTEMI). We compared differences in care by the shock status of 235 541 patients with STEMI and NSTEMI treated at 392 US hospitals from 2007 to 2011. Cardiogenic shock occurred in 12.2% of patients with STEMI versus 4.3% of patients with NSTEMI. Compared with STEMI shock, NSTEMI shock was more likely in patients who were older and predominantly women; had diabetes mellitus, hypertension, previous heart failure, MI, or peripheral arterial disease; and who received coronary artery bypass grafting (11.6% versus 21.2%; P<0.0001) but less likely to have received percutaneous coronary intervention (84.2% versus 35.3%; P<0.0001). Compared with patients with STEMI presenting with shock at admission, patients with NSTEMI presenting with shock had longer delays to percutaneous coronary intervention (1.2 versus 3.2 hours) and coronary artery bypass grafting (7.9 versus 55.9 hours). Cardiogenic shock in patients with STEMI was associated with a lower mortality risk (33.1% shock versus 2.0% no shock; adjusted odds ratio, 14.1; 95% confidence interval, 13.0-15.4; interaction P value <0.0001) compared with patients with NSTEMI (40.8% shock versus 2.3% no shock, odds ratio, 19.0; 95% confidence interval, 17.1-21.2). Cardiogenic shock is associated with high mortality in patients with STEMI and NSTEMI. However, urgent revascularization is more commonly pursued in patients with STEMI presenting with shock than in patients with NSTEMI. More research is needed to improve the outcomes for patients with MI presenting with shock, particularly those presenting with NSTEMI.


The effect of a hip-strengthening program on mechanics during running and during a single-leg squat.
Block randomized controlled trial. To investigate whether a strengthening and movement education program, targeting the hip abductors and hip external rotators, alters hip mechanics during running and during a single-leg squat. Abnormal movement patterns during running and single-leg squatting have been associated with a number of running-related injuries in females. Therapeutic interventions for these aberrant movement patterns typically include hip strengthening. While these strengthening programs have been shown to improve symptoms, it is unknown if the underlying mechanics during functional movements is altered. Twenty healthy females with excessive hip adduction during running, as determined by instrumented gait analysis, were recruited. The runners were matched by age and running distance, and randomized to either a training group or a control group. The training group completed a hip strengthening and movement education program 3 times per week for 6 weeks in addition to single-leg squat training with neuromuscular reeducation consisting of mirror and verbal feedback on proper mechanics. The control group did not receive an intervention but maintained the current running distance. Using a handheld dynamometer and standard motion capture procedures, hip strength and running and single-leg squat mechanics were compared before and after the strengthening and movement education program. While hip abductor and external rotation strength increased significantly (P<.005) in the training group, there were no significant changes in hip or knee mechanics during running. However, during the single-leg squat, hip adduction, hip internal rotation, and contralateral pelvic drop all decreased significantly (P = .006, P = .006, and P = .02, respectively). The control group exhibited no changes in hip strength, nor in the single-leg squat or running mechanics at the conclusion of the 6-week study. A training program that included hip strengthening and movement training specific to single-leg squatting did not alter running mechanics but did improve single-leg squat mechanics. These results suggest that hip strengthening and movement training, when not specific to running, do not alter abnormal running mechanics. Therapy, level 2b.


Ethanol, isobutanol, and biohydrocarbons as gasoline components in relation to gaseous emissions and particulate matter.
The exhaust emissions of three cars using different biofuels were explored at a temperature of -7 °C. The biofuels studied contained both low- and high-concentration ethanol blends, isobutanol, and biohydrocarbons. A multipoint fuel injection car (MPFI), direct-injection spark-ignition car (DISI), and flex-fuel car (FFV) represented three different spark-ignition-car technologies. At -7 °C, substantial emissions were observed for the three cars, and differences were found among ethanol, isobutanol, and biohydrocarbons as fuel components. For example, E85 resulted in high acetaldehyde, formaldehyde, ethanol, ethene, and acetylene emissions when compared to E30 or lower ethanol concentrations. Isobutanol-containing fuel showed elevated butyraldehyde, methacrolein, and isobutanol emissions. The highest particulate matter (PM) emissions, associated polyaromatic hydrocarbon (PAH) and indirect mutagenicity emissions were detected with the DISI car. Oxygenated fuels reduced PM emissions and associated priority PAH emissions in the DISI car. PM and PAH emissions from the MPFI and FFV cars were generally low. A combination of 10% ethanol and biohydrocarbon components did not change emissions significantly when compared to ethanol-only-containing E10 gasoline. Therefore, a combination of ethanol or isobutanol with biohydrocarbon components offers an option to reach high gasoline bioenergy content for E10-compatible cars.


Sleep Timing in Late Autumn and Late Spring Associates With Light Exposure Rather Than Sun Time in College Students.
Timing of the human sleep-wake cycle is determined by social constraints, biological processes (sleep homeostasis and circadian rhythmicity) and environmental factors, particularly natural and electrical light exposure. To what extent seasonal changes in the light-dark cycle affect sleep timing and how this varies between weekdays and weekends has not been firmly established. We examined sleep and activity patterns during weekdays and weekends in late autumn (standard time, ST) and late spring (daylight saving time, DST), and expressed their timing in relation to three environmental reference points: clock-time, solar noon (SN) which occurs one clock hour later during DST than ST, and the midpoint of accumulated light exposure (50% LE). Observed sleep timing data were compared to simulated data from a mathematical model for the effects of light on the circadian and homeostatic regulation of sleep. A total of 715 days of sleep timing and light exposure were recorded in 19 undergraduates in a repeated-measures observational study. During each three-week assessment, light and activity were monitored, and self-reported bed and wake times were collected. Light exposure was higher in spring than in autumn. 50% LE did not vary across season, but occurred later on weekends compared to weekdays. Relative to clock-time, bedtime, wake-time, mid-sleep, and midpoint of activity were later on weekends but did not differ across seasons. Relative to SN, sleep and activity measures were earlier in spring than in autumn. Relative to 50% LE, only wake-time and mid-sleep were later on weekends, with no seasonal differences. Individual differences in mid-sleep did not correlate with SN but correlated with 50% LE. Individuals with different habitual bedtimes responded similarly to seasonal changes. Model simulations showed that light exposure patterns are sufficient to explain sleep timing in spring but less so in autumn. The findings indicate that during autumn and spring, the timing of sleep associates with actual light exposure rather than sun time as indexed by SN.


Identifying and intervening on barriers to healthcare access among members of a small Korean community in the southern USA.
We used community-based participatory research (CBPR) to explore barriers to healthcare access and utilization and identify potentially effective intervention strategies to increase access among members of the Korean community in North Carolina (NC). Our CBPR partnership conducted 8 focus groups with 63 adult Korean immigrants in northwest NC and 15 individual in-depth interviews and conducted an empowerment-based community forum. We identified 20 themes that we organized into four domains, including practical barriers to health care, negative perceptions about care, contingencies for care, and provider misconceptions about local needs. Forum attendees identified four strategies to improve Korean community health. Despite the implementation of the Patient Protection and Affordable Care Act (ACA), many Korean community members will continue to remain uninsured, and among those who obtain insurance, many barriers will remain. It is imperative to ensure the health of this highly neglected and vulnerable community. Potential strategies include the development of (1) low-literacy materials to educate members of the Korean community about how to access healthcare services, (2) lay health advisor programs to support navigation of service access and utilization, (3) church-based programming, and (4) provider education to reduce misconceptions about Korean community needs.


The effect of group cohesion on rehabilitation outcome in cancer survivors.
Group-based physical training interventions have been shown to be effective in increasing quality of life in cancer survivors. Until now, however, the impact of cohesion within the group on intervention outcome has not been investigated. We examined self-reported individual group cohesion ratings collected in the first half of a 12-week rehabilitation programme for cancer survivors (N=132). Four dimensions of group cohesion were measured, i.e. the bond with the group as whole, the bond with other members, cooperation within the group and the instrumental value. Quality of life, physical functioning and fatigue were assessed before and after the intervention using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30. Linear multiple multivariate regression analysis was conducted to explore the relationship between group cohesion and intervention outcome. The relationship between group cohesion and outcome was significantly modified by gender. Higher ratings of cooperation within the group predicted better post-intervention quality of life and physical functioning and less fatigue in men, and better quality of life and physical functioning in women. Additionally, women who reported a stronger bond with other members showed a lower quality of life after the intervention. No relationship was found between the instrumental value and the outcome variables. Some dimensions of group cohesion seem to be associated with intervention outcome. The underlying mechanisms need to be unravelled.


Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome.
The proteasome is a sophisticated ATP-dependent molecular machine responsible for protein degradation in all known eukaryotic cells. It remains elusive how conformational changes of the AAA-ATPase unfoldase in the regulatory particle (RP) control the gating of the substrate-translocation channel leading to the proteolytic chamber of the core particle (CP). Here we report three alternative states of the ATP-γ-S-bound human proteasome, in which the CP gates are asymmetrically open, visualized by cryo-EM at near-atomic resolutions. At least four nucleotides are bound to the AAA-ATPase ring in these open-gate states. Variation in nucleotide binding gives rise to an axial movement of the pore loops narrowing the substrate-translation channel, which exhibit remarkable structural transitions between the spiral-staircase and saddle-shaped-circle topologies. Gate opening in the CP is thus regulated by nucleotide-driven conformational changes of the AAA-ATPase unfoldase. These findings demonstrate an elegant mechanism of allosteric coordination among sub-machines within the human proteasome holoenzyme.


Diagnosis of bronchiectasis and airway wall thickening in children with cystic fibrosis: Objective airway-artery quantification.
To quantify airway and artery (AA)-dimensions in cystic fibrosis (CF) and control patients for objective CT diagnosis of bronchiectasis and airway wall thickness (AWT). Spirometer-guided inspiratory and expiratory CTs of 11 CF and 12 control patients were collected retrospectively. Airway pathways were annotated semi-automatically to reconstruct three-dimensional bronchial trees. All visible AA-pairs were measured perpendicular to the airway axis. Inner, outer and AWT (outer-inner) diameter were divided by the adjacent artery diameter to compute AinA-, AoutA- and AWTA-ratios. AA-ratios were predicted using mixed-effects models including disease status, lung volume, gender, height and age as covariates. Demographics did not differ significantly between cohorts. Mean AA-pairs CF: 299 inspiratory; 82 expiratory. 131 inspiratory; 58 expiratory. All ratios were significantly larger in inspiratory compared to expiratory CTs for both groups (p<0.001). AoutA- and AWTA-ratios were larger in CF than in controls, independent of lung volume (p<0.01). Difference of AoutA- and AWTA-ratios between patients with CF and controls increased significantly for every following airway generation (p<0.001). Diagnosis of bronchiectasis is highly dependent on lung volume and more reliably diagnosed using outer airway diameter. Difference in bronchiectasis and AWT severity between the two cohorts increased with each airway generation. • More peripheral airways are visible in CF patients compared to controls. • Structural lung changes in CF patients are greater with each airway generation. • Number of airways visualized on CT could quantify CF lung disease. • For objective airway disease quantification on CT, lung volume standardization is required.


Entomopathogenic nematodes are not an alternative to fenamiphos for management of plant-parasitic nematodes on golf courses in Florida.
With the cancellation of fenamiphos in the near future, alternative nematode management tactics for plant-parasitic nematodes (PPN) on golf courses need to be identified. The use of entomopathogenic nematodes (EPN) has been suggested as one possible alternative. This paper presents the results of 10 experiments evaluating the efficacy of EPN at managing PPN on turfgrasses and improving turf performance. These experiments were conducted at various locations throughout Florida over the course of a decade. In different experiments, different EPN species were tested against different species of PPN. Separate experiments evaluated multiple rates and applications of EPN, compared different EPN species, and compared single EPN species against multiple species of PPN. In a few trials, EPN were associated with reductions in certain plant-parasite species, but in other trials were associated with increases. In most trials, EPN had no effect on plant parasites. Because EPN were so inconsistent in their results, we conclude that EPN are not acceptable alternatives to fenamiphos by most turf managers in Florida at this time.


Increased expression of serum amyloid A in glaucoma and its effect on intraocular pressure.
To search for and validate potential molecular pathogenic mechanisms in the trabecular meshwork (TM) responsible for the elevated intraocular pressure (IOP) associated with glaucoma. Gene chip arrays were used to identify differential gene expression in glaucomatous TM tissues. Serum amyloid A (SAA) upregulation was subsequently confirmed with quantitative PCR (QPCR) and ELISA. The effect of SAA on gene expression of cultured human TM cells was tested with gene chip arrays and verified with ELISA, and its effect on IOP was evaluated in the human ocular perfusion organ culture. Microarray analysis showed that the expression of SAA2 was increased in TM tissues from donors with glaucoma. This finding was subsequently confirmed by QPCR. The SAA mRNA levels were increased in glaucoma TM tissues by more than 5-fold (P < 0.05) and in cultured TM cells derived from donors with glaucoma by 25-fold (P < 0.05) compared with controls. SAA protein levels in the TM of glaucoma patients were also significantly (P < 0.05) elevated by 2.9-fold. Treatment of cultured human TM cells with recombinant SAA affected gene expression, including a 22-fold up-regulation of interleukin-8 (P < 0.001). SAA increased IOP by approximately 40% (P < 0.05) in the human ocular perfusion organ culture without any observable changes in the morphology of the tissues involved in aqueous outflow. These findings indicate that SAA, which is an acute-phase apolipoprotein that plays important roles in infection, inflammation, and tissue repair, may contribute to the pathogenic changes to the TM in glaucoma.


Beyond Medical Care: How Different National Models of Care Impact the Experience of Adolescent and Young Adult Cancer Patients.
Patient experience is positively associated with clinical effectiveness, quality care, and patient safety. This study examines the experience of care of adolescents and young adult (AYA) cancer patients from Australia and the United States, allowing a comparison of patient experiences in the context of different national models of cancer care delivery. Participants (n = 190) were aged 15-29 years and received cancer treatment from 2014 to 2019. Australians (n = 118) were recruited nationally by health care professionals. U.S. participants (n = 72) were recruited nationally via social media. The survey included demographic and disease variables, and questions regarding medical treatment, information and support provision, care coordination, and satisfaction across the treatment pathway. Sensitivity analyses examined the possible contribution of age and gender. Most patients from both countries were satisfied or very satisfied with their medical treatment (chemotherapy, radiotherapy, and surgery). There were significant differences between countries in the provision of fertility preservation services, age-appropriate communication, and psychosocial support. Our findings suggest when a national system of oversight with both state and federal funding is implemented, as is the case in Australia but not in the United States, significantly more AYAs with cancer receive age-appropriate information and support services, and improved access to specialist services such as fertility care. A national approach with government funding and centralized accountability appears to be associated with substantial benefits for the well-being of AYAs undergoing cancer treatment.


Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice.
The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R ), expressing the "trafficking compromised" GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory.


Comparison of the capacity between public and private health facilities to manage under-five children with febrile illnesses in Uganda.
Public health facilities are usually the first to receive interventions compared to private facilities, yet majority of health seeking care is first done with the latter. This study compared the capacity to manage acute febrile illnesses in children below 5 years in private vs public health facilities in order to design interventions to improve quality of care. A survey was conducted within 57 geographical areas (parishes), from August to October 2014 in Mukono district, central Uganda. The survey comprised both facility and health worker assessment. Data were collected on drug stocks, availability of treatment guidelines, diagnostic equipment, and knowledge in management of malaria, pneumonia and diarrhoea, using a structured questionnaire. A total of 53 public and 241 private health facilities participated in the study. While similar proportions of private and public health facilities stocked Coartem, the first-line anti-malarial drug, (98 vs 95%, p = 0.22), significantly more private than public health facilities stocked quinine (85 vs 53%, p < 0.01). Stocks of obsolete anti-malarial drugs, such as chloroquine, were reported in few public and private facilities (3.7 vs 12.5%, p = 0.06). Stocks of antibiotics-amoxycillin and gentamycin were similar in both sectors (≥90% for amoxicillin; ≥50 for gentamycin). Training in malaria was reported by 65% of public health facilities vs 56% in the private sector, p = 0.25), while, only 21% in the public facility and 12% in the private facilities, p = 0.11, reported receiving training in pneumonia. Only 55% of public facilities had microscopes. Malaria treatment guidelines were significantly lacking in the private sector, p = 0.01. Knowledge about first-line management of uncomplicated malaria, pneumonia and diarrhoea was significantly better in the public facilities compared to the private ones, though still sub-optimal. Deficiencies of equipment, supplies and training exist even in public health facilities. In order to significantly improve the capacity to handle acute febrile illness among children under five, training in proper case management, availability of supplies and diagnostics need to be addressed in both sectors.


Women with human immunodeficiency virus infection and abnormal Papanicolaou smears: a prospective study of colposcopy and clinical outcome.
To determine the effect of human immunodeficiency virus (HIV) infection on colposcopic and histologic findings and clinical outcome in women who have abnormal Papanicolaou smears. We conducted a prospective study of women with abnormal Papanicolaou smears from among those participating in a longitudinal study of HIV infection, human papillomavirus infection, and genital neoplasia. Women with squamous intraepithelial lesions (SIL) on blindly interpreted Papanicolaou smears were referred for colposcopy and standard gynecologic care. Colposcopic and histologic findings were correlated with cytology, and differences between HIV seropositives and seronegatives were analyzed. Thirty-eight of 48 women referred underwent colposcopy, of whom 36 (94.7%) had colposcopic or histologic findings no more severe than those suggested by Papanicolaou smear. Seventeen of 25 HIV seropositives (68%) had cervical or vaginal condyloma or neoplasia, compared with three of 13 seronegatives (23%) (odds ratio [OR] 7.1, 95% confidence interval [CI] 1.5-33.0). Among seropositives, seven (28%) had cervical intraepithelial neoplasia (CIN) grade II or III; ten (40%) had cervical or vaginal condyloma, CIN I, or both; and eight (32%) had no vaginal or cervical SIL. There was no case of invasive carcinoma. Seven seropositives (28%) had or developed multicentric disease, compared with no seronegatives (P = .07). Follow-up ranged at 3-37 months and showed that all three treated seronegative women and five of ten treated seropositive women had normal examinations. Three seropositive patients had persistent disease without progression, and two had progression of condyloma. No CIN II, CIN III, or invasive carcinoma was seen during follow-up. Among women seropositive for HIV who had SIL on a Papanicolaou smear, colposcopic and histologic findings were predicted reliably by the cytologic smear. Rapid progression of CIN after standard gynecologic care for early genital lesions was not seen.


Liquid phase epitaxial growth of heterostructured hierarchical MOF thin films.
Precise control of epitaxial growth of MOF-on-MOF thin films, for ordered hierarchical tbo-type structures is demonstrated. The heterostructured MOF thin film was fabricated by successful sequential deposition of layers from two different MOFs. The 2-periodic layers, edge-transitive 4,4-square lattices regarded as supermolecular building layers, were commendably cross-linked using a combination of inorganic/organic and organic pillars.


Complete Genome Sequence of Hospital-Acquired Methicillin-Resistant Staphylococcus aureus Strain WCUH29.
The hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) strain WCUH29 has been intensively and widely used as a model system for identification and evaluation of novel antibacterial targets and pathogenicity. In this announcement, we report the complete genome sequence of HA-MRSA WCUH29 (NCIMB 40771).


Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity.
The association between obesity and cardiovascular disease (CVD) is proven, but why some adults with obesity develop CVD while others remain disease-free is poorly understood. Here, we investigated whether mitochondrial DNA (mtDNA) methylation in platelets is altered prior to CVD development in a population of adults with overweight and obesity. We devised a nested case-control study of 200 adults with overweight or obesity who were CVD-free at baseline, of whom 84 developed CVD within 5 years, while 116 remained CVD-free. Platelet mtDNA was isolated from plasma samples at baseline, and mtDNA methylation was quantified in mitochondrially encoded cytochrome-C-oxidase I (MT-CO1; nt6797 and nt6807), II (MT-CO2; nt8113 and nt8117), and III (MT-CO3; nt9444 and nt9449); tRNA leucine 1 (MT-TL1; nt3247 and nt3254); D-loop (nt16383); tRNA phenylalanine (MT-TF; nt624); and light-strand-origin-of-replication (MT-OLR; nt5737, nt5740, and nt5743) by bisulfite-pyrosequencing. Logistic regression was used to estimate the contribution of mtDNA methylation to future CVD risk. ROC curve analysis was used to identify the optimal mtDNA methylation threshold for future CVD risk prediction. A model was generated incorporating methylation at three loci (score 0, 1, or 2 according to 0, 1, or 2-3 hypermethylated loci, respectively), adjusted for potential confounders, such as diastolic and systolic blood pressure, fasting blood glucose, and cholesterol ratio. mtDNA methylation at MT-CO1 nt6807 (OR = 1.08, 95% CI 1.02-1.16; P = 0.014), MT-CO3 nt9444 (OR = 1.22, 95% CI 1.02-1.46, P = 0.042), and MT-TL1 nt3254 (OR = 1.30, 95% CI 1.05-1.61, P = 0.008) was higher at baseline in those who developed CVD by follow-up, compared with those who remained CVD-free. Combined use of the three loci significantly enhanced risk prediction, with hazard ratios of 1.38 (95% CI 0.68-2.78) and 2.68 (95% CI 1.41-5.08) for individuals with score 1 or 2, respectively (P = 0.003). Methylation at these sites was independent of conventional CVD risk factors, including inflammation markers, fasting blood glucose concentration, and blood pressure. Methylations of MT-CO1, MT-CO3, and MT-TL1 are, together, strong predictors of future CVD incidence. Since methylation of these mtDNA domains was independent of conventional CVD risk factors, these markers may represent a novel intrinsic predictor of CVD risk in adults with overweight and obesity.


Looking on the Bright Side Reduces Worry in Pregnancy: Training Interpretations in Pregnant Women.
Recent evidence suggests that anxiety is more common than depression in the perinatal period, however there are few interventions available to treat perinatal anxiety. Targeting specific processes that maintain anxiety, such as worry, may be one potentially promising way to reduce anxiety in this period. Given evidence that negative interpretation bias maintains worry, we tested whether interpretation bias could be modified, and whether this in turn would lead to less negative thought (i.e., worry) intrusions, in pregnant women with high levels of worry. Participants (N = 49, at least 16 weeks gestation) were randomly assigned to either an interpretation modification condition (CBM-I) which involved training in accessing positive meanings of emotionally ambiguous scenarios, or an active control condition in which the scenarios remained ambiguous and unresolved. Relative to the control condition, participants in the CBM-I condition generated significantly more positive interpretations and experienced significantly less negative thought intrusions. Our findings indicate that worry is a modifiable risk factor during pregnancy, and that it is possible to induce a positive interpretation bias in pregnant women experiencing high levels of worry. Although preliminary, our findings speak to exciting clinical possibilities for the treatment of worry and the prevention of perinatal anxiety.


Action potentials and insulin secretion: new insights into the role of Kv channels.
Coordinated electrical activity allows pancreatic beta-cells to respond to secretagogues with calcium entry followed by insulin secretion. Metabolism of glucose affects multiple membrane proteins including ion channels, transporters and pumps that collaborate in a cascade of electrical activity resulting in insulin release. Glucose induces beta-cell depolarization resulting in the firing of action potentials (APs), which are the primary electrical signal of the beta-cell. They are shaped by orchestrated activation of ion channels. Here we give an overview of the voltage-gated potassium (Kv) channels of the beta-cell, which are responsible in part for the falling phase of the AP, and how their regulation affects insulin secretion. beta cells contain several Kv channels allowing dynamic integration of multiple signals on repolarization of glucose-stimulated APs. Recent studies on Kv channel regulation by cAMP and arachidonic acid and on the Kv2.1 null mouse have greatly increased our understanding of beta-cell excitation-secretion coupling.


RMo1 confers blast resistance in barley and is located within the complex of resistance genes containing Mla, a powdery mildew resistance gene.
Isolates of Magnaporthe oryzae (the causal agent of rice blast disease) can infect a range of grass species, including barley. We report that barley Hordeum vulgare cv. Baronesse and an experimental line, BCD47, show a range of resistance reactions to infection with two rice blast isolates. The complete resistance of Baronesse to the isolate Ken 54-20 is controlled by a single dominant gene, designated RMo1. RMo1 mapped to the same linkage map position on chromosome 1H as the powdery mildew resistance locus Mla and an expressed sequence tag (k04320) that corresponds to the barley gene 711N16.16. A resistance quantitative trait locus (QTL), at which Baronesse contributed the resistance allele, to the isolate Ken 53-33 also mapped at the same position as RMo1. Synteny analysis revealed that a corresponding region on rice chromosome 5 includes the bacterial blight resistance gene xa5. These results indicate that a defined region on the short arm of barley chromosome 1H, including RMo1 and Mla, harbors genes conferring qualitative and quantitative resistance to multiple pathogens. The partial resistance of BCD47 to Ken53-33 is determined by alleles at three QTL, two of which coincide with the linkage map positions of the mildew resistance genes mlo and Mlf.


A comparison of measures of reading and intelligence as risk factors for the development of myopia in a UK cohort of children.
Evidence suggests that reading may be an important risk factor for myopia, but recent reports find that performance in non-verbal intelligence tests may be more important or that near-work is not associated with myopia. Non-cycloplegic autorefraction data were available at the ages of 7 and 10 years from a birth cohort study. Children whose right eye spherical equivalent autorefraction was <or=-1.50 D were categorised as "likely to be myopic." The authors tested associations between school-based Standardised Assesment Tests (SATS) for reading and mathematics, maternal report of child liking reading, the Wescher Objective Reading Dimension (WORD) test results, verbal and non-verbal IQ, and the child being in the "likely to be myopic" group. 6871 children (59.7% of remaining cohort) had refractive and risk factor data at 7, of whom 1.5% were in the "likely to be myopic" group. Predictors (odds ratios, OR: 95% CI) of concurrent (at 7) risk for myopia were good performance in the SATS reading (2.60:1.61, 4.19; p<0.001), SATS maths (1.90: 1.19, 3.05; p = 0.008), the WORD (2.72:1.60, 4.64; p = 0.001) and verbal IQ tests (1.99, 1.13, 3.52; p = 0.055) after adjustment for the number of myopic parents (p = 0.014) and ethnicity (p = 0.129). However, the strongest predictor of incident myopia developing between 7 and 10 years was the parental report of whether the child liked reading: (4.05:1.27, 12.89; p = 0.031), adjusted for parental myopia (p = 0.033) and ethnicity (p = 0.008). Factors associated with reading may play a part in myopia development. Further comparisons of different measures of reading-related activity or verbal ability may help clarify which of the related behavioural characteristics are causally related to myopia prevalence.


Preventing malaria in pregnancy through community-directed interventions: evidence from Akwa Ibom State, Nigeria.
Despite massive anti-malaria campaigns across the subcontinent, effective access to intermittent preventive treatment (IPTp) and insecticide-treated nets (ITNs) among pregnant women remain low in large parts of sub-Saharan Africa. The slow uptake of malaria prevention products appears to reflect lack of knowledge and resistance to behavioural change, as well as poor access to resources, and limited support of programmes by local communities and authorities. A recent community-based programme in Akwa Ibom State, Nigeria, is analysed to determine the degree to which community-directed interventions can improve access to malaria prevention in pregnancy. Six local government areas in Southern Nigeria were selected for a malaria in pregnancy prevention intervention. Three of these local government areas were selected for a complementary community-directed intervention (CDI) programme. Under the CDI programme, volunteer community-directed distributors (CDDs) were appointed by each village and kindred in the treatment areas and trained to deliver ITNs and IPTp drugs as well as basic counseling services to pregnant women. Relative to women in the control area, an additional 7.4 percent of women slept under a net during pregnancy in the treatment areas (95% CI [0.035, 0.115], p-value < 0.01), and an additional 8.5 percent of women slept under an ITN after delivery and prior to the interview (95% CI [0.045, 0.122], p-value < 0.001). The effects of the CDI programme were largest for IPTp adherence, increasing the fraction of pregnant women taking at least two SP doses during pregnancy by 35.3 percentage points [95% CI: 0.280, 0.425], p-value < 0.001) relative to the control group. No effects on antenatal care attendance were found. The presented results suggest that the inclusion of community-based programmes can substantially increase effective access to malaria prevention, and also increase access to formal health care access in general, and antenatal care attendance in particular in combination with supply side interventions. Given the relatively modest financial commitments they require, community-directed programmes appear to be a cost-effective way to improve malaria prevention; the participatory approach underlying CDI programmes also promises to strengthen ties between the formal health sector and local communities.


Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype.
A characteristic feature of chronic myeloid leukaemia (CML) is the inevitable advancement from a treatable chronic phase to a fatal, drug-resistant stage referred to as blast crisis. The molecular mechanisms responsible for this disease transition remain unknown. As increased expression of Bcr-Abl has been associated with blast crisis CML, we have established transfectants in 32D cells that express low and high levels of Bcr-Abl, and assessed their drug sensitivity. Cells with high Bcr-Abl expression levels are resistant to conventional cytotoxic drugs, and also require higher levels of STI571 (an inhibitor of Bcr-Abl), to induce cell death. Co-treatment with cytotoxic drugs and STI571 increased the sensitivity of the drug-resistant cells. Despite the drug-resistant phenotype, high Bcr-Abl levels concomitantly increased the expression of p53, p21, Bax and down-regulated Bcl-2. These cells maintain a survival advantage irrespective of a reduced proportion of cycling cells and the pro-apoptotic shift in gene expression. In addition, the level of Bcr-Abl expression (high or low) does not alter the growth factor independence and elevated Bcl-xL expression observed. Our study indicates that drug resistance can be primarily attained by increased Bcr-Abl expression, and highlights the potential of therapy which combines STI571 with conventional cytotoxic drugs.


HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications.
Reversible acetylation mediated by histone deacetylases (HDACs) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumor cells. As HDAC inhibition prompts tumor cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anti-cancer agent, many of which have entered clinical trials. Although the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumor types undergo a favorable response, in particular hematological malignancies. Vorinostat and romidepsin have been approved for treating cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anti-cancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of these inhibitors in the treatment of cancer.


Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration.
Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.


Dietary intake of fibre and risk of knee osteoarthritis in two US prospective cohorts.
Dietary fibre reduces body weight and inflammation both of which are linked with knee osteoarthritis (OA). We examined the association between fibre intake and risk of knee OA. We used data from the Osteoarthritis Initiative (OAI) of 4796 participants and Framingham Offspring Osteoarthritis Study (Framingham) of 1268 persons. Dietary intake of fibre was estimated at baseline, and incident radiographic OA (ROA) and symptomatic OA (SxOA) were followed annually until 48 months in OAI and assessed 9 years later in Framingham. Knee pain worsening was also examined in OAI. Generalised estimating equations were applied in multivariable regression models. In OAI, we identified 869 knees with SxOA, 152 knees with ROA and 1964 knees with pain worsening among 4051 subjects with valid dietary intake (baseline mean age: 61.2 years; mean body mass index (BMI): 28.6). In Framingham, 143 knees with SxOA and 176 knees with ROA among 971 such subjects (baseline mean age: 53.9 years; mean BMI: 27.0) were identified. In both cohorts, dietary total fibre was inversely associated with risk of SxOA (p trend <0.03) with significantly lower risk at the highest versus lowest quartile (OR (95% CI): 0.70 (0.52, 0.94) for OAI and 0.39 (0.17, 0.88) for Framingham). Furthermore, dietary total and cereal fibre were significantly inversely associated with knee pain worsening in OAI (p trend <0.02). No apparent association was found with ROA. Findings from two longitudinal studies consistently showed that higher total fibre intake was related to a lower risk of SxOA, while the relation to ROA was unclear.


States with stronger health insurance rate review authority experienced lower premiums in the individual market in 2010-13.
States have varying degrees of review authority over health insurance carriers' rates, including prior approval authority over proposed rates and requirements for loss ratios, the proportion of premium revenues spent on medical claims. The Affordable Care Act (ACA) requires carriers in certain categories of health insurance to provide public justification for rate increases of 10 percent or more. We collected data on how states changed their rate review authority and requirements during 2010-13, the years immediately after enactment of the ACA, and we combined these data with carrier filings. We found that adjusted premiums in the individual market in states that had prior-approval authority combined with loss ratio requirements were lower in 2010-13 ($3,489) than premiums in states with no rate review authority or that had only file-and-use regulations, which gave the states no authority to block rate increases ($3,617). Adjusted premiums declined modestly in prior-approval states with loss ratio requirements, from $3,526 in 2010 to $3,452 in 2013, while premiums increased from $3,422 to $3,683 in states with no rate review authority or file-and-use regulations only. Our findings suggest that states with prior approval authority and loss ratio requirements constrained health insurance premium increases.


Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients.
Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.


Incidence of traumatic brain injury across the full disease spectrum: a population-based medical record review study.
Extremely few objective estimates of traumatic brain injury incidence include all ages, both sexes, all injury mechanisms, and the full spectrum from very mild to fatal events. We used unique Rochester Epidemiology Project medical records-linkage resources, including highly sensitive and specific diagnostic coding, to identify all Olmsted County, MN, residents with diagnoses suggestive of traumatic brain injury regardless of age, setting, insurance, or injury mechanism. Provider-linked medical records for a 16% random sample were reviewed for confirmation as definite, probable, possible (symptomatic), or no traumatic brain injury. We estimated incidence per 100,000 person-years for 1987-2000 and compared these record-review rates with rates obtained using Centers for Disease Control and Prevention (CDC) data-systems approach. For the latter, we identified all Olmsted County residents with any CDC-specified diagnosis codes recorded on hospital/emergency department administrative claims or death certificates during 1987-2000. Of sampled individuals, 1257 met record-review criteria for incident traumatic brain injury; 56% were ages 16-64 years, 56% were male, and 53% were symptomatic. Mechanism, sex, and diagnostic certainty differed by age. The incidence rate per 100,000 person-years was 558 (95% confidence interval = 528-590) versus 341 (331-350) using the CDC data-system approach. The CDC approach captured only 40% of record-review cases. Seventy-four percent of missing cases presented to the hospital/emergency department; none had CDC-specified codes assigned on hospital/emergency department administrative claims or death certificates; and 66% were symptomatic. Capture of symptomatic traumatic brain injuries requires a wider range of diagnosis codes, plus sampling strategies to avoid high rates of false-positive events.


Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation.
The bacterial CRISPR-Cas9 system has emerged as a multifunctional platform for sequence-specific regulation of gene expression. This Review describes the development of technologies based on nuclease-deactivated Cas9, termed dCas9, for RNA-guided genomic transcription regulation, both by repression through CRISPR interference (CRISPRi) and by activation through CRISPR activation (CRISPRa). We highlight different uses in diverse organisms, including bacterial and eukaryotic cells, and summarize current applications of harnessing CRISPR-dCas9 for multiplexed, inducible gene regulation, genome-wide screens and cell fate engineering. We also provide a perspective on future developments of the technology and its applications in biomedical research and clinical studies.


Phase I/II study of gemcitabine and cisplatin in the treatment of advanced non-small cell lung cancer: preliminary results.
Sixty-six patients with advanced non-small cell lung cancer have been entered into a phase I/II study of a combination of gemcitabine and cisplatin. An initial phase I portion of the study has been completed, and 16 patients have been entered using a fixed dose of gemcitabine 1,000 mg/m2 as a 30-minute intravenous infusion weekly for 3 weeks. Cisplatin was administered on day 15 following gemcitabine with appropriate prehydration and posthydration. The study was designed to allow for sequential groups of three patients to receive three dose levels of cisplatin (60 mg/m2, 75 mg/ m2, and 100 mg/m2). Dose modification and patient numbers were to be increased at any dose level if significant toxicity was observed. The regimen was well tolerated at all doses, and the final level of cisplatin 100 mg/m2 was expanded to 10 patients before the phase II portion was opened. Neutropenia (World Health Organization grade 4 in three patients) and thrombocytopenia (grade 3 or 4 in five patients) were the main hematologic toxicities recorded. These episodes were brief and uncomplicated. Grade 3 nausea and vomiting occurred in 12 patients, but was no worse than would be expected from cisplatin alone. Alopecia, when it occurred, was minimal (no hair loss in 10 patients and grade 1 or 2 in six patients). No significant renal toxicity or neurotoxicity was seen. A phase II study with cisplatin 100 mg/m2 and gemcitabine 1,000 mg/m2 has been opened, and to date 43 patients are evaluable for response. Eighteen (42%) patients have achieved partial remissions. The study will close when 50 evaluable patients have been entered.


Human β-defensin 3 increases the TLR9-dependent response to bacterial DNA.
Human β-defensin 3 (hBD3) is a cationic antimicrobial peptide with potent bactericidal activity in vitro. HBD3 is produced in response to pathogen challenge and can modulate immune responses. The amplified recognition of self-DNA by human plasmacytoid dendritic cells has been previously reported, but we show here that hBD3 preferentially enhances the response to bacterial DNA in mouse Flt-3 induced dendritic cells (FLDCs) and in human peripheral blood mononuclear cells. We show the effect is mediated through TLR9 and although hBD3 significantly increases the cellular uptake of both E. coli and self-DNA in mouse FLDCs, only the response to bacterial DNA is enhanced. Liposome transfection also increases uptake of bacterial DNA and amplifies the TLR9-dependent response. In contrast to hBD3, lipofection of self-DNA enhances inflammatory signaling, but the response is predominantly TLR9-independent. Together, these data show that hBD3 has a role in the innate immune-mediated response to pathogen DNA, increasing inflammatory signaling and promoting activation of the adaptive immune system via antigen presenting cells including dendritic cells. Therefore, our data identify an additional immunomodulatory role for this copy-number variable defensin, of relevance to host defence against infection and indicate a potential for the inclusion of HBD3 in pathogen DNA-based vaccines.


Complete Genome Sequence of Streptacidiphilus sp. Strain 15-057A, Obtained from Bronchial Lavage Fluid.
Streptacidiphilus sp. strain 15-057A was isolated from a bronchial lavage sample and represents the only member of the genus not isolated from acidic soils. A single circular chromosome of 7.01 Mb was obtained by combining Illumina and PacBio sequencing data. Bioinformatic analysis detected 63 putative secondary biosynthetic gene clusters and recognized 43 transposons.


Nectar, not colour, may lure insects to their death.
We experimentally demonstrate in the field that prey of the carnivorous plant Sarracenia purpurea are attracted to sugar, not to colour. Prey capture (either all taxa summed or individual common taxa considered separately) was not associated with total red area or patterning on pitchers of living pitcher plants. We separated effects of nectar availability and coloration using painted 'pseudopitchers', half of which were coated with sugar solution. Unsugared pseudopitchers captured virtually no prey, whereas pseudopitchers with sugar solution captured the same amount of prey as living pitchers. In contrast to a recent study that associated red coloration with prey capture but that lacked controls for nectar availability, we infer that nectar, not colour, is the primary means by which pitcher plants attract prey.


Nutrient intake among US adults with disabilities.
Physical, mental and financial barriers among persons with disabilities limit their access to healthier diet. The present study investigated the relationship between disabilities and nutrient intake among US adults. Data originated from National Health and Nutrition Examination Survey 2007-2008 and 2009-2010 waves (n = 11,811). Five disability categories include activities of daily living (ADLs), instrumental activities of daily living (IADLs), leisure and social activities (LSAs), lower extremity mobility (LEM) and general physical activities (GPAs). Nutrient intakes from food and dietary supplements were calculated from 24-h dietary recalls. Adherence to dietary reference intakes and dietary guideline recommendations was compared between people with and without disabilities and across disability categories in the statistical analysis. GPAs, IADLs, LSAs, LEM and ADLs occupied 24.5%, 13.3%, 9.9%, 9.2% and 9.2% of US adults, respectively (not mutually exclusive). Only 42.3%, 11.3%, 63.8%, 47.7%, 48.7%, 9.7%, 48.7%, 90.7%, 21.7% and 4.7% of adults had saturated fat, fibre, cholesterol, vitamin A, vitamin C, vitamin D, calcium, iron, sodium and potassium intakes from food within recommended levels, respectively. Dietary supplement use moderately improved vitamin C, vitamin D and calcium intakes. People with disabilities were less likely to meet recommended levels on saturated fat, fibre (except GPAs), vitamin A (except GPAs), vitamin C (except GPAs), calcium and potassium intakes than persons without disability. Nutrient intake differed across disability categories, with ADLs least likely to meet recommended intakes. Interventions targeting persons with disabilities through nutrition education and financial assistance are warranted to promote healthy diet and reduce disparities.


P38 initiates degeneration of midbrain GABAergic and glutamatergic neurons in diabetes models.
Diabetes mellitus may cause tau protein hyperphosphorylation and neurodegeneration, but the exact mechanism by which diabetic conditions induce tau pathology remains unclear. Tau protein hyperphosphorylation is considered a major pathological hallmark of neurodegeneration and can be triggered by diabetes. Various tau-directed kinases, including P38, can be activated upon diabetic stress and induce tau hyperphosphorylation. Despite extensive research efforts, the exact tau specie(s) and kinases driving neurodegeneration in diabetes mellitus have not been clearly elucidated. We herein employed different techniques to determine the exact molecular mechanism of tau pathology triggered by diabetes in in vivo and in vitro models. We showed that diabetes-related stresses and glucose metabolism deficiency could induce cis P-tau (an early driver of the tau pathology) accumulation in the midbrain and corpus callosum of the diabetic mice models and cells treated with 2-deoxy-D-glucose, respectively. We found that the active phosphorylated level of P38 was increased in the treated cells and diabetic mice models. We observed that oxidative stress activated P38, which directly and indirectly drove tau pathology in the GABAergic and glutamatergic neurons of the midbrain of the diabetic mice after 96 h, which accumulated in the other neighboring brain areas after 2 months. Notably, P38 inhibition suppressed tau pathogenicity and risk-taking behaviors in the animal models after 96 h. The data establish P38 as a central mediator of diabetes mellitus-induced tau pathology. Our findings provide mechanistic insight into the consequences of this metabolic disorder on the nervous system.


EH and UIM: endocytosis and more.
Exogenously and endogenously originated signals are propagated within the cell by functional and physical networks of proteins, leading to numerous biological outcomes. Many protein-protein interactions take place between binding domains and short peptide motifs. Frequently, these interactions are inducible by upstream signaling events, in which case one of the two binding surfaces may be created by a posttranslational modification. Here, we discuss two protein networks. One, the EH-network, is based on the Eps15 homology (EH) domain, which binds to peptides containing the sequence Asp-Pro-Phe (NPF). The other, which we define as the monoubiquitin (mUb) network, relies on monoubiquitination, which is emerging as an important posttranslational modification that regulates protein function. Both networks were initially implicated in the control of plasma membrane receptor endocytosis and in the regulation of intracellular trafficking routes. The ramifications of these two networks, however, appear to extend into many other aspects of cell physiology as well, such as transcriptional regulation, actin cytoskeleton remodeling, and DNA repair. The focus of this review is to integrate available knowledge of the EH- and mUb networks with predictions of genetic and physical interactions stemming from functional genomics approaches.


HIV Infection Alters the Spectrum of HPV Subtypes Found in Cervical Smears and Carcinomas from Kenyan Women.
Infection with high risk HPV is implicated in pre-cancerous squamous intraepithelial lesions and their progression to cervical cancer. In the developed countries, infection with HPV 16 and 18 accounts for ~70% of cervical cancers, but it has been established that HPV type prevalence differs according to worldwide geographical location. In sub Saharan Africa infection with HPV is known to be augmented by HIV, which is endemic in this region. It is not yet clear, however, whether this ultimately influences progression to cervical cancer. Papillocheck(TM) and multiplex PCR were used to determine the range of HPV genotypes found in cervical smears and carcinomas from HIV positive and negative Kenyan women. Smear samples from HIV-positive women had a higher prevalence of: multiple HPV infections; high-risk HPVs 52, 58, 68, potential high risk 53/70, low-risk 44/55 and abnormal cytology compared to HIV-negative women. A low overall prevalence (~8%) of types 16/18 was found in all smear samples tested (n = 224) although this increased in invasive cervical carcinoma tissues to ~80% for HIV-negative and ~46% for HIV-positive women. Furthermore, HPV45 was more common in cervical carcinoma tissues from HIV-positive women. In summary HIV infection appears to alter the spectrum of HPV types found in both cervical smears and invasive cervical carcinomas. It is hypothesised there could be a complex interplay between these viruses which could either positively or negatively influence the rate of progression to cervical cancer.


Effect of graded nerve pressure injuries on motor function.
The purpose of this study was to determine the minimum amount of nerve fibers required to maintain normal motor function after nerve injury in rats. The authors first confirmed that a common peroneal nerve injury caused more aggravating effects on lower limb motor function than tibial nerve injury, as assessed by the static sciatic index (SSI). Thereafter, rats were subjected to varying degrees of crush injury to the common peroneal nerve. At 48 hours after the injury, motor function was assessed using the SSI and slope-walking ability (with slope angles of 30° and 45°). The tibialis anterior muscle, a main muscle innervated by the common peroneal nerve, was removed. Muscle sections were co-labeled with neuronal class III β-tubulin polyclonal antibody to identify the presence of axons and Alexa Fluor 488-conjugated α-bungarotoxin to identify the presence of motor endplates. The evaluation of neuromuscular innervation showed a correlation between SSI scores and ratios of residual axons (rs = 0.68, p < 0.01), and there was a statistically significant difference between slope-walking ability and ratios of residual axons (p < 0.01). Moreover, the ratios of residual axons in the nerve-crushed rats with normal motor function (SSI above -20) ranged from 36.5% to 88.7%, and those ratios in the success group with slope-walking angles of 30° and 45° ranged from 14.7% to 88.7% and from 39.8% to 88.7%, respectively. In this study of rodents, less than half of the motor axons were sufficient to maintain normal motor function of the lower limb.


The Glomerular Endothelium Restricts Albumin Filtration.
Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.


Self-Reported Physical Activity and Exercise Patterns in Children With Sickle Cell Disease.
Sickle cell disease (SCD) significantly affects physical functioning. We examined physical activity (PA) patterns in children with SCD versus a national sample and factors associated with PA and participation in physical education and organized sports. One hundred children with SCD completed a 58-item survey with questions from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) Physical Activity Questionnaire and others on physical education and sports, disease impact, and physical functioning. Compared with NHANES participants, more children with SCD (67 vs 42%, p < .01) reported doing at least 10 min of moderate-to-vigorous intensity PA (MVPA)/week. Children with SCD also reported spending more days in MVPA (2.3 vs. 1.4 days/week, p < .01). However, fewer reported spending ³ 60 min/day in either vigorous PA (VPA) (24 vs. 43%, p = .01) or MVPA (17 vs 23%, p < .01). In addition, 90% and 48% of children with SCD participated in physical education and sports, respectively. Greater disease impact on PA and physical functioning were associated with lower participation. Children with SCD are active at moderate to vigorous intensity for shorter durations. Negative personal beliefs about disease impact and poor physical functioning represent barriers to PA in SCD.


Competition between Al3+ and Fe3+ binding to human transferrin and toxicological implications: structural investigations using ultra-high resolution ESI MS and CD spectroscopy.
Human serum transferrin (hTF) is an iron binding protein with the primary task of ensuring well-controlled transport of Fe3+-ions in the bloodstream. Furthermore, hTF has been identified as a key component in the trafficking of Al3+-ions from the serum to cells. It is clear that binding alone does not guarantee cellular uptake via the transferrin receptor, since this is determined by the structural properties of the metal-protein complex. The conformation of the metallated hTF is critically important for delivery of Fe3+ or any other metal into the cell. The combination of ultra-high resolution ESI mass spectrometry and CD spectroscopy together provide accurate species distribution of the Fe3+ during stepwise addition to apo-hTF and an indirect indication of the tertiary structure of the metallated protein. These two methods together are extremely fine probes of structural changes as a function of precise metal binding status at micromolar concentrations. Simulation of the precise domain distribution could be determined during the stepwise metallation from 0 to 2 Fe3+ added. Analysis of the ESI-MS data for the stepwise metallation of apo-hTF and Al1 or 2-hTF with Fe3+ was carried out and used to simulate the experimental speciation based on the reported KF values. There are six main conclusions: (1) Fe3+ binds predominantly, initially to the C-lobe. (2) The CD spectral properties indicate that the C-lobe metallation dominates the structural properties of both binding sites; N-lobe metallation modifies the C-lobe structure. (3) Fe3+ metallation of the mixed Al1-2-hTF results in the dominant form of Fe1Al1-hTF. (4) The first Fe3+ bound to Al1-hTF binds predominantly in the C-lobe domain. (5) The CD spectral properties when Fe3+ binds to Al1-2-hTF indicates that Al-N-lobe occupation mirrors the structural effects of N-lobe occupation by Fe3+. (6) With respect to how Al3+ might enter the cell, the formation of a hybrid form Al1Fe1-hTF might enable the Al3+ to enter the cell via receptor-mediated endocytosis due to the binding of Fe3+ in the C-lobe of the protein which is primarily responsible for the structure of the metal-protein complex.


Role of Autophagy in HIV Pathogenesis and Drug Abuse.
Autophagy is a highly regulated process in which excessive cytoplasmic materials are captured and degraded during deprivation conditions. The unique nature of autophagy that clears invasive microorganisms has made it an important cellular defense mechanism in a variety of clinical situations. In recent years, it has become increasingly clear that autophagy is extensively involved in the pathology of HIV-1. To ensure survival of the virus, HIV-1 viral proteins modulate and utilize the autophagy pathway so that biosynthesis of the virus is maximized. At the same time, the abuse of illicit drugs such as methamphetamine, cocaine, morphine, and alcohol is thought to be a significant risk factor for the acquirement and progression of HIV-1. During drug-induced toxicity, autophagic activity has been proved to be altered in various cell types. Here, we review the current literature on the interaction between autophagy, HIV-1, and drug abuse and discuss the complex role of autophagy during HIV-1 pathogenesis in co-exposure to illicit drugs.


Crosstalk between different family members: IL27 recapitulates IFNγ responses in HCC cells, but is inhibited by IL6-type cytokines.
Interleukin-27 (IL27) is a type-I-cytokine of the IL6/IL12 family predominantly secreted by activated macrophages and dendritic cells. In the liver, IL27 expression was observed to be upregulated in patients with hepatitis B, and sera of hepatocellular carcinoma (HCC) patients contain significantly elevated levels of IL27 compared to healthy controls or patients with hepatitis and/or liver cirrhosis. In this study, we show that IL27 induces STAT1 and STAT3 phosphorylation in 5 HCC lines and 3 different types of non-transformed liver cells. We were especially interested in the relevance of the IL27-induced STAT3 activation in liver cells. Thus, we compared the IL27 responses with those induced by IFNγ (STAT1-dominated response) or IL6-type cytokines (IL6, hyper-IL6 (hy-IL6) or OSM) (STAT3-dominated response) by microarray analysis and find that in HCC cells, IL27 induces an IFNγ-like, STAT1-dependent transcriptional response, but we do not find an effective STAT3-dependent response. Validation experiments corroborate the finding from the microarray evaluation. Interestingly, the availability of STAT1 seems critical in the shaping of the IL27 response, as the siRNA knock-down of STAT1 revealed the ability of IL27 to induce the acute-phase protein γ-fibrinogen, a typical IL6 family characteristic. Moreover, we describe a crosstalk between the signaling of IL6-type cytokines and IL27: responses to the gp130-engaging cytokine IL27 (but not those to IFNs) can be inhibited by IL6-type cytokine pre-stimulation, likely by a SOCS3-mediated mechanism. Thus, IL27 recapitulates IFNγ responses in liver cells, but differs from IFNγ by its sensitivity to SOCS3 inhibition.


Extinction and dopamine receptor blockade after intermittent reinforcement training: failure to observe functional equivalence.
Response decrements in an operant task produced by either extinction or by the dopamine receptor blocker pimozide were examined in three experiments which employed intermittent reinforcement schedules. In contrast to the congruency between these treatments previously observed following continuous reinforcement training, treatment with pimozide was markedly more effective than extinction in decreasing performance after training with variable interval, fixed interval, and fixed ratio reinforcement. The two treatments also produced substantially different patterns of responding. A shift from extinction to pimozide did not alter the progressive decline in response rate over days, but a shift from pimozide to extinction caused a pronounced increase of performance. These results indicate that the pimozide and extinction treatment did not produce functionally equivalent effects, and that the role of dopamine on reward processes should not be inferred from comparisons between pimozide and extinction.


Prevalence and cross-immunity of Eimeria species on Korean chicken farms.
Epidemiology of Eimeria species in poultry flocks is important to increase the effectiveness of vaccinations and prophylactic strategies on chicken farms. In this study, fecal samples from 356 chicken farms were collected randomly and examined for the prevalence of Eimeria species. Through microscopic examination, it was determined that 78.7% of the tested farms were positive in Eimeria-infection. Seven Eimeria species were detected in all the positive farms by PCR amplification of the internal transcribed spacer 1 (ITS-1) region with species-specific primers. E. acervulina and E. tenella were the most prevalent, followed by E. brunetti and E. praecox (87.5, 62.5, 59.3, and 37.5% of the farms, respectively). Each of E. maxima, E. mitis, and E. necatrix was identified in 31.3% of the farms. Individual positive fecal samples contained multiple Eimeria species (mean=3.4). Since E. maxima is known to generate antigenic variants, cross-immunity was investigated for four isolates of E. maxima from the poultry farms in different regions of Korea. The extent of cross-protection varied from 54.3 to 100% against the heterologous isolates. The results obtained from this large-scale survey will be a useful reference for controlling coccidiosis in the poultry industry.


Twenty-five years of breast-feeding research in Midwifery.
This paper explores some of the significant changes that have taken place with regard to the protection, promotion and support of breast feeding during the past three decades. The period covered since the first issue of Midwifery in 1985, has been marked by some dramatic reversals of harmful discourses and detrimental practices with regard to infant and young child feeding and more specifically breast feeding. Midwifery has spanned this period with the publication of 80 papers on breast feeding. This collection of papers has both influenced and reflected upon changes in international and national breast-feeding strategies and practices. Six papers have been selected for a special virtual edition of Midwifery to reflect the diversity of breast-feeding research in terms of issues explored, methodology and country of origin (www.midwiferyjournal.com). Considerable progress is reflected in these papers. However, there are still enormous challenges ahead in working towards the optimisation of infant and young child feeding. In addition to continuing to conduct and collate robust scientific and epidemiological research we need further studies that explore the political, economic, socio-cultural and psychological factors influencing women's infant feeding practices. Our professional practice needs to continue to improve in order to provide women and families with appropriate support, encouragement and resources to enable them to breastfeed effectively. Finally, we need to continue to challenge the systems and approaches at organisational and community levels that impede women in their endeavours to feed their infants in optimum ways.


Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction.
Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.


Exercise behavior in adolescents with mild congenital heart disease.
Most children with congenital heart disease (CHD) are expected to survive to adolescence and adulthood owing to medical advances and care management. These adolescents need to be well informed about their exercise capacity and take greater personal responsibility for their exercise behavior as they mature. The aims of this study were to compare the amount and intensity of exercise engaged in by male and female adolescents with mild CHD while on summer vacation and during the academic semester and to determine the extent to which their exercise behavior met cardiologists' recommendations, based on New York Heart Association functional classification. A repeated-measure design was used to evaluate exercise behavior in 126 adolescents 12 to 18 years old with mild CHD from the outpatient cardiology departments of 3 medical centers in Taiwan. Exercise, classified as mild, moderate, or vigorous, was evaluated during summer vacation and during the fall semester using a 7-day self-reported exercise log. Patients engaged in significantly more mild and total exercise during summer vacation than they did during the fall semester. They also engaged in significantly less vigorous exercise during summer vacation than they did in the fall semester. Female respondents engaged in significantly less moderate (P = .019), vigorous (P < .001), and total (P = .015) exercise than did their male counterparts but showed no difference in mild exercise. During the summer and fall, nearly 50% of the adolescents followed their cardiologist's recommendations for exercise. Adolescents with mild CHD engaged in more exercise during summer vacation but engaged in more vigorous exercise during the fall semester. Approximately one half did not follow the exercise intensity recommended by cardiologists. Inadequate exercise patterns may lead to cardiovascular complications. Planned interventions related to exercise instruction are needed for adolescents with CHD.


Altered expression of urokinase-type plasminogen activator and plasminogen activator inhibitor in high-risk soft tissue sarcomas.
In recent years, classification of soft-tissue sarcomas (STS) has improved with cytogenetic analyses, but their clinical behavior is still not easily predictable. The aim of this study was to detect alterations in the urokinase-type plasminogen system, involved in tumor growth and invasion, by comparing mRNA levels of its components with those of paired normal tissues, and relating them with patient clinical course. Real-time PCR was performed on human STS cell lines and tissues from highly malignant STS, including leiomyosarcomas and malignant fibrous histiocytomas, to evaluate the expression of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of gene products was also performed. Median mRNA values of all genes studied were higher in tumors than in paired normal tissues. In agreement with data on STS cell lines, significant up-regulation for uPA and PAI-1 genes compared to reference values was seen. Moreover, different levels of expression were related to histotype and metastatic phenotype. There was accordance between uPA mRNA and protein expression, while immunodetection of PAI-1 product was weak and scattered. Clearly, the controversial role of PAI-1 protein requires further biological analyses, but evident involvement of uPA/PAI-1 gene overexpression in STS malignancy may highlight a molecular defect useful in discriminating STS high-risk patients.


Antidepressant Monotherapy and Combination Therapy with Acupuncture in Depressed Patients: A Resting-State Functional Near-Infrared Spectroscopy (fNIRS) Study.
Depression is a common psychiatric illness affecting over 300 million people globally. Acupuncture has been reported to be a safe complementary treatment for depression. This study is aimed to investigate the efficacy and mechanism of combining acupuncture with antidepressants in treating depression compared to the sole use of antidepressants. Seventy depression patients were randomly assigned to the treatment group (n = 50) and control group (n = 20). The treatment group received acupuncture combined antidepressants treatment for 3 weeks, while the control group took antidepressants monotherapy for 3 weeks. Among the 70 patients, 40 participants (20 control; 20 treatment) were randomized for studying functional connectivity (FC) of the dorsolateral prefrontal cortex (DLPFC) measured by the functional near-infrared spectroscopy. The primary outcome was HAMD-17 and secondary outcomes were PHQ-9, and the relationships of resting-state FC (rsFC) with the depression severity. PHQ-9 and HAMD-17 scores in the treatment group were significantly lower than those in the control group at Week 3 (p = 0.01) with effect sizes of -0.4 and -0.61 respectively. The rsFC in F1, F3, AF3, AF7, FC3, FC5 (left DLPFC, 10-20 system), AF8, and F6 (right DLPFC) in the treatment group had significant temporal correlation (p < 0.05, FDR corrected) in DLPFC compared to the channels in the control group. No significant correlation was found between the changes of rsFC and depression severity. In conclusion, depressed patients receiving acupuncture combined with antidepressants have improvement of depressive symptoms and the stronger rsFC in the DLPFC compared to those using antidepressants alone.


Panmictic and Clonal Evolution on a Single Patchy Resource Produces Polymorphic Foraging Guilds.
We develop a stochastic, agent-based model to study how genetic traits and experiential changes in the state of agents and available resources influence individuals' foraging and movement behaviors. These behaviors are manifest as decisions on when to stay and exploit a current resource patch or move to a particular neighboring patch, based on information of the resource qualities of the patches and the anticipated level of intraspecific competition within patches. We use a genetic algorithm approach and an individual's biomass as a fitness surrogate to explore the foraging strategy diversity of evolving guilds under clonal versus hermaphroditic sexual reproduction. We first present the resource exploitation processes, movement on cellular arrays, and genetic algorithm components of the model. We then discuss their implementation on the Nova software platform. This platform seamlessly combines the dynamical systems modeling of consumer-resource interactions with agent-based modeling of individuals moving over a landscapes, using an architecture that lays transparent the following four hierarchical simulation levels: 1.) within-patch consumer-resource dynamics, 2.) within-generation movement and competition mitigation processes, 3.) across-generation evolutionary processes, and 4.) multiple runs to generate the statistics needed for comparative analyses. The focus of our analysis is on the question of how the biomass production efficiency and the diversity of guilds of foraging strategy types, exploiting resources over a patchy landscape, evolve under clonal versus random hermaphroditic sexual reproduction. Our results indicate greater biomass production efficiency under clonal reproduction only at higher population densities, and demonstrate that polymorphisms evolve and are maintained under random mating systems. The latter result questions the notion that some type of associative mating structure is needed to maintain genetic polymorphisms among individuals exploiting a common patchy resource on an otherwise spatially homogeneous landscape.


Coral immunology and resistance to disease.
Scleractinian corals (phylum Cnidaria, class Anthozoa) have innate immunological responses against infections. Research has recently suggested that corals also possess an adaptive-like immunological repertoire that recognizes specific pathogens and allografts. While evolutionarily distinct, the corals' innate and adaptive-like immunity systems are not mutually exclusive because the phagocytic cells of the non-specific, innate immune system may activate specific adaptive immunological responses. Warming oceans may immunocompromise coral hosts, making them more susceptible to tropical marine diseases, independent of the virulence of the pathogen. The ability of corals to ward off both primary and opportunistic infections, through adaptive-like mechanisms, may play a critical role in the corals' ability to fight future disease infection. Here we show evidence that corals possess immunological repertoires that extend well beyond simple innate defenses. The extent to which corals have developed such an adaptive-like immune repertoire will determine whether corals will survive climate change and other anthropogenic disturbances.


Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma.
Among patients with cervical cancer, little is known about the significance of persistent human papillomavirus (HPV) expression after chemoradiation (CRT). This study evaluated associations between early posttreatment HPV clearance and patient outcomes with an added focus on the value of posttherapy positron emission tomography (PET) imaging. Included patients underwent pretreatment testing indicating a high-risk HPV infection and posttreatment testing with a messenger RNA (mRNA)-based genital swab after CRT. Posttherapy responses were stratified on the basis of HPV mRNA detection into an early clearance (EC) group (no mRNA) and a persistent expression (PE) group (detectable mRNA) on the basis of an evaluation at a median of 6 weeks after therapy. The Kaplan-Meier method was used to compare outcomes, and multivariable analysis was used to identify predictors of outcomes. Seventy-two of the 97 eligible patients (74.2%) had EC. The mean follow-up time was 25 months (range, 4-56 months), and 2-year pelvic control (76.9% vs 50.2%; P = .01) and overall survival (OS; 80.9% vs 52.2%; P < .01) were superior among EC patients. In the multivariable analysis, EC predicted for improved survival (hazard ratio [HR] for mortality, 0.46; 95% confidence interval [CI], 0.21-0.96; P = .047), as did a complete response (CR) on posttherapy PET (HR for less than a CR on PET, 6.17; 95% CI, 2.58-14.72; P < .01). In a subset analysis of patients with a posttherapy PET CR, HPV clearance retained prognostic significance (2-year OS, 95.6% with EC vs 66.7% with PE; P = .04), whereas PE patients without a PET CR had the worst survival (35.9%; P < .01 for trend). Early posttherapy clearance of HPV is associated with improved survival in cervical cancer. Evaluating HPV expression at this 6-week time point provides prognostic information beyond posttherapy PET imaging and may aid in risk stratification and decisions for treatment escalation.


Who Is Your Doctor? Analysis of Patient-Reported and EHR-Imputed Primary Care Physician.
Significant efforts have been made to improve physician-to-physician communication and care coordination during transition of care in order to reduce adverse events and readmissions. As electronic health records (EHRs) become widely available, many hospitals have implemented physician collaboration and hand-off tools to automatically send admission notifications, discharge summaries, and pending laboratory results to a patient's primary care physician (PCP). However, the effectiveness of such tools depends on a fundamental question that remains unstudied: who is the patient's PCP? Missing or outdated PCP information may become the bottleneck to effective patient-centered care coordination regardless of existing efforts on promoting interoperability among healthcare providers. In this paper, we characterized patient-reported PCPs and experimented with an imputation algorithm that automatically infers a patient's primary provider based on patient-provider encounter data. We compared the imputation results with patient-reported PCPs and suggested practical uses of our findings.


Prevalence of marijuana use disorders in the United States: 1991-1992 and 2001-2002.
Among illicit substance use disorders, marijuana use disorders are the most prevalent in the population. Yet, information about the prevalence of current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) marijuana use disorders and how prevalence has changed is lacking. To examine changes in the prevalence of marijuana use, abuse, and dependence in the United States between 1991-1992 and 2001-2002. Face-to-face interviews were conducted in 2 large national surveys conducted 10 years apart: the 1991-1992 National Longitudinal Alcohol Epidemiologic Survey ([NLAES] n = 42,862) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions ([NESARC] n = 43,093). Rates of past year marijuana use, abuse, and dependence. Among the adult US population, the prevalence of marijuana use remained stable at about 4.0% over the past decade. In contrast, the prevalence of DSM-IV marijuana abuse or dependence significantly (P =.01) increased between 1991-1992 (1.2%) and 2001-2002 (1.5%), with the greatest increases observed among young black men and women (P<.001) and young Hispanic men (P =.006). Further, marijuana use disorders among marijuana users significantly increased (P =.002) in the absence of increased frequency and quantity of marijuana use, suggesting that the concomitant increase in potency of delta-9-tetrahydrocannabinol (Delta9-THC) may have contributed to the rising rates. Despite the stability in the overall prevalence of marijuana use, more adults in the United States had a marijuana use disorder in 2001-2002 than in 1991-1992. Increases in the prevalence of marijuana use disorders were most notable among young black men and women and young Hispanic men. Although rates of marijuana abuse and dependence did not increase among young white men and women, their rates have remained high. The results of this study underscore the need to develop and implement new prevention and intervention programs targeted at youth, particularly minority youth.