Gray wolves as climate change buffers in Yellowstone.
Understanding the mechanisms by which climate and predation patterns by top predators co-vary to affect community structure accrues added importance as humans exert growing influence over both climate and regional predator assemblages. In Yellowstone National Park, winter conditions and reintroduced gray wolves (Canis lupus) together determine the availability of winter carrion on which numerous scavenger species depend for survival and reproduction. As climate changes in Yellowstone, therefore, scavenger species may experience a dramatic reshuffling of food resources. As such, we analyzed 55 y of weather data from Yellowstone in order to determine trends in winter conditions. We found that winters are getting shorter, as measured by the number of days with snow on the ground, due to decreased snowfall and increased number of days with temperatures above freezing. To investigate synergistic effects of human and climatic alterations of species interactions, we used an empirically derived model to show that in the absence of wolves, early snow thaw leads to a substantial reduction in late-winter carrion, causing potential food bottlenecks for scavengers. In addition, by narrowing the window of time over which carrion is available and thereby creating a resource pulse, climate change likely favors scavengers that can quickly track food sources over great distances. Wolves, however, largely mitigate late-winter reduction in carrion due to earlier snow thaws. By buffering the effects of climate change on carrion availability, wolves allow scavengers to adapt to a changing environment over a longer time scale more commensurate with natural processes. This study illustrates the importance of restoring and maintaining intact food chains in the face of large-scale environmental perturbations such as climate change.


DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop.
Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.


Wear and Corrosion Interactions at the Titanium/Zirconia Interface: Dental Implant Application.
Dental implants have been shown to have predictable success, but esthetic complications often arise. To reduce tissue shadowing from titanium, zirconia abutments may be used; however, the literature suggests that the use of zirconia leads to greater destruction of the implant interface that may result in biological complications such as titanium tattoos and heavy metal toxicity. Previous studies have examined the mechanical aspects of this implant/abutment relationship, but they have not accounted for the corrosive degradation that also takes place in the dynamic environment of the oral cavity. This study investigated the combined effect of both wear and corrosion on the materials at the implant and abutment interface. Using a simulated oral tribocorrosive environment, titanium (Ti) and zirconia (Zr) abutment materials were slid against titanium and Roxolid implant alloys. The four couplings (Ti/Ti, Ti/Rox, Zr/Ti, Zr/Rox) were selected for the tribocorrosion tests (N = 3). The testing was conducted for 25K cycles, and the coefficient of friction (CoF) and voltage evolution were recorded simultaneously. Following the tribocorrosion assays, the wear volume loss was calculated, and surface characterization was performed. Statistical analysis was completed using a one-way ANOVA followed by post-hoc Bonferroni comparisons. Zr/Ti groups had the highest CoF (1.1647), and Ti/Ti had the lowest (0.5033). The Zr/Ti coupling generated significantly more mechanical damage than the Ti/Ti group (p = 0.021). From the corrosion aspect, the Ti/Ti groups had the highest voltage drop (0.802 V), indicating greater corrosion susceptibility. In comparison, the Zr/Roxolid group had the lowest voltage drop (0.628 V) and significantly less electrochemical degradation (p = 0.019). Overall, the Ti/Ti group had the largest wear volume loss (15.1 × 107 μm3 ), while the Zr/Ti group had the least volume loss (2.26 × 107 μm3 ). Both zirconia couplings had significantly less wear volume than the titanium couplings (p < 0.001). This study highlights the synergistic interaction between wear and corrosion, which occurs when masticatory forces combine with the salivary environment of the oral cavity. Overall, the zirconia groups outperformed the titanium groups. In fact, the titanium groups generated 5 to 6 times more wear to the implant alloys as compared with the zirconia counterparts. The best performing group was Zr/Ti, and the worst performing group was Ti/Ti.


Verification of a Central Pacemaker in Brain Stem by Phase-Coupling Analysis Between HR Interval- and BOLD-Oscillations in the 0.10-0.15 Hz Frequency Band.
The origin of slow intrinsic oscillations in resting states of functional magnetic resonance imaging (fMRI) signals is still a matter of debate. The present study aims to test the hypothesis that slow blood oxygenation level-dependent (BOLD) oscillations with frequency components greater than 0.10 Hz result from a central neural pacemaker located in the brain stem. We predict that a central oscillator modulates cardiac beat-to-beat interval (RRI) fluctuations rapidly, with only a short neural lag around 0.3 s. Spontaneous BOLD fluctuations in the brain stem, however, are considerably delayed due to the hemodynamic response time of about ∼2-3 s. In order to test these predictions, we analyzed the time delay between slow RRI oscillations from thorax and BOLD oscillations in the brain stem by calculating the phase locking value (PLV). Our findings show a significant time delay of 2.2 ± 0.2 s between RRI and BOLD signals in 12 out of 23 (50%) participants in axial slices of the pons/brain stem. Adding the neural lag of 0.3 s to the observed lag of 2.2 s we obtain 2.5 s, which is the time between neural activity increase and BOLD increase, termed neuro-BOLD coupling. Note, this time window for neuro-BOLD coupling in awake humans is surprisingly of similar size as in awake head-fixed adult mice (Mateo et al., 2017).


Prevalence of Tuberculosis in HIV-positive Prisoners: A Systematic Review and Meta-analysis.
Tuberculosis (TB) and HIV constitute the main burden of infectious diseases worldwide. Imprisonment is an important risk factor for contracting TB, especially among those living with HIV. This systematic review summarizes the available data on the prevalence of TB among HIV-positive prisoners; which may support improved targeted TB/HIV prevention plans. We electronically examined published studies up to December 2017 with the aim of finding articles that investigated the prevalence of TB in HIV-positive prisoners. MEDLINE, SCOPUS, Embase, and Web of Science electronic databases were searched with no restriction on language or time. A random effects model was used to conduct the meta-analysis and generate a summary estimate for the global prevalence of TB among HIV-positive prisoners; and subgroup estimates by continent. The meta-analysis included 22 studies published from 1992 to 2016. In total, 2,465 articles were retrieved and 22 papers met inclusion criteria. Eligible papers contained 220,101 prisoners, with 1,611 cases of TB in 6,126 HIV-positive subjects. Globally, the pooled prevalence of TB in HIV-positive prisoners was 32.6% [95% confidence interval (CI): 27.5% to 38.2%; p-value for heterogeneity=0.001]. Results of the subgroup analysis by continent were as follows: Africa, 14% (CI: 8% to 24%); North/South America, 37% (CI: 31% to 44%); Asia, 35% (CI: 12% to 68%); and Europe, 25% (CI: 12% to 45%). The prevalence of TB among HIV-positive prisoners is high worldwide. Screening of TB in this population is essential for the treatment of both diseases. Syndemics of TB and HIV in prisoners during the past three decades have created an alarming situation across the world. Hence, coordinated policies are essential for the early identification and effective treatment of this vulnerable population.


[Analysis of Factors Affecting Effectiveness of Medical Device Registration Self-inspection from Perspective of Technical Evaluation].
Type inspection is a necessary precondition of technical evaluation of medical device. The implementation of The Provisions for Administration of Self-Test for Medical Device Registration facilitates the registration pathway for applicants. How to improve the effectiveness of registration self-test has drawn attention from many stakeholders. In this study, we analyzed and discussed the factors affecting the validity of registration self-test from technical evaluation perspective, and proposed suggestions for improvement accordingly. The aim of this article is to boost the reliability and effectiveness of registration self-test and offer a reference for applicants to carry out registration self-test.


High incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa.
To evaluate the incidence of respiratory distress syndrome (RDS) in infants born to mothers with placenta previa and to assess the risk factors for RDS. Ninety-nine pregnant women with placenta previa who delivered by cesarean section at 30-35 weeks of gestation were compared retrospectively with 102 pregnant women matched for week of gestation and birth year, who underwent elective cesarean section. Maternal characteristics, neonatal outcome, and incidence of RDS were analyzed. Umbilical cord blood samples were collected at delivery and were used to determine cortisol, epinephrine, and norepinephrine levels. Student's t-test, the chi-square test, and Fisher's exact test were used for statistical comparisons. P < 0.05 was considered significant. The Mann-Whitney U test was used for comparison of continuous variables. Preeclampsia, histological chorioamnionitis, and premature rupture of membranes were significantly lower in the placenta previa group (placenta previa: 2.0% vs. control: 14.7%, P < 0.01; 14.1% vs. 30.1%, P < 0.01; 7.1% vs. 17.6%, P < 0.05, respectively). The incidence of RDS was significantly higher in the placenta previa group than in the control group (29.3% vs. 6.9%, P < 0.0001). The cortisol level in umbilical cord blood in the placenta previa group was lower than in the control group (median 7.3, range 4.4-14.9 microg/dl vs. median 10.6, range 4.9-30.3 microg/dl, P < 0.05). There were no significant differences in epinephrine or norepinephrine levels between the two groups. The incidence of RDS in infants delivered at 30-35 weeks' gestation by cesarean section was significantly higher in mothers with placenta previa than in women without placenta previa. This may reflect decreased fetal stress since the cord blood cortisol levels were found to be lower in women with placenta previa.


The neural representation of typical and atypical experiences of negative images: comparing fear, disgust and morbid fascination.
Negative stimuli do not only evoke fear or disgust, but can also evoke a state of 'morbid fascination' which is an urge to approach and explore a negative stimulus. In the present neuroimaging study, we applied an innovative method to investigate the neural systems involved in typical and atypical conceptualizations of negative images. Participants received false feedback labeling their mental experience as fear, disgust or morbid fascination. This manipulation was successful; participants judged the false feedback correct for 70% of the trials on average. The neuroimaging results demonstrated differential activity within regions in the 'neural reference space for discrete emotion' depending on the type of feedback. We found robust differences in the ventrolateral prefrontal cortex, the dorsomedial prefrontal cortex and the lateral orbitofrontal cortex comparing morbid fascination to control feedback. More subtle differences in the dorsomedial prefrontal cortex and the lateral orbitofrontal cortex were also found between morbid fascination feedback and the other emotion feedback conditions. This study is the first to forward evidence about the neural representation of the experimentally unexplored state of morbid fascination. In line with a constructionist framework, our findings suggest that neural resources associated with the process of conceptualization contribute to the neural representation of this state.


[Yersinia enterocolitica serovar 2a, wb, 3:b,c biovar 5 in hares and sheep].
During the last fourty years the "hare type" of Yersinia enterocolitica was detected in the brown hare and other mammals in several European countries. In northern Germany (Province of Schleswig-Holstein) the pathogen was not found in the post mortem materials of the cattle, swine and horses during the years 1990-1996. In approximately 1,000 sheep studied this yersinia was cultured from the internal organs of one diarrhoeic lamb. The examination of some 200 perished hares reveals one animal with granulomatous splenomegaly and culture of this pathogen. Yersinia enterocolitica is one of the pathogens causing pseudotuberculosis-like lesions in the hare.


Four European Salmonella Typhimurium datasets collected to develop WGS-based source attribution methods.
Zoonotic Salmonella causes millions of human salmonellosis infections worldwide each year. Information about the source of the bacteria guides risk managers on control and preventive strategies. Source attribution is the effort to quantify the number of sporadic human cases of a specific illness to specific sources and animal reservoirs. Source attribution methods for Salmonella have so far been based on traditional wet-lab typing methods. With the change to whole genome sequencing there is a need to develop new methods for source attribution based on sequencing data. Four European datasets collected in Denmark (DK), Germany (DE), the United Kingdom (UK) and France (FR) are presented in this descriptor. The datasets contain sequenced samples of Salmonella Typhimurium and its monophasic variants isolated from human, food, animal and the environment. The objective of the datasets was either to attribute the human salmonellosis cases to animal reservoirs or to investigate contamination of the environment by attributing the environmental isolates to different animal reservoirs.


Review article: intestinal barrier dysfunction and central nervous system disorders--a controversial association.
Central nervous system (CNS) development and physiopathology are greatly affected by environmental stimuli. The intestinal barrier restricts the entrance of toxins, pathogens, and antigens while modulating the expression of various neuroactive compounds. The existence of a rich gut-to-brain communication raises the possibility that intestinal barrier alterations may take part in the pathophysiology of CNS disorders. To review evidence associating intestinal barrier dysfunction with the development of CNS disorders. Literature search was conducted on PubMed using the following terms: intestinal barrier, intestinal permeability, central nervous system, mental disorders, schizophrenia, autism, stress, anxiety, depression, and neurodegeneration. Clinical and animal model studies of the association between intestinal barrier and schizophrenia, autism spectrum disorders, neurodegenerative diseases or depression were reviewed. The majority of reports concentrated on schizophrenia and autism spectrum disorders. About half of these described increased intestinal permeability/mucosal damage in patients compared with healthy controls, with up to 43% of children with autism spectrum disorders and up to 35% of schizophrenia patients displaying abnormally high urinary excretion of the sugars used as permeability markers. However, another substantial group of studies did not find such differences. In autism spectrum disorders, some reports show that the use of diets such as the gluten-free casein-free diet may contribute to the normalisation of lactulose/mannitol ratio, but to date there is no adequately controlled study showing improvement in behavioural symptoms following these dietary interventions. Evidence of altered intestinal permeability in individuals suffering from CNS disorders is limited and cannot be regarded as proven. Moreover the efficacy of targeting gut barrier in the management of neurological and behavioural aspects of CNS disorders has not yet been established, and needs further investigation.


Incidence and characterization of Clostridium difficile in a secondary care hospital in Spain.
Clostridium difficile (C. difficile) is a major nosocomial infectious agent in hospitals. Previous studies have addressed the high proportion of infection episodes that are overlooked in health care facilities. the main aim of this study was to characterize C. difficile clinical cases that occurred in a secondary care hospital during a five-month period. for this purpose, a total of 137 stool samples from the same number of patients with diarrhea were analyzed for the presence of C. difficile by culture techniques. An enzyme immunoassay (EIA) test for the detection of C. difficile and its toxins was also used in 50 cases (36.5%) for diagnostic purposes. a total of 14 (10.2%) C. difficile isolates were obtained, of which nine (64.3%) were toxigenic. A mean incidence of 3.2 episodes of C. difficile infections (CDI) per 10,000 patients-days was estimated for the study period. Around 56% of the CDI cases were determined as hospital-acquired, whereas 44% originated in the community. Among these, only two episodes (22.2%) were detected in the hospital by the EIA test, which indicated that the hospital CDI detection protocol needed to be revised. One unusual C. difficile isolate was negative for all toxin genes examined and also for the non-toxigenic strain assay, which highlights the need to perform genome sequencing to study its pathogenicity locus insertion site organization. A stable metronidazole-resistant C. difficile strain and three strains showing multidrug resistance were detected in this study, suggesting that C. difficile antimicrobial susceptibility surveillance programs should be established in this health-care facility.


Socio-economic differences in HIV/AIDS mortality in South Africa.
To quantify socio-economic differences in the risk of HIV/AIDS mortality in South Africa for different measures of socio-economic status. Systematic literature search in Web of Knowledge and PubMed. Measures of relative risk (RR) were pooled separately for education, income, assets score and employment status as measures of socio-economic status, using inverse-variance weighted DerSimonian-Laird random effects meta-analyses. Ten studies were eligible for inclusion comprising over 175 000 participants and 6700 deaths. For income (RR 1.55, 95% confidence interval (CI) 1.15-2.09), assets score (RR 1.63, 95% CI 1.12-2.36) and employment status (RR 1.52, 95% CI 1.21-1.92), persons of low socio-economic status had an over 50% higher risk of dying from HIV/AIDS. The RR of 1.10 for education was not significant (95% CI 0.74-1.65). Future research should identify effective strategies to reduce HIV/AIDS mortality and alleviate the consequences of HIV/AIDS deaths, particularly for poorer households.


Deutetrabenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication-What is the number needed to treat, number needed to harm and likelihood to be helped or harmed?
Deutetrabenazine is a deuterated formulation of tetrabenazine. The aim of this systematic review is to describe the efficacy, tolerability and safety of deutetrabenazine for the treatment of tardive dyskinesia (TD). The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'deutetrabenazine' OR 'SD-809', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), received approval for the treatment of TD in adults based on a clinical trial development programme that included two 12-week parallel group, randomised and placebo-controlled studies. Deutetrabenazine dose is determined individually for each patient based on reduction of TD and tolerability. The recommended starting dose of deutetrabenazine for TD is 6 mg BID, administered with food, and can be increased at weekly intervals in increments of 6 mg/day to a maximum recommended daily dosage of 24 mg BID. The percentage of responders in the fixed-dose Phase III acute study, as defined by a rating of "much improved" or "very much improved" on the clinical global impression of change, was 46% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 26% for placebo, yielding a NNT of 5 (95% CI 3-19); the percentage of responders as defined by an improvement in Abnormal Involuntary Movement Scale (AIMS) severity score (sum of items 1-7) of 50% or more, was 34% for deutetrabenazine (pooled dose groups 12 and 18 mg BID) vs 12% for placebo, yielding a NNT of 5 (95% CI 3-11). Pooling the data across both short-term studies, NNT for AIMS response for the therapeutic doses of deutetrabenazine vs placebo was 7 (95% CI 4-18). Discontinuation because of an adverse event occurred among 3.6% of patients randomised to deutetrabenazine (any dose) vs 3.1% for placebo, yielding a NNH of 189 (not significant). The Likelihood to be Helped or Harmed comparing success (AIMS response) vs discontinuation because of an adverse event is 27. The most common adverse reactions (that occurred in ≥4% of deutetrabenazine-treated patients with TD and greater than placebo) were nasopharyngitis and insomnia, with NNH values of 50 (not significant) and 34 (95% CI 18-725), respectively. Deutetrabenazine is the second FDA-approved agent specifically indicated for the treatment of TD. Head-to-head comparisons with other VMAT2 inhibitors among patients with TD in the "real world" are needed.


Quality by Design Approach for Development and Characterisation of Solid Lipid Nanoparticles of Quetiapine Fumarate.
Quetiapine fumarate, a 2nd generation anti-psychotic drug has oral bioavailability of 9% because of hepatic first pass metabolism. Reports suggest that co-administration of drugs with lipids affects their absorption pathways, enhances lymphatic transport thus bypassing hepatic first-pass metabolism resulting in enhanced bioavailability. The present work aimed at developing, and characterising potentially lymphatic absorbable Solid Lipid Nanoparticles (SLN) of quetiapine fumarate by Quality by Design approach. Hot emulsification followed by ultrasonication was used as a method of preparation. Precirol ATO5, Phospholipon 90G and Poloxamer 188 were used as a lipid, stabilizer and surfactant respectively. A32 Central Composite design optimised the 2 independent variables, lipid concentration and stabilizer concentration and assessed their effect on percent Entrapment Efficiency (%EE: Y1). The lyophilized SLNs were studied for stability at 5 ±3οC and 25 ± 2οC/60 ± 5% RH for 3 months. The optimised formula derived for SLN had 270mg Precirol ATO5 and 107mg of Phospholipon 90G giving %EE of 76.53%. Mean particle size was 159.8nm with polydispersity index 0.273 and zeta potential -6.6mV. In-vitro drug release followed Korsmeyer-Peppas kinetics (R2=0.917) with release exponent n=0.722 indicating non-Fickian diffusion. Transmission electron microscopy images exhibited particles to be spherical and smooth. Fourier-transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction studies ascertained drug-excipient compatibility. Stability studies suggested 5οC as appropriate temperature for storage and preserving important characteristics within acceptable limits. Development and optimisation by Quality by Design were justified as it yielded SLN having acceptable characteristics and potential application for intestinal lymphatic transport.


Comparing the risk factors associated with serious versus and less serious work-related injuries in Ontario between 1991 and 2006.
The objective of this study was to examine and compare the demographic and labor market risks for more serious and less serious work-related injuries and illnesses. Secondary analysis of accepted workers' compensation claims in Ontario, combined with labor force estimates for the period 1991 to 2006. Serious injuries and illnesses were claims resulting in wage replacement. Less serious injuries and illnesses were claims only requiring health care. Regression models examined the relationship between demographic and labor market characteristics (age, gender, industry, job tenure, and unemployment) and claim type. Relative risk estimates for serious and less serious claims were not concordant across age, gender and industry employment groups. For example, while the mining and utilities and the construction industry had an increased probability of reporting NLTCs, they had a decreased probability of reporting LTCs. The risk for serious and less serious work-related injury and illness claims differ by demographic and labor market groups. The use of composite measures that combine wage-replacement and health care only claims should be considered when using compensation data for surveillance and primary prevention targeting strategies.


Group B beta-hemolytic streptococcal sepsis in the neonate.
In the past 40 years, the predominant organisms responsible for neonatal sepsis have changed. Whereas Group A betahemolytic streptococci were originally most common and staphylococci later became the major pathogens, Group B beta-hemolytic streptococci have become increasingly important in recent years. Predisposing factors include premature rupture of membranes, prolonged difficult labor, prematurity and congenital anomalies. The causes and clinical features of early-onset infection (in the first week of life) and late-onset infection are different.


Real-Life Distribution of KRAS and NRAS Mutations in Metastatic Colorectal Carcinoma from French Routine Genotyping.
In metastatic colorectal cancer, KRAS and NRAS genotyping is mandatory before prescription of panitumumab or cetuximab. In order to perform such molecular tests, the French National Cancer Institute has set up a nationwide network of molecular centers. We report here the percentage of these mutations according to a prospective nonselected cohort of incident metastatic colorectal carcinoma patients. A total of 6,803 patients were tested between July 1, 2013, and December 31, 2013. Overall, 49.06% of patients harbored a mutation in either KRAS or NRAS. Mutations of NRAS exons 3 and 4 were very rare. No NRAS exon 3 at c.59 or exon 4 at c.117 mutations were retrieved, and only 1 NRAS exon 4 at c.146 mutation was detected. This present cohort is likely to represent most of the incident cases of metastatic colorectal adenocarcinomas arising in France over 6 months and is to our knowledge the largest population set genotyped for these genes in this condition. This is a unique opportunity to observe the frequency of RAS mutations regardless of most inclusion bias.


Suppression of delayed type hypersensitivity to herpes simplex virus type 1 following immunization with anti-idiotypic antibody: an example of split tolerance.
Intraperitoneal (i.p.) immunization with herpes simplex virus type 1 (HSV-1) or an anti-idiotypic antibody (anti-id C) prepared against a monoclonal antibody specific for glycoprotein C of HSV-1, tolerizes mice for an HSV-1 delayed type hypersensitivity (DTH) response. This tolerization could be adoptively transferred to naive X-irradiated mice by splenic T cells, and was specific for HSV-1 DTH. Thus, DTH-tolerized mice responded to vaccinia virus or HSV-2 challenge, while remaining tolerized for HSV-1 DTH. In addition, these animals demonstrated a form of split tolerance such that HSV antibody, cytotoxic T cell and lymphoproliferative responses were detected in vitro. Thus, anti-id C induced a T cell population capable of specifically suppressing the HSV-1 DTH response, mimicking the effect of i.p. and intravenous immunization with HSV-1 found previously.


Monteggia 'fracture'-dislocation with bowing of the ulna: a pitfall for the unwary emergency physician.
We recently encountered a child who fell on the left outstretched hand. She complained of left elbow pain subsequently and radiographs showed a supposedly isolated radial head dislocation. This was spontaneously reduced when the left forearm was extended for another radiograph. She was discharged from the emergency department with her left elbow in a long backslab, but returned within half an hour with recurrence of the radial head dislocation without repeat trauma. Only when the radiograph was reviewed was a subtle plastic bowing deformity of the ulna seen. This proved the axiom, that in forearm parallel long bone injuries, always consider the possibility of Monteggia or Galeazzi lesions when there is apparently isolated radial or ulna head dislocations. The clinician must always look very carefully for a fracture of the accompanying long bone, as even bowing 'fractures' might occur.


Interspecific variation in vessel size, growth and drought tolerance of broad-leaved trees in semi-arid regions of Kenya.
In semi-arid regions, trees often wither during the dry season. Withering is sometimes manifest as die-back, whereby whithering results in shoot death, which progresses downward from the uppermost part of the crown. In this study, we measured the relationships between height growth and diameter at breast height, die-back frequency and severity, vessel size and specific hydraulic conductivity of four evergreen (Senna siamea (Lamk) H.S. Irwin & Barneby, Jacaranda mimosifolia D. Don, Azadirachta indica A.H.L. Juss and Acacia gerrardii Benth.) and one deciduous (Melia volkensii Gürke) plantation tree species in Kenya, which has a conspicuous dry season. Die-back occurred readily in some species, but not in others. Senna siamea showed the highest specific hydraulic conductivity and the highest growth rate among the five species and was quite susceptible to die-back. Among species, height growth and specific hydraulic conductivity were positively correlated with vessel size and negatively correlated with die-back frequency, suggesting a trade-off between growth rate and drought tolerance. This implies that an adaptation to rapid growth under humid conditions leads to low drought tolerance. However, the deciduous tree Melia volkensii showed high specific hydraulic conductivity and growth, with no symptoms of die-back, implying that a mechanism associated with the deciduous habit results in drought avoidance by reducing the requirement for water during the dry season.


Optimizing Making Every Contact Count (MECC) interventions: A strategic behavioral analysis.
This Strategic Behavioral Analysis aimed to: identify barriers and facilitators to health care professionals' implementation of Making Every Contact Count (MECC); code behavioral components of nationally delivered interventions to improve MECC implementation; assess the extent to which these components are theoretically congruent with identified theoretical domains representing barriers and facilitators. Comparing national interventions that aim to support implementation of behavior change related activity to the barriers and facilitators for the target behavior enables identification of opportunities being missed in practice; thereby, facilitating intervention optimization. A mixed-method study involving: a systematic review to identify barriers and facilitators to implementing MECC classified using the COM-B model and Theoretical Domains Framework (TDF); a content analysis of national interventions to improve MECC implementation in England using the Behavior Change Wheel (BCW) and Behavior Change Techniques Taxonomy (BCTTv1); linking intervention content to barriers identified in the systematic review. Across 27 studies, the most frequently reported barriers related to eight TDF domains: Environmental Context and Resources, Beliefs About Capabilities, Knowledge, Beliefs About Consequences, Intentions, Skills, Social Professional Role and Identity, and Emotions. National interventions aimed at supporting MECC implementation included on average 5.1 BCW intervention functions (Education, Modeling, Persuasion, and Training were used in all interventions) and 8.7 BCTs. Only 21% of BCTs potentially relevant to key domains were used across interventions. The majority of BCTs linked to seven of the eight most important domains were not used in any existing interventions. Intervention developers should seize missed opportunities by incorporating more theoretically relevant BCTs to target barriers to implementing MECC. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Home-based, square-stepping exercise program among older adults with multiple sclerosis: results of a feasibility randomized controlled study.
There is very little known about exercise rehabilitation approaches for older adults with multiple sclerosis (MS), yet this growing segment of the MS population experiences declines in cognition and mobility associated with disease progression and aging. We conducted a RCT examining the feasibility of a 12-week, home-based Square-Stepping Exercise (SSE) program in older adults with MS. Older adults with MS (N = 26) with mild-to-moderate levels of disability were recruited and randomized into the intervention (i.e., SSE) or a minimal activity, attention-control conditions. Participants in the SSE condition received a mat for home-based practice of the step patterns, an instruction manual, and a logbook along with a pedometer for monitoring compliance. Both conditions received weekly Skype™ calls and had biweekly meetings with an exercise trainer. Feasibility was assessed based on process, resource, management and scientific outcomes. Regarding scientific outcomes, participants in both conditions completed in-lab assessments before and after the 12-week period. Twenty-five participants completed the study (96%) and the total cost of the study was $13,387.00 USD. Pedometer data demonstrated good compliance with the SSE intervention condition. Effect sizes calculated for all treatment outcomes ranged from small-to-moderate for both mobility and cognitive variables between the intervention and attention-control conditions, thereby providing preliminary evidence that participation in the SSE program may improve cognition and mobility function. The results support the feasibility, acceptability, and possible efficacy of a home-based SSE intervention for older adults with MS.


PASS2.7: a database containing structure-based sequence alignments and associated features of protein domain superfamilies from SCOPe.
Sequence alignments are models that capture the structural, functional and evolutionary relationships between proteins. Structure-guided sequence alignments are helpful in the case of distantly related proteins with poor sequence identity, thus rendering routine sequence alignment methods ineffective. Protein Alignment organized as Structural Superfamilies or PASS2 database provides such sequence alignments of protein domains within a superfamily as per the Structural Classification of Proteins extended (SCOPe) database. The current update of PASS2 (i.e. PASS2.7) is following the latest release of SCOPe (2.07) and we provide data for 14 323 protein domains that are <40% identical and are organized into 2024 superfamilies. Several useful features derived from the alignments, such as conserved secondary structural motifs, HMMs and residues conserved across the superfamily, are also reported. Protein domains that are deviant from the rest of the members of a superfamily may compromise the quality of the alignment, and we found this to be the case in ∼7% of the total superfamilies we considered. To improve the alignment by objectively identifying such 'outliers', in this update, we have used a k-means-based unsupervised machine learning method for clustering superfamily members, where features provided were length of domains aligned, Cα-RMSD derived from the rigid-body superposition of all members and gaps contributed to the alignment by each domain. In a few cases, we have split the superfamily as per the clusters predicted and provided complete data for each cluster. A new feature included in this update is absolutely conserved interactions (ACIs) between residue backbones and side chains, which are obtained by aligning protein structure networks using structure-guided sequence alignments of superfamilies. ACIs provide valuable information about functionally important residues and the structure-function relationships of proteins. The ACIs and the corresponding conserved networks for backbone and sidechain have been marked on the superimposed structure separately. The updated version of the PASS2 database is available at http://caps.ncbs.res.in/pass2/.


Multiplex PCR allows rapid and accurate diagnosis of bloodstream infections in newborns and children with suspected sepsis.
Sepsis is a major health problem in newborns and children. Early detection of pathogens allows initiation of appropriate antimicrobial therapy that strongly correlates with positive outcomes. Multiplex PCR has the potential to rapidly identify bloodstream infections, compensating for the loss of blood culture sensitivity. In an Italian pediatric hospital, multiplex PCR (the LightCycler SeptiFast test) was compared to routine blood culture with 1,673 samples obtained from 803 children with suspected sepsis; clinical and laboratory information was used to determine the patient infection status. Excluding results attributable to contaminants, SeptiFast showed a sensitivity of 85.0% (95% confidence interval [CI] = 78.7 to 89.7%) and a specificity of 93.5% (95% CI = 92.1 to 94.7%) compared to blood culture. The rate of positive results was significantly higher with SeptiFast (14.6%) than blood culture (10.3%) (P < 0.0001), and the overall positivity rate was 16.1% when the results of both tests were combined. Staphylococcus aureus (11.6%), coagulase-negative staphylococci (CoNS) (29.6%), Pseudomonas aeruginosa (16.5%), and Klebsiella spp. (10.1%) were the most frequently detected. SeptiFast identified 97 additional isolates that blood culture failed to detect (24.7% P. aeruginosa, 23.7% CoNS, 14.4% Klebsiella spp., 14.4% Candida spp.). Among specimens taken from patients receiving antibiotic therapy, we also observed a significantly higher rate of positivity of SeptiFast than blood culture (14.1% versus 6.5%, respectively; P < 0.0001). On the contrary, contaminants were significantly more frequent among blood cultures than SeptiFast (n = 97 [5.8%] versus n = 26 [1.6%]), respectively; P < 0.0001). SeptiFast served as a highly valuable adjunct to conventional blood culture in children, adding diagnostic value and shortening the time to result (TTR) to 6 h.


[Influence of different concentrations of fluoride in the water on epidemiologic indicators of oral health/disease].
The scope of this study was to evaluate access to fluoride sources and oral health hygiene of 237 schoolchildren aged nine to sixteen, from three locations with different fluoride concentrations in the water. The fluoride level in the water of each area was analyzed by the selective electrode technique for the fluoride ion and the prevalence of dental caries and fluorosis were evaluated, respectively, by the DMFT and TSIF index, revealing a statistically significant difference (ANOVA; p <0,05) in the three locations: area without artificial fluoridation (DMTF 5.32 ± 3.49) and 16% of dental fluorosis; area with artificial fluoridation of 0.8 ppmF (DMTF 1.88 ± 2.22) and 94% of dental fluorosis; area with natural fluoridation of 2.54 ppmF (DMTF 3.96 ± 2.38) and 100% of dental fluorosis. The findings suggest that the epidemiologic indicators of oral health/disease are influenced by the presence of fluoride in the water supply and that supervision and orientation are fundamental in the correct use of fluoridated compositions, taking advantage of the maximum benefit in the control of dental caries with minimum risk of the occurrence of dental fluorosis.


Lectin-like domain of thrombomodulin binds to its specific ligand Lewis Y antigen and neutralizes lipopolysaccharide-induced inflammatory response.
Thrombomodulin (TM), a widely expressing glycoprotein originally identified in vascular endothelium, is an important cofactor in the protein C anticoagulant system. TM appears to exhibit anti-inflammatory ability through both protein C-dependent and -independent pathways. We presently have demonstrated that recombinant N-terminal lectinlike domain of TM (rTMD1) functions as a protective agent against sepsis caused by Gram-negative bacterial infections. rTMD1 caused agglutination of Escherichia coli and Klebsiella pneumoniae and enhanced the macrophage phagocytosis of these Gram-negative bacteria. Moreover, rTMD1 bound to the Klebsiella pneumoniae and lipopolysaccharide (LPS) by specifically interacting with Lewis Y antigen. rTMD1 inhibited LPS-induced inflammatory mediator production via interference with CD14 and LPS binding. Furthermore, rTMD1 modulated LPS-induced mitogen-activated protein kinase and nuclear factor-kappaB signaling pathway activations and inducible nitric oxide synthase expression in macrophages. Administration of rTMD1 protected the host by suppressing inflammatory responses induced by LPS and Gram-negative bacteria, and enhanced LPS and bacterial clearance in sepsis. Thus, rTMD1 can be used to defend against bacterial infection and inhibit LPS-induced inflammatory responses, suggesting that rTMD1 may be valuable in the treatment of severe inflammation in sepsis, especially in Gram-negative bacterial infections.


Dissociable effects of arousal and valence on prefrontal activity indexing emotional evaluation and subsequent memory: an event-related fMRI study.
Prefrontal cortex (PFC) activity associated with emotional evaluation and subsequent memory was investigated with event-related functional MRI (fMRI). Participants were scanned while rating the pleasantness of emotionally positive, negative, and neutral pictures, and memory for the pictures was tested after scanning. Emotional evaluation was measured by comparing activity during the picture rating task relative to baseline, and successful encoding was measured by comparing activity for subsequently remembered versus forgotten pictures (Dm effect). The effect of arousal on these measures was indicated by greater activity for both positive and negative pictures than for neutral ones, and the effect of valence was indicated by differences in activity between positive and negative pictures. The study yielded three main results. First, consistent with the valence hypothesis, specific regions in left dorsolateral PFC were more activated for positive than for negative picture evaluation, whereas regions in right ventrolateral PFC showed the converse pattern. Second, dorsomedial PFC activity was sensitive to emotional arousal, whereas ventromedial PFC activity was sensitive to positive valence, consistent with evidence linking these regions, respectively, to emotional processing and self-awareness or appetitive behavior. Finally, successful encoding (Dm) activity in left ventrolateral and dorsolateral PFC was greater for arousing than for neutral pictures. This finding suggests that the enhancing effect of emotion on memory formation is partly due to an augmentation of PFC-mediated strategic, semantic, and working memory operations. These results underscore the critical role of PFC in emotional evaluation and memory, and disentangle the effects of arousal and valence across PFC regions associated with different cognitive functions.


Detection of plant viruses in natural environments by using RNA-Seq.
Sequencing of RNA by next generation sequencers, RNA-Seq, is revolutionizing virus detection. In addition to the unbiased detection of various viruses from wild plants in natural environments, RNA-Seq also allows for the parallel collection of host plant transcriptome data. Host transcriptome data are highly valuable for studying the responses of hosts to viral infections, as well as viral host manipulation. When detecting viruses using RNA-Seq, it is critical to choose appropriate methods for the removal of rRNA from total RNA. Although viruses with polyadenylated genomes can be detected by RNA-Seq following mRNA purification using oligo-dT beads, viruses with non-polyadenylated genomes are not effectively detected. However, such viruses can be detected by RNA-Seq using the rRNA selective depression method. The high-throughput and cost-effective method of RNA-Seq library preparation which is described here allows us to detect a broad range of viruses in wild plants.


Rice: Importance for Global Nutrition.
Rice, a staple food for more than half of the world's population, is grown in >100 countries with 90% of the total global production from Asia. Although there are more than 110,000 cultivated varieties of rice that vary in quality and nutritional content, after post-harvest processing, rice can be categorized as either white or brown. Regional and cultural preferences as well as need for stability during storage and transport are the final determinants of market availability and final consumption. In addition to calories, rice is a good source of magnesium, phosphorus, manganese, selenium, iron, folic acid, thiamin and niacin; but it is low in fiber and fat. Although brown rice is promoted as being "healthier" because of bioactive compounds, including minerals and vitamins not present in white rice after polishing, white rice is more widely consumed than brown. This is for several reasons, including cooking ease, palatability, and shelf life. Polished rice has a higher glycemic load and may impact glucose homeostasis but when combined with other foods, it can be considered part of a "healthy" plate. With the projected increase in the global population, rice will remain a staple. However, it will be important to encourage intake of the whole grain (brown rice) and to identify ways to harness the phytonutrients that are lost during milling. Furthermore, as the world faces environmental challenges, changing demographics and consumer demands, farmers, healthcare providers, food manufacturers and nutritionists must work collaboratively to assure adequate supply, nutritional integrity and sustainability of rice production systems globally.


Neurodevelopmental outcomes following neonatal late-onset sepsis and blood culture-negative conditions.
Determine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC). Retrospective cohort study. 24 neonatal centres. Infants born 1/1/2006-31/12/2014, at 22-26 weeks gestation, with birth weight 401-1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded. LOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition. Death or NDI was assessed at 18-26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age. Of 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants. Infants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.


Differential sensitivity of fibroblasts to epidermal growth factor is related to cyclic AMP concentration.
The differential sensitivity of various cell lines to the mitogenic effects of epidermal growth factor (EGF) was investigated. Two lines of evidence suggest that cellular capacity to respond proliferatively to EGF is related to intracellular cyclic AMP concentration. First, the ability of three density-arrested cell lines to synthesize DNA in response to EGF was directly proportional to the basal cyclic AMP level of the cells at quiescence. Second, treatment of cultures with various agents known to promote intracellular cyclic AMP accumulation increased the sensitivity of all three cell lines to EGF. The mechanism whereby cyclic AMP modulates EGF responsiveness is not known; cholera toxin did not affect the cellular capacity to bind or internalize and process EGF. Although platelet-derived growth factor (PDGF) had no effect on cyclic AMP levels, transient treatment of quiescent cultures with this polypeptide also enhanced EGF sensitivity. In agreement with previous data and in contrast to cholera toxin, PDGF induced the down-regulation of EGF receptors in the three cell lines. These data suggest that the capacity of various cell types to respond to EGF is subject to both intracellular regulation by cyclic AMP and extracellular modulation by factors such as PDGF which can affect EGF receptor activity.


Developmental venous anomaly of petrous veins: intraoperative findings and indocyanine green video angiographic study.
We describe the intraoperative findings and results of an indocyanine green (ICG) video angiographic study in a patient with a developmental venous anomaly of the petrous veins. A 56-year-old man sought treatment after experiencing lacerating facial pain on the right side for almost 2 years. His neurological examination results were normal. A magnetic resonance imaging scan revealed the presence of a venous angioma in close relationship with the trigeminal nerve and the intrapontine tract of its fibers. The patient underwent a retrosigmoid craniotomy to explore the cerebellopontine angle. Near-infrared ICG video angiography was used to study the venous pattern of circulation. The venous angioma did not appear to be the source of any compression and was left untouched. At the entry zone of the nerve root, the trigeminal nerve was found to be compressed by a loop of the superior cerebellar artery, which was moved and repositioned away from the nerve. Near-infrared ICG video angiography disclosed an unexpected difference in filling time between developmental venous anomaly drainage veins and normal veins. The patient's pain resolved after microvascular decompression. Near-infrared ICG video angiography was particularly accurate and useful in the study of the venous dynamic of circulation. Further studies are required to confirm the supposed capability of ICG video angiography to differentiate developmental venous anomaly drainage veins and normal veins. Although magnetic resonance imaging supported the involvement of the venous angioma in the etiopathogenesis of this patient's trigeminal pain, surgical exploration disclosed a different cause.


Activity of H(+)-ATPase in ruminal bacteria with special reference to acid tolerance.
Batch culture experiments showed that permeabilized cells and membranes of Ruminococcus albus and Fibrobacter succinogenes, acid-intolerant celluloytic bacteria, have only one-fourth to one-fifth as much H(+)-ATPase as Megasphaera elsdenii and Streptococcus bovis, which are relatively acid tolerant. Even in the cells grown in continuous culture at pH 7.0, the acid-intolerant bacteria contained less than half as much H(+)-ATPase as the acid-tolerant bacteria. The amounts of H(+)-ATPase in the acid-tolerant bacteria were increased by more than twofold when the cells were grown at the lowest pH permitting growth, whereas little increase was observed in the case of the acid-intolerant bacteria. These results indicate that the acid-intolerant bacteria not only contain smaller amounts of H(+)-ATPase at neutral pH but also have a lower capacity to enhance the level of H(+)-ATPase in response to low pH than the acid-tolerant bacteria. In addition, the H(+)-ATPases of the acid-intolerant bacteria were more sensitive to low pH than those of the acid-tolerant bacteria, although the optimal pHs were similar.


Neuroprotective efficacy of estrogen in experimental spinal cord injury in rats.
Spinal cord injury (SCI) leads to neurological deficits and motor dysfunction. Methylprednisolone, the only drug used for treating SCI, renders limited neuroprotection and remains controversial. Estrogen is one of the most potent multiactive neuroprotective agents and it is currently under investigation in our laboratory for its efficacy in SCI. The present review briefly summarizes our earlier findings on the therapeutic potential of pharmacological/supraphysiological levels of estrogen in SCI and outlines our ongoing research, highlighting the efficacy of physiological levels of estrogen against neuronal injury, axonal degeneration, and gliosis and also the molecular mechanisms of such neuroprotection in experimental SCI. Furthermore, our ongoing studies designed to explore the different translational potential of estrogen therapy suggest that this multiactive steroid may act as an adjunct therapy to promote angiogenesis, thus enhancing the functional recovery following chronic SCI. Taken together, these studies confirm that estrogen is a potential therapeutic agent for treating SCI.


Computational Insights into Materials and Interfaces for Capacitive Energy Storage.
Supercapacitors such as electric double-layer capacitors (EDLCs) and pseudocapacitors are becoming increasingly important in the field of electrical energy storage. Theoretical study of energy storage in EDLCs focuses on solving for the electric double-layer structure in different electrode geometries and electrolyte components, which can be achieved by molecular simulations such as classical molecular dynamics (MD), classical density functional theory (classical DFT), and Monte-Carlo (MC) methods. In recent years, combining first-principles and classical simulations to investigate the carbon-based EDLCs has shed light on the importance of quantum capacitance in graphene-like 2D systems. More recently, the development of joint density functional theory (JDFT) enables self-consistent electronic-structure calculation for an electrode being solvated by an electrolyte. In contrast with the large amount of theoretical and computational effort on EDLCs, theoretical understanding of pseudocapacitance is very limited. In this review, we first introduce popular modeling methods and then focus on several important aspects of EDLCs including nanoconfinement, quantum capacitance, dielectric screening, and novel 2D electrode design; we also briefly touch upon pseudocapactive mechanism in RuO2. We summarize and conclude with an outlook for the future of materials simulation and design for capacitive energy storage.


Seasonal microhabitat selection by an endoparasitoid through adaptive modification of host behavior.
Differences in the distribution of parasitized and unparasitized hosts has been used to infer modification of host behavior by insect parasitoids. Data are presented showing that not only do parasitized hosts behave differently from unparasitized ones, but that the behavior of parasitized hosts varies in function of the physiological state of the parasitoid. Aphids containing nondiapausing parasitoids leave the aphid colony and mummify on the upper surface of the leaves, whereas those containing diapausing parasitoids leave the host plant and mummify in concealed sites. Modification of host behavior by diapausing parasitoids results in the selection of a suitable microhabitat that reduces the incidence of hyperparasitism and should decrease the action of adverse climatic conditions during the lengthy dormant period.


Enhanced photoluminescence emission from anthracene-doped polyphenylsiloxane glass.
Anthracene-doped polyphenylsiloxane (PPS) glass containing silver nanoparticles (AgNPs) of appropriate size was synthesized in a form of solid thin films for modifying light emission characteristics. The photoluminescence (PL) emission from the anthracene molecules at ~2.95 eV was resonantly coupled to the localized surface plasmon (LSP) polariton modes that were induced by the excitation of ~30 nm sized AgNPs. The increase in absorption of incident photons within a highly scattering medium, energy transfer from the localized excitons to the LSP modes, and the electrostatic Coulomb effects of the excitons in the presence of metal NPs all resulted in a significant enhancement of PL emission. The PL enhancement is dependent on the concentration of the anthracene molecules. The integrated PL intensity enhancement at the optimum concentration of anthracene molecules in the PPS glass with AgNPs is found to exceed 50.


GIS-based multi-criteria analysis for Arabica coffee expansion in Rwanda.
The Government of Rwanda is implementing policies to increase the area of Arabica coffee production. Information on the suitable areas for sustainably growing Arabica coffee is still scarce. This study aimed to analyze suitable areas for Arabica coffee production. We analyzed the spatial distribution of actual and potential production zones for Arabica coffee, their productivity levels and predicted potential yields. We used a geographic information system (GIS) for a weighted overlay analysis to assess the major production zones of Arabica coffee and their qualitative productivity indices. Actual coffee yields were measured in the field and were used to assess potential productivity zones and yields using ordinary kriging with ArcGIS software. The production of coffee covers about 32 000 ha, or 2.3% of all cultivated land in the country. The major zones of production are the Kivu Lake Borders, Central Plateau, Eastern Plateau, and Mayaga agro-ecological zones, where coffee is mainly cultivated on moderate slopes. In the highlands, coffee is grown on steep slopes that can exceed 55%. About 21% percent of the country has a moderate yield potential, ranging between 1.0 and 1.6 t coffee ha-1, and 70% has a low yield potential (<1.0 t coffee ha-1). Only 9% of the country has a high yield potential of 1.6-2.4 t coffee ha-1. Those areas are found near Lake Kivu where the dominant soil Orders are Inceptisols and Ultisols. Moderate yield potential is found in the Birunga (volcano), Congo-Nile watershed Divide, Impala and Imbo zones. Low-yield regions (<1 t ha-1) occur in the eastern semi-dry lowlands, Central Plateau, Eastern Plateau, Buberuka Highlands, and Mayaga zones. The weighted overlay analysis and ordinary kriging indicated a large spatial variability of potential productivity indices. Increasing the area and productivity of coffee in Rwanda thus has considerable potential.


COVID-19 vaccination strategies in settings with limited rollout capacity: a mathematical modelling case study in Sierra Leone.
COVID-19 vaccine coverage in low- and middle-income countries continues to be challenging. As supplies increase, coverage is increasingly becoming determined by rollout capacity. We developed a deterministic compartmental model of COVID-19 transmission to explore how age-, risk-, and dose-specific vaccine prioritisation strategies can minimise severe outcomes of COVID-19 in Sierra Leone. Prioritising booster doses to older adults and adults with comorbidities could reduce the incidence of severe disease by 23% and deaths by 34% compared to the use of these doses as primary doses for all adults. Providing a booster dose to pregnant women who present to antenatal care could prevent 38% of neonatal deaths associated with COVID-19 infection during pregnancy. The vaccination of children is not justified unless there is sufficient supply to not affect doses delivered to adults. Our paper supports current WHO SAGE vaccine prioritisation guidelines (released January 2022). Individuals who are at the highest risk of developing severe outcomes should be prioritised, and opportunistic vaccination strategies considered in settings with limited rollout capacity.


Paroxysmal extreme pain disorder mutations within the D3/S4-S5 linker of Nav1.7 cause moderate destabilization of fast inactivation.
Single-point missense mutations in the peripheral neuronal voltage-gated sodium channel Nav1.7 are implicated in the painful inherited neuropathy paroxysmal extreme pain disorder (PEPD). The Nav1.7 PEPD mutations are located in regions of the channel suggested to play important roles in fast inactivation. PEPD mutations in the putative inactivation gate have been reported to significantly impair fast inactivation, resulting in pronounced persistent currents. However, PEPD mutations in the S4-S5 linker of domain 3 (D3/S4-S5) had not been characterized and the roles of specific residues in this linker in channel gating are unclear. We functionally characterized two of the D3/S4-S5 PEPD mutations (V1298F and V1299F) and compared their effects on gating to an adjacent non-PEPD mutation (V1300F) and the I1461T PEPD mutation, located in the putative inactivation gate. The primary effect of the V1298F and V1299F mutations is to shift the voltage dependence of fast inactivation by approximately 20 mV in the depolarizing direction. We observed a similar effect with the PEPD mutation I1461T. Interestingly, while all three PEPD mutations increased persistent currents, the relative amplitudes (approximately 6% of peak) were much smaller than previously reported for the I1461T mutation. In contrast, the main effect of the V1300F mutation was a depolarizing shift in the voltage dependence of activation. These data demonstrate that (1) mutations within D3/S4-S5 affect inactivation of Nav1.7 in a residue-specific manner and (2) disruption of the fast-inactivated state by PEPD mutations can be more moderate than previously indicated, which has important implications for the pathophysiology of PEPD.


Parental Age and Risk of Pediatric Cancer in the Offspring: A Population-Based Record-Linkage Study in California.
Linking birth records and cancer registry data from California, we conducted a population-based study with 23,419 cases and 87,593 matched controls born during 1978-2009 to investigate the relationship of parental age to risk of pediatric cancer. Compared with children born to mothers aged 20-24 years, those born to mothers in older age groups had a 13%-36% higher risk of pediatric cancer; the odds ratio for each 5-year increase in maternal age was 1.06 (95% confidence interval (CI): 1.04, 1.09). For cancer diagnosed in children in age groups 0-14 years and 15-19 years, the odds ratios for each 5-year increase in maternal age were 1.05 (95% CI: 1.02, 1.07) and 1.14 (95% CI: 1.09, 1.19), respectively. Having an older father also conferred an increased risk, with an odds ratio for each 5-year increase of 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-19 years and 1.03 (95% CI: 1.02, 1.05) for cancer diagnosed at ages 0-14 years. While advancing maternal age increased risk of leukemia and central nervous system tumors, older paternal age was not associated with risk of either type. Both maternal and paternal older ages were associated with risk of lymphoma. In this large, population-based record-linkage study, advancing parental age, especially advancing maternal age, was associated with higher pediatric cancer risk, with variations across types of cancer.


Positive and negative effects of a threatened parrotfish on reef ecosystems.
Species that are strong interactors play disproportionately important roles in the dynamics of natural ecosystems. It has been proposed that their presence is necessary for positively shaping the structure and functioning of ecosystems. We evaluated this hypothesis using the case of the world's largest parrotfish (Bolbometopon muricatum), a globally imperiled species. We used direct observation, animal tracking, and computer simulations to examine the diverse routes through which B. muricatum affects the diversity, dispersal, relative abundance, and survival of the corals that comprise the foundation of reef ecosystems. Our results suggest that this species can influence reef building corals in both positive and negative ways. Field observation and simulation outputs indicated that B. muricatum reduced the abundance of macroalgae that can outcompete corals, but they also feed directly on corals, decreasing coral abundance, diversity, and colony size. B. muricatum appeared to facilitate coral advancement by mechanically dispersing coral fragments and opening up bare space for coral settlement, but they also damaged adult corals and remobilized a large volume of potentially stressful carbonate sediment. The impacts this species has on reefs appears to be regulated in part by its abundance-the effects of B. muricatum were more intense in simulation scenarios populated with high densities of these fish. Observations conducted in regions with high and low predator (e.g., sharks) abundance generated results that are consistent with the hypothesis that these predators of B. muricatum may play a role in governing their abundance; thus, predation may modulate the intensity of the effects they have on reef dynamics. Overall our results illustrate that functionally unique and threatened species may not have universally positive impacts on ecosystems and that it may be necessary for environmental managers to consider the diverse effects of such species and the forces that mediate the strength of their influence.


Fused Particle Fabrication 3-D Printing: Recycled Materials' Optimization and Mechanical Properties.
Fused particle fabrication (FPF) (or fused granular fabrication (FGF)) has potential for increasing recycled polymers in 3-D printing. Here, the open source Gigabot X is used to develop a new method to optimize FPF/FGF for recycled materials. Virgin polylactic acid (PLA) pellets and prints were analyzed and were then compared to four recycled polymers including the two most popular printing materials (PLA and acrylonitrile butadiene styrene (ABS)) as well as the two most common waste plastics (polyethylene terephthalate (PET) and polypropylene (PP)). The size characteristics of the various materials were quantified using digital image processing. Then, power and nozzle velocity matrices were used to optimize the print speed, and a print test was used to maximize the output for a two-temperature stage extruder for a given polymer feedstock. ASTM type 4 tensile tests were used to determine the mechanical properties of each plastic when they were printed with a particle drive extruder system and were compared with filament printing. The results showed that the Gigabot X can print materials 6.5× to 13× faster than conventional printers depending on the material, with no significant reduction in the mechanical properties. It was concluded that the Gigabot X and similar FPF/FGF printers can utilize a wide range of recycled polymer materials with minimal post processing.


Last-male sperm precedence in Rhynchophorus ferrugineus (Olivier): observations in laboratory mating experiments with irradiated males.
The Red Palm Weevil (RPW) Rhynchophorus ferrugineus (Olivier 1790) is an invasive pest from southeastern Asia and Melanesia that in the last 30 years has spread widely in the Middle East and Mediterranean Basin. Its stem-boring larvae cause great damage to several palm species of the Arecaceae family, many of which are economically important for agricultural and ornamental purposes. Therefore, great attention has recently been focused in studying this species to identify sustainable and effective eradication strategies, such as sterile insect technique (SIT). The rapid spread of RPW is associated with its high reproductive success. To evaluate the suitability of a SIT strategy, particular physiological and behavioral aspects of RPW reproduction, such as the presence of polyandry and post-copulatory sperm selection mechanisms, were investigated. To determine paternity of progeny from multiply mated females, double-crossing experiments were carried out confining individual females with either a wild-type male or a γ-irradiated male (Co-60). Fecundity and fertility of females were scored to evaluate post-copulatory sperm selection. Results showed that progeny were almost exclusively produced by the sperm of the second male, suggesting that a last-male sperm precedence is expressed at high levels in this species, and providing interesting insights for an area-wide RPW management strategy such as the SIT.


A support vector machine-based cure rate model for interval censored data.
The mixture cure rate model is the most commonly used cure rate model in the literature. In the context of mixture cure rate model, the standard approach to model the effect of covariates on the cured or uncured probability is to use a logistic function. This readily implies that the boundary classifying the cured and uncured subjects is linear. In this article, we propose a new mixture cure rate model based on interval censored data that uses the support vector machine to model the effect of covariates on the uncured or the cured probability (i.e. on the incidence part of the model). Our proposed model inherits the features of the support vector machine and provides flexibility to capture classification boundaries that are nonlinear and more complex. The latency part is modeled by a proportional hazards structure with an unspecified baseline hazard function. We develop an estimation procedure based on the expectation maximization algorithm to estimate the cured/uncured probability and the latency model parameters. Our simulation study results show that the proposed model performs better in capturing complex classification boundaries when compared to both logistic regression-based and spline regression-based mixture cure rate models. We also show that our model's ability to capture complex classification boundaries improve the estimation results corresponding to the latency part of the model. For illustrative purpose, we present our analysis by applying the proposed methodology to the NASA's Hypobaric Decompression Sickness Database.


Tribological testing of skin products: gender, age, and ethnicity on the volar forearm.
Few studies have focused on the simultaneous measurement of the friction and electrical properties of skin. This work investigates the feasibility of using these measurements to differentiate between the effects of chemicals commonly applied to the skin. In addition, this study also compares the condition of the skin and its response to application of chemicals across gender, ethnicity, and age at the volar forearm. Friction and electrical tests were performed on 59 healthy volunteers with the UMT Series Micro-Tribometer (UMT). A 13-mm-diameter copper cylindrical friction/electrical probe was pressed onto the skin with a weight of 20 g and moved across the skin at a constant velocity of 0.4 mm/s. Each volunteer served as his or her own control. The friction and electrical impedance measurements were performed for polyvinylidene chloride occlusion and for the application of glycerin and petrolatum. No differences were found across age, gender, or ethnicity at the volar forearm. Polyvinylidene chloride (PVDC) occlusion showed a small increase in the friction and a small decrease in the electrical impedance; petrolatum increased the friction by a greater amount but its effect on the impedance was comparable to PVDC occlusion; glycerin increased the friction by an amount comparable to petrolatum, but it decreased the impedance to a much greater degree than petrolatum or the PVDC occlusion. An amplitude/mean measurement of the friction curves of glycerin and petrolatum showed that glycerin has a significantly higher amplitude/mean than petrolatum. The properties of the volar forearm appear to be independent of age, gender, and ethnicity. Also, the simultaneous measurement of friction and electrical impedance was useful in differentiating between compounds administered to the skin.


Disposition of 8-methoxypsoralen in the rat: methodology for measurement, dose-dependent pharmacokinetics, tissue distribution and identification of metabolites.
The pharmacokinetics and metabolism of 8-methoxypsoralen (8-MOP) were measured in the catheterized rat after a single i.v. dose. Blood samples were collected serially and analyzed using a sensitive and specific assay for [14C]-8-MOP. Total body clearance of 8-MOP was 7.3, 3.9, 1.7, 1.0, 0.78 and 0.42 liters/kg/hr at doses of 0.2, 1.0, 2.5, 5.0, 10 and 20 mg/kg, respectively. The decline in total body clearance indicates that elimination of 8-MOP is dose-dependent in the rat. After i.v. administration of 10 mg/kg of 8-MOP, 71 and 26% of the dose was recovered within 72 hr in the urine and feces, respectively. Unchanged 8-MOP accounted for less than 1% of the excreted radioactivity. In tissue distribution studies at 0.5, 2 and 5 hr after i.v. administration, 8-MOP distributed rapidly to all tissues and concentrated in the fat and kidneys. The concentration of 8-MOP in the skin was 0.4 to 0.6 times that in the blood. Eleven metabolites of 8-MOP were detected in the urine. The metabolites identified after enzymatic hydrolysis were 8-hydroxypsoralen; 5-hydroxy-8-methoxypsoralen; 5,8-dihydroxypsoralen; 5,8-dioxopsoralen; 6-(7-hydroxy-8-methoxycoumaryl)-acetic acid and 8-MOP (formed by ring closure of a coumaric acid metabolite). Thus, these studies indicate that 8-MOP is metabolized in the rat by 1) O-demethylation; 2) hydroxylation at position 5; 3) hydrolysis of the lactone ring and 4) oxidation of the furan ring, a pathway already confirmed in insects, dogs and humans.


Opium trade and the spread of HIV in the Golden Crescent.
The Golden Crescent region of South Asia-comprising Afghanistan, Iran, and Pakistan-is a principal global site for opium production and distribution. Over the past few decades, war, terrorism, and a shifting political landscape have facilitated an active heroin trade throughout the region. Protracted conflict has exacerbated already dire socio-economic conditions and political strife within the region and contributed to a consequent rise in opiate trafficking and addiction among the region's inhabitants. The worsening epidemic of injection drug use has paralleled the rising incidence of HIV and other blood-borne infections in the region and drawn attention to the broader implications of the growing opiate trade in the Golden Crescent. The first step in addressing drug use is to recognize that it is not a character flaw but a form of mental illness, hence warranting humane treatment of drug users. It is also recommended that the governments of the Golden Crescent countries encourage substitution of opium with licit crops and raise awareness among the general public about the perils of opium use.


Intercenter variability in outcome for patients treated with direct coronary angioplasty during acute myocardial infarction.
Direct coronary angioplasty is an effective therapy for acute myocardial infarction, but its success may be dependent on both ready availability and operator skill. The purpose of this study was to investigate the impact of the center performing direct coronary angioplasty for acute myocardial infarction while controlling for parameters known to affect outcome. The study group consisted of 99 patients with ST elevation who were treated with direct angioplasty in four high-volume centers. Patients were injected with technetium-99m sestamibi intravenously and then taken to the cardiac catheterization laboratory. Antegrade flow was graded before and after direct coronary angioplasty. Single photon emission computed tomography was performed 1 to 6 hours after injection to measure myocardium at risk and residual blood flow to the jeopardized zone using previously published quantitative methods. A repeat sestamibi injection and tomographic acquisition were performed at hospital discharge to measure actual infarct size. There were no significant differences by center for baseline clinical characteristics, mean myocardium at risk (29% to 37% left ventricle [LV]), time to reperfusion (3.1 to 4.1 hours), residual blood flow, infarct location, or antegrade flow. Despite these similarities, there were differences in outcome measures by center. Mean infarct size was as follows: center 1, 15%; center 2, 12%; center 3, 10%, center 4, 23% (all LV; p = 0.11 ). Mean left ventricular ejection fraction at discharge also demonstrated significant differences: center 1, 0.57; center 2, 0.47; center 3, 0.53; center 4, 0.47 (p = 0.002). The prevalence of Thrombolysis in Myocardial Infarction grade 3 flow after angioplasty significantly differed by center: center 1, 92%; center 2, 94%; center 3, 87%; center 4, 71 %; (p = 0.01). There was a low mortality rate for all four centers ranging from 0% to 6%. After adjustment for myocardium at risk, residual blood flow, and time to reperfusion, the primary outcome of the center where the angioplasty was performed was an independent determinant of both infarct size and left ventricular ejection fraction. The success of direct coronary angioplasty in reducing infarct size and preserving left ventricular function depends on the center performing the procedure. Direct measurement of the effectiveness of this reperfusion modality in community practice is required to assess the impact of this effect.


Detection and characterization of regulatory elements using probabilistic conditional random field and hidden Markov models.
By altering the electrostatic charge of histones or providing binding sites to protein recognition molecules, Chromatin marks have been proposed to regulate gene expression, a property that has motivated researchers to link these marks to cis-regulatory elements. With the help of next generation sequencing technologies, we can now correlate one specific chromatin mark with regulatory elements (e.g. enhancers or promoters) and also build tools, such as hidden Markov models, to gain insight into mark combinations. However, hidden Markov models have limitation for their character of generative models and assume that a current observation depends only on a current hidden state in the chain. Here, we employed two graphical probabilistic models, namely the linear conditional random field model and multivariate hidden Markov model, to mark gene regions with different states based on recurrent and spatially coherent character of these eight marks. Both models revealed chromatin states that may correspond to enhancers and promoters, transcribed regions, transcriptional elongation, and low-signal regions. We also found that the linear conditional random field model was more effective than the hidden Markov model in recognizing regulatory elements, such as promoter-, enhancer-, and transcriptional elongation-associated regions, which gives us a better choice.


Resuscitation of Dormant "Non-culturable" Mycobacterium tuberculosis Is Characterized by Immediate Transcriptional Burst.
Under unfavorable conditions such as host immune responses and environmental stresses, human pathogen Mycobacterium tuberculosis may acquire the dormancy phenotype characterized by "non-culturability" and a substantial decrease of metabolic activity and global transcription rates. Here, we found that the transition of M. tuberculosis from the dormant "non-culturable" (NC) cells to fully replicating population in vitro occurred not earlier than 7 days after the start of the resuscitation process, with predominant resuscitation over this time interval evidenced by shortening apparent generation time up to 2.8 h at the beginning of resuscitation. The early resuscitation phase was characterized by constant, albeit low, incorporation of radioactive uracil, indicating de novo transcription immediately after the removal of the stress factor, which resulted in significant changes of the M. tuberculosis transcriptional profile already after the first 24 h of resuscitation. This early response included transcriptional upregulation of genes encoding enzymes of fatty acid synthase system type I (FASI) and type II (FASII) responsible for fatty acid/mycolic acid biosynthesis, and regulatory genes, including whiB6 encoding a redox-sensing transcription factor. The second resuscitation phase took place 4 days after the resuscitation onset, i.e., still before the start of active cell division, and included activation of central metabolism genes encoding NADH dehydrogenases, ATP-synthases, and ribosomal proteins. Our results demonstrate, for the first time, that the resuscitation of dormant NC M. tuberculosis is characterized by immediate activation of de novo transcription followed by the upregulation of genes controlling key metabolic pathways and then, cell multiplication.


Improving lesbian, gay, bisexual, transgender, and queer/questioning health: Using a standardized patient experience to educate advanced practice nursing students.
Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ) persons account for 3.5% of the population. Nursing programs in the United States provide a median of 2.13 hours of formal content regarding LGBTQ health, which contributes to iatrogenic barriers to care. Patient experiences related to inadequate provider preparation include misguided treatment strategies, impedance of communication, and abuse. A pilot educational project was developed to provide advanced practice nursing (APRN) students meaningful clinical interactions with LGBTQ-identifying standardized patients (SPs) to better prepare them to care for LGBTQ patients with cultural humility. This project was determined to be Exempt by the Institutional Review Board at the University of Michigan. Implemented in an advanced health assessment course with 99 APRN students, components of the project included course readings, lecture content, laboratory activities, an SP experience, and both large and small debriefing sessions. The SP experience itself was a 15-minute clinical encounter with a patient presenting with "abdominal pain," with an emphasis on history-taking, communication, and cultural humility. Qualitative data analysis was performed using the constant comparison method to interpret the results from student evaluations and other written feedback. This pilot project has promise to inform future educational offerings and set the standard for LGBTQ health content and application for APRN students. Further research is needed to evaluate the quality of LGBTQ content in APRN curricula to improve the ability of APRN students to provide care to LGBTQ patients.


Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma.
Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-γ, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard.


[Efferent connections of the caudate nucleus of the cat studied using retrograde axonal transport of horseradish peroxidase].
The origin of descending efferent pathways from the caudate nucleus was studied by retrograde axonal transport of horseradish peroxidase. Widespread topically organized projections were observed to the paleostriatum and the substantia nigra and less numerous to the thalamus. The main source of these projections were small and medium-size cells. A particular role of the subthalamic nucleus in the descending efferent system of the caudate nucleus is pointed out: this nucleus besides projections to the caudate nucleus itself possesses direct connections with principal output structures of the latter--the the paleostriatum and substantia nigra.


Resection of carcinoma in situ and minimally invasive carcinoma of the pancreas in a patient presenting with stenosis and post-stenotic dilatation of the main pancreatic duct on endoscopic ultrasonography and positive serial pancreatic juice aspiration cytology.
We report a rare case of a 67-year-old man who underwent resection of carcinoma in situ and minimally invasive carcinoma of the pancreas. The patient presented with upper abdominal and back pain. No definite pancreatic mass was detected on abdominal ultrasonography, computed tomography, magnetic resonance imaging (MRI), or endoscopic ultrasonography (EUS). However, EUS and MRI demonstrated stenosis of the main pancreatic duct (MPD) in the body and post-stenotic dilatation, resulting in mild dilatation of MPD in the tail. Serial pancreatic juice aspiration cytology after endoscopic nasopancreatic drainage was suggestive of pancreatic adenocarcinoma. Examination of the distal pancreatectomy specimen demonstrated carcinoma in situ in MPD and branches, with multiple intraepithelial neoplastic lesions in the background pancreas and an additional focus of minimally invasive carcinoma.


blaCTX-M-65 is carried by a Tn1722-like element on an IncN conjugative plasmid of ST131 Escherichia coli.
Escherichia coli clinical isolate WCE307 was found to belong to phylogroup B2, O25b and sequence type (ST) 131 and had blaCTX-M-65, which was carried by an IncN conjugative plasmid, pWCE307. On pWCE307, the ISEcp1Δ-blaCTX-M-65-IS903D-ironΔ structure was located in a Tn1722-like element flanked by 5 bp direct target repeats. This context was highly similar to that on pKC396, an IncN plasmid from E. coli isolate KC396 of ST131 from Germany. The Tn1722-like elements carrying blaCTX-M-65 on pWCE307 and pKC396 are likely to be hybrids of Tn1722 and Tn5051, resulting from double crossover at the res sites and the tnpA genes. The left end of the Tn1722-like elements was partially missing. As ISEcp1 and Tn1722 were both incomplete, blaCTX-M-65 might have been trapped in this context. A plasmid multilocus sequence typing (pMLST) scheme with five targets, repN, stbB, traI, traB and the korB-orfI spacer region, was developed for IncN plasmid typing. pMLST revealed that the five alleles of pWCE307 and pKC396 were identical, indicating that WCE307 and KC396 are likely to have originated very recently from a common strain, suggesting the international spread of blaCTX-M-65 mediated by ST131 E. coli.


The intersection of social determinants of health, the microbiome, and health outcomes in immigrants: A scoping review.
In the present scoping review, we explore whether existing evidence supports the premise that social determinants of health (SDoH) affect immigrant health outcomes through their effects on the microbiome. We adapt the National Institute on Minority Health and Health Disparities' research framework to propose a conceptual model that considers the intersection of SDoH, the microbiome, and health outcomes in immigrants. We use this conceptual model as a lens through which to explore recent research about SDoH, biological factors associated with changes to immigrants' microbiomes, and long-term health outcomes. In the 17 articles reviewed, dietary acculturation, physical activity, ethnicity, birthplace, age at migration and length of time in the host country, socioeconomic status, and social/linguistic acculturation were important determinants of postmigration microbiome-related transformations. These factors are associated with progressive shifts in microbiome profile with time in host country, increasing the risks for cardiometabolic, mental, immune, and inflammatory disorders and antibiotic resistance. The evidence thus supports the premise that SDoH influence immigrants' health postmigration, at least in part, through their effects on the microbiome. Omission of important postmigration social-ecological variables (e.g., stress, racism, social/family relationships, and environment), limited research among minoritized subgroups of immigrants, complexity and inter- and intra-individual differences in the microbiome, and limited interdisciplinary and biosocial collaboration restrict our understanding of this area of study. To identify potential microbiome-based interventions and promote immigrants' well-being, more research is necessary to understand the intersections of immigrant health with factors from the biological, behavioral/psychosocial, physical/built environment, and sociocultural environment domains at all social-ecological levels.


Experiences of UK and Irish family carers of people with profound and multiple intellectual disabilities during the COVID-19 pandemic.
People with profound and multiple intellectual disabilities (PMID) have high and intensive support needs that ordinarily place significant strain on family carers. This was further heightened by the removal of many external supports during the COVID-19 pandemic. We sought to explore the experiences of family carers of people with PMID during the COVID-19 pandemic and understand what the longer-term impact might be on their lives. Focus group interviews (n = 32) were conducted with family carers (n = 126) from the four countries of the UK and the Republic of Ireland. Participants were asked questions relating to their experiences of the COVID-19 pandemic, coping strategies, and challenges faced. All focus groups were conducted using the online platform, Zoom. These were audio recorded, transcribed verbatim and analysed employing inductive thematic analysis. Three main themes were generated from the data including (1.0) COVID-19 as a double-edged sword (2.0), The struggle for support (3.0), Constant nature of caring. These included 11 subthemes. (1.1) 'COVID-19 as a catalyst for change', (1.2) 'Challenges during COVID-19: dealing with change', (1.3) 'Challenges during COVID-19: fear of COVID-19', (1.4); 'The online environment: the new normal' (2.1) 'Invisibility of male carers', (2.2) 'Carers supporting carers', (2.3) 'The only service you get is lip service: non-existent services', (2.4); 'Knowing your rights' (3.1) 'Emotional response to the caring role: Feeling devalued', (3.2) 'Emotional response to the caring role: Desperation of caring', (3.3) 'Multiple demands of the caring role.' The COVID-19 pandemic presented immense challenges to family carers of people with PMID but also provided some opportunities. Families had already struggled to receive many of the supports and services to which they were entitled to only to have these removed at the onset of the pandemic. The experiences of male carers have been largely absent from the literature with this research showing they want to be included in decision making and require tailored support services. Service providers should see the end of the COVID-19 pandemic as providing opportunity to re-examine current provision and design services with family carers. As the direct threat from COVID-19 diminishes and the experiences of those who lived through this period come to the fore, there is a need to re-examine current models and provision of support to family carers to better meet their needs.


High-resolution differential scanning calorimetric study of myosin, functional domains, and supramolecular structures.
High-resolution differential scanning calorimetry (DSC) has been employed to study the thermal stability of myosin, its major constitutive fragments (S-1, light chains, and rod), and also reconstituted thick filaments. The thermal denaturation of soluble myosin was complex and was characterized by a multistep endothermic process for the temperature range from 41 to 60 degrees C. The shape of the endotherm was highly dependent on the pH and the ionic strength of the solution, although the delta Hcal (calorimetric enthalpy) of denaturation (1715 +/- 75 kcal/mol) was insensitive to these changes for the solvent conditions used in this study. This value also agrees, within experimental error, with the sum of the denaturation enthalpies obtained for isolated fragments (1724 +/- 79 kcal/mol). In identical conditions of ionic strength, pH, and heating rate, the computer-calculated differential endotherms of domains belonging to S-1 and light chains were superimposable with those of the isolated fragments. Their responses to changes in the solvent condition were also similar. We suggest that the observed functional independence of the major domains in myosin reflects also the independence of their structural stability. The thermal unfolding of the isolated rod was multiphasic and readily reversible (95%). It occurred between 41 and 60 degrees C, with an delta Hcal of 1058 +/- 59 kcal/mol. The melting of S-1 showed a single peak at 46.3 +/- 0.1 degrees C with an delta Hcal of 255 +/- 12 kcal/mol. Light chains melted at 51.0 +/- 0.2 degrees C with an delta Hcal of 85 +/- 15 kcal/mol.(ABSTRACT TRUNCATED AT 250 WORDS)


TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species.
TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia-reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other "natural" compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.