Risk of nosocomial transmission of coronavirus disease 2019: an experience in a general ward setting in Hong Kong.
Coronavirus disease 2019 (COVID-19) was first reported in Wuhan in December 2019 and has rapidly spread across different cities within and outside China. Hong Kong started to prepare for COVID-19 on 31st December 2019 and infection control measures in public hospitals were tightened to limit nosocomial transmission within healthcare facilities. However, the recommendations on the transmission-based precautions required for COVID-19 in hospital settings vary from droplet and contact precautions, to contact and airborne precautions with placement of patients in airborne infection isolation rooms. To describe an outbreak investigation of a patient with COVID-19 who was nursed in an open cubicle of a general ward before the diagnosis was made. Contacts were identified and risk categorized as 'close' or 'casual' for decisions on quarantine and/or medical surveillance. Respiratory specimens were collected from contacts who developed fever, and/or respiratory symptoms during the surveillance period and were tested for SARS-CoV-2. A total of 71 staff and 49 patients were identified from contact tracing, seven staff and 10 patients fulfilled the criteria of 'close contact'. At the end of 28-day surveillance, 76 tests were performed on 52 contacts and all were negative, including all patient close contacts and six of the seven staff close contacts. The remaining contacts were asymptomatic throughout the surveillance period. Our findings suggest that SARS-CoV-2 is not spread by an airborne route, and nosocomial transmissions can be prevented through vigilant basic infection control measures, including wearing of surgical masks, hand and environmental hygiene.


Observation of plasmon propagation, redirection, and fan-out in silver nanowires.
We report the coupling of free-space photons (vacuum wavelength of 830 nm) to surface plasmon modes of a silver nanowire. The launch of propagating plasmons, and the subsequent emission of photons, is selective and occurs only at ends and other discontinuities of the nanowire. In addition, we observe that the nanowires redirect the plasmons through turns of radii as small as 4 microm. We exploit the radiating nature of discontinuities to find a plasmon propagation length >3 +/- 1 microm. Finally, we observe that interwire plasmon coupling occurs for overlapping wires, demonstrating plasmon fan-out at subwavelength scales.


Perspectives of people living with dementia and their care partners about the impact on social health when participating in a co-designed Dementia café.
Those diagnosed with dementia and those who provide care and support often feel socially isolated with limited opportunities for social engagement, increasing the potential for loneliness and further isolation that is detrimental to social health. This study examined how a co-designed dementia café impacted on the self-reported social health of community dwelling people with dementia and their care partners in the North-West of England. Semi-structured interviews were conducted at two time periods (summer of 2019 and spring of 2020), with five people living with dementia and eight care partners. The key finding was that participating in the cafés led to a sense of belonging and purpose that was beneficial to well-being and social health for all participants. Community-based initiatives that provide opportunities for peer support for the person with the diagnosis and the care partner are essential so that people living with dementia may rebuild their confidence as well as retaining opportunities to socialise.


Public and Patients' Perspectives Towards Data and Sample Sharing for Research: An Overview of Empirical Findings.
We aimed to review the attitudes and perspectives of the public and patients towards the sharing of data and biospecimens for research and to identify common dimensions, regardless of setting. Our review included systematic, scoping or thematic reviews of empirical studies retrieved from Medline (PubMed interface), Web of Science, Scopus, ProQuest and Cochrane Reviews. The main themes identified and synthesised across the 14 reviews were readiness and motivations; potential risks and safeguards; trust, transparency and accountability; autonomy and preferred type of consent; and factors influencing data and biospecimen sharing and consent. Sociodemographic factors and research and individual context remain relevant influencing factors in all settings, while preferences for types of consent are highly heterogeneous. Trusted environments and adapted consent options with participant engagement are relevant to improve research participation.


Halogenated 4-(phenoxymethyl)piperidines as potential radiolabeled probes for sigma-1 receptors: in vivo evaluation of [123I]-1-(iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]pip eri dine.
Several halogenated 4-(4-phenoxymethyl)piperidines were synthesized as potential sigma receptor ligands. The affinity and selectivity of these compounds were determined using in vitro receptor binding assays, and their log P values were estimated using HPLC analysis. The effect of various N-substituents on the sigma-1 and sigma-2 dissociation constants was examined. These substituents included fluoroalkyl, hydroxyalkyl, iodopropenyl, and selected ortho-, meta-, and para-substituted benzyl groups. Also determined were the effects of various moieties on the phenoxy ring; specifically 4-iodo, 4-bromo, 4-nitro, 4-cyano, 3-bromo, and pentafluoro substituents were examined. The ranges in the dissociation constants of these compounds for sigma-1 and sigma-2 receptors were 0.38-24.3 and 3.9-361 nM, respectively. The ratio of Ki (sigma-2/sigma-1) ranged from 1.19 to 121. One of the most promising of the iodinated ligands, 1-(trans-iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl]piperidi ne (4), was labeled with 123I and studied in vivo in adult male rats. High uptake and good retention of radioactivity was observed in the brain and many other organs known to possess sigma receptors. Blocking studies revealed high specific binding of [123I]-4 to sigma receptors in the brain, lung, kidney, heart, muscle, and other organs known to possess these sites. These results indicate that [123I]-4 and other halogenated 4-(phenoxymethyl)piperidines of this series may provide useful probes for in vivo tomographic studies of sigma receptors.


Analyzing Dynamic Protein Complexes Assembled On and Released From Biolayer Interferometry Biosensor Using Mass Spectrometry and Electron Microscopy.
In vivo, proteins are often part of large macromolecular complexes where binding specificity and dynamics ultimately dictate functional outputs. In this work, the pre-endosomal anthrax toxin is assembled and transitioned into the endosomal complex. First, the N-terminal domain of a cysteine mutant lethal factor (LFN) is attached to a biolayer interferometry (BLI) biosensor through disulfide coupling in an optimal orientation, allowing protective antigen (PA) prepore to bind (Kd 1 nM). The optimally oriented LFN-PAprepore complex then binds to soluble capillary morphogenic gene-2 (CMG2) cell surface receptor (Kd 170 pM), resulting in a representative anthrax pre-endosomal complex, stable at pH 7.5. This assembled complex is then subjected to acidification (pH 5.0) representative of the late endosome environment to transition the PAprepore into the membrane inserted pore state. This PApore state results in a weakened binding between the CMG2 receptor and the LFN-PApore and a substantial dissociation of CMG2 from the transition pore. The thio-attachment of LFN to the biosensor surface is easily reversed by dithiothreitol. Reduction on the BLI biosensor surface releases the LFN-PAprepore-CMG2 ternary complex or the acid transitioned LFN-PApore complexes into microliter volumes. Released complexes are then visualized and identified using electron microscopy and mass spectrometry. These experiments demonstrate how to monitor the kinetic assembly/disassembly of specific protein complexes using label-free BLI methodologies and evaluate the structure and identity of these BLI assembled complexes by electron microscopy and mass spectrometry, respectively, using easy-to-replicate sequential procedures.


Cognitive dysfunction and poor health literacy are common in veterans presenting with acute coronary syndrome: insights from the MEDICATION study.
Patient nonadherence to cardiac medications following acute coronary syndrome (ACS) is associated with increased risk of recurrent events. However, the prevalence of cognitive dysfunction and poor health literacy among ACS patients and their association with medication nonadherence are poorly understood. We assessed rates of cognitive dysfunction and poor health literacy among participants of a clinical trial that tested the effectiveness of an intervention to improve medication adherence in patients hospitalized with ACS. Of 254 patients, 249 completed the Rapid Estimate of Adult Literacy in Medicine, Revised (REALM-R) survey, an assessment of risk for poor literacy, and the St Louis University Mental Status (SLUMS) exam, a tool assessing for neurocognitive deficits, during ACS hospitalization. We assessed if SLUMS or REALM-R scores were associated with medication adherence. Based on SLUMS score, 14% of patients were categorized as having dementia, and 52% with mild neurocognitive disorder (MNCD). Based on REALM-R score of ≤6, 34% of patients were categorized as at risk for poor health literacy. There was no association between poor health literacy and medication nonadherence. Of those with MNCD, 35.5% were nonadherent, compared to 17.5% with normal cognitive function and 6.7% with dementia. In multivariable analysis, cognitive dysfunction was associated with medication nonadherence (P=0.007), mainly due to an association between MNCD and nonadherence (odds ratio =12.2, 95% confidence interval =1.9 to 243; P=0.007). Cognitive status was not associated with adherence in patients randomized to the intervention. Cognitive dysfunction and risk for poor health literacy are common in patients hospitalized with ACS. We found an association between MNCD and medication nonadherence in the usual care group but not in the intervention group. These findings suggest efforts to screen for MNCD are needed during ACS hospitalization to identify patients at risk for nonadherence and who may benefit from an adherence intervention.


YidC and SecY mediate membrane insertion of a Type I transmembrane domain.
YidC has been identified recently as an evolutionary conserved factor that is involved in the integration of inner membrane proteins (IMPs) in Escherichia coli. The discovery of YidC has inspired the reevaluation of membrane protein assembly pathways in E. coli. In this study, we have analyzed the role of YidC in membrane integration of a widely used model IMP, leader peptidase (Lep). Site-directed photocross-linking experiments demonstrate that both YidC and SecY contact nascent Lep very early during biogenesis, at only 50-amino acid nascent chain length. At this length the first transmembrane domain (TM), which acquires a type I topology, is not even fully exposed outside the ribosome. The pattern of interactions appears dependent on the position of the cross-linking probe in the nascent chain. Upon elongation, nascent Lep remains close to YidC and comes into contact with lipids as well. Our results suggest a role for YidC in both the reception and lipid partitioning of type I TMs.


Hematopoiesis in regenerated bone marrow within hydroxyapatite scaffold.
We examined whether regenerated bone marrow (BM) with BM-derived stromal cells (BMSCs) on hydroxyapatite (HA) scaffolds can reconstitute the functional niche. Ly5.2 BMSCs on HA scaffolds were implanted s.c. onto the backs of Ly5.2 recipient mice. Lineage negative Ly5.1 BM cells expressing luciferase (luc) were i.v. administered into the recipient mice. Eight weeks after primary transplantation, secondary implantation was performed; the scaffolds removed from the first recipient mice were s.c. implanted into secondary recipient mice. Luc+ cells were detected in the scaffolds for 6 mo after secondary implantation. Injection of G-CSF resulted in wide distribution of bioluminescence from the original scaffolds to the whole body. Even after removing the scaffolds from the secondary recipient mice, luc+ cells were emitted by G-CSF stimulation, indicating that regenerated BM is capable of supporting hematopoietic stem cells (HSCs) and delivering HSCs to native BM in vivo. These data suggest that the functional niche is reconstituted at least partly and that regenerated BM on the scaffold may be used as a portable source of HSCs.


Network diversity and economic development.
Social networks form the backbone of social and economic life. Until recently, however, data have not been available to study the social impact of a national network structure. To that end, we combined the most complete record of a national communication network with national census data on the socioeconomic well-being of communities. These data make possible a population-level investigation of the relation between the structure of social networks and access to socioeconomic opportunity. We find that the diversity of individuals' relationships is strongly correlated with the economic development of communities.


Intramuscular testosterone enanthate plus very low dosage oral levonorgestrel suppresses spermatogenesis without causing weight gain in normal young men: a randomized clinical trial.
The development of a safe, well-tolerated, effective, and reversible male hormonal contraceptive would be a major clinical advance for couples planning their family size and for control of population growth. High-dosage parenteral testosterone (T) esters alone or in combination with a progestogen (eg, depot medroxyprogesterone) have been shown to confer effective and reversible male contraception in clinical trials, but these regimens are associated with weight gain and suppression of serum high-density lipoprotein cholesterol (HDL) levels. We have previously demonstrated that intramuscular T enanthate 100 mg weekly plus oral levonorgestrel (LNG) 125, 250, or 500 microg daily suppresses spermatogenesis to levels associated with effective contraception, but there is a LNG-dosage-dependent effect of weight gain and HDL suppression. We hypothesized that intramuscular T enanthate 100 mg weekly plus a very low dosage of oral LNG would effectively suppress spermatogenesis in normal men without inducing weight gain or HDL suppression. We conducted a randomized trial comparing 6 months of intramuscular T enanthate (100 mg weekly) plus 31.25 microg of oral LNG daily (T+LNG 31; n = 20) or 62.5 microg of oral LNG daily (T+LNG 62; n = 21). The 2 regimens were equally effective in suppressing spermatogenesis to azoospermia, fewer than 1 million sperm/mL and fewer than 3 million sperm/mL (T+LNG 31 [60%, 85%, and 90%] vs T+LNG 62 [62%, 91%, and 95%] for azoospermia, fewer than 1 million and fewer than 3 million, respectively; P = NS). The T+LNG 31 group did not gain weight (0.25 +/- 1.08 kg; P = NS compared with baseline), but the T+LNG 62 group gained 2.5 +/- 0.77 kg (P < .05 compared with baseline). Serum HDL cholesterol levels declined significantly in both groups (percentage decline month 6 of treatment vs baseline: 12.0% +/- 2.6% and 15.1% +/- 3.0%; P < .05 for T+LNG 31 and 62 respectively). Serum low-density lipoprotein cholesterol levels also declined in both groups (percentage decline month 6 of treatment vs baseline: 6.9 +/- 3.9 and 6.0% +/- 4.1%; P < .05 for T+LNG 31 and P = NS for T+LNG 62). There were no clinically significant adverse events or significant changes in hematology or chemistry profiles in either group during the study. We conclude that 1) intramuscular T plus oral LNG has a very potent synergistic effect in suppressing spermatogenesis at LNG dosages equal to or lower than dosages used in common female oral contraceptive regimens and 2) large, long-term contraceptive efficacy trials should be conducted with a variety of androgen-progestogen combinations including long-acting T formulations such as depot T pellets or intramuscular T undecanoate plus depot LNG or very low dosage oral LNG.


Quercetin facilitates cell death and chemosensitivity through RAGE/PI3K/AKT/mTOR axis in human pancreatic cancer cells.
The triggering of gemcitabine (GEM) drug resistance in pancreatic cancer by the receptor for advanced glycation end products (RAGE) has been demonstrated. Hence, finding a safe and effective adjuvant for preventing pancreatic cancer progression is imperative. Quercetin is a flavonoid that is abundant in apples, grapes, red raspberry, and onions and has been reported to inhibit RAGE. This research aimed to investigate the mechanisms of quercetin in regulating cell death and enhancing drug effects through RAGE reduction, especially in GEM-resistant pancreatic cancer cells. Our results showed that silencing RAGE expression by RAGE-specific siRNA transfection significantly increased cell death by apoptosis, autophagy and GEM-induced cytotoxicity by suppressing the PI3K/AKT/mTOR axis in MIA Paca-2 and MIA Paca-2 GEMR cells (GEM-resistant cells). Notably, quercetin showed a dramatic effect similar to RAGE silencing that effectively attenuated RAGE expression to facilitate cell cycle arrest, autophagy, apoptosis, and GEM chemosensitivity in MIA Paca-2 GEMR cells, suggesting that an additional reaction occurred under combined quercetin and GEM treatment. In conclusion, the results demonstrated that the molecular mechanisms of quercetin in regulating apoptosis and autophagy-related pathways and increasing GEM chemosensitivity in pancreatic cancer cells involved inhibition of RAGE expression.


Observation of curative effects of huatuojiaji in the treatment of 300 cases of apoplexy.
Huatuojiaji are extra-channel acupoints which are first described in A Handbook of Prescriptions for Emergencies, and the clinical application of which has been expanded a great deal in modern times. In the end of 1970s, the successful application of Huatuojiaji points in acupuncture anaesthesia brought the research on Huatuojiaji points to its climax; and in recent years, great progress has been made in the study of clinical application, improvement of curative effects and functional mechanism of Huatuojiaji points. According to the theories of acupuncture and moxibustion that puncturing Huatuojiaji can dredge channels, promote flow of qi, regulate yin and yang, and activate the Du Channel and the Urinary Bladder Channel, 300 cases of apoplexy were thus treated with good curative effects. There are altogether 56 points, 28 on each side of the spine, 0.5 cun lateral to the spinous process. The prescription for apoplexy includes C1-7, T1-9 and L2-4. Of the 300 cases of apoplexy, 100 were cured, 107 markedly effective, 87 improved, and 6 ineffective, the total effective rate being 98%.


Interactions between impulsivity and MDPV self-administration in rats.
Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are recreational drugs of abuse often identified in 'bath salts' preparations. Humans report compulsive patterns of bath salts use, and previous work suggests that a subset of rats develop unusually high levels of MDPV self-administration. This study aims to test the hypothesis that high levels of impulsivity (e.g., inability to withhold responding for a sucrose reward) will predispose rats to high levels of MDPV self-administration relative to rats with lower levels of impulsivity. The 1-choice serial reaction time task (1-CSRTT) was used to assess impulsivity (i.e., premature responding) in 10 female and 10 male Sprague Dawley rats. Rats were then allowed to self-administer 0.032 mg/kg/inf MDPV or 0.32 mg/kg/inf cocaine, after which full dose-response curves for MDPV (0.001-0.1 mg/kg/inf) or cocaine (0.01-1 mg/kg/inf) were generated under a FR5 schedule of reinforcement. After a history of self-administering MDPV or cocaine, impulsivity was reassessed under the 1-CSRTT, prior to evaluating the acute effects of MDPV (0.032-0.32 mg/kg) or cocaine (0.1-1 mg/kg) on impulsivity. Level of impulsivity was not correlated with subsequent levels of either MDPV or cocaine self-administration, and level of drug self-administration was also not correlated with subsequent levels of impulsivity, although acute administration of MDPV and cocaine did increase premature responding. In failing to find direct relationships between either impulsivity and subsequent drug-taking behaviour, or drug-taking behaviour and subsequent assessments of impulsivity, these findings highlight the complexity inherent in the associations between impulsive behaviour and drug-taking behaviour in both animal models and humans.


Reduced field of view under the surgical microscope due to personal protective equipment: lessons learned during the COVID-19 pandemic.
During the coronavirus disease 2019 (COVID-19) pandemic, neurosurgeons all around the globe continue to operate in emergency cases using new self-protective measures. Personal protective equipment (PPE) use is recommended in all surgeries. The authors have experienced varying degrees of field of view (FOV) loss under the surgical microscope with different PPE. Herein, they aimed to investigate the effects of different PPE on FOV while using the surgical microscope. Fifteen neurosurgeons and neurosurgery residents participated in this study. Three kinds of PPE (safety spectacles, blast goggles, and face shields) were tested while using a surgical microscope. FOV was measured using a 12 × 12-cm checkered sheet of paper on which every square had an area of 25 mm2 under the microscope. The surgical microscope was positioned perpendicular to the test paper, and the zoom was fixed. Each participant marked on the test sheet the peripheral borders of their FOV while using different PPE and without wearing any PPE. A one-way repeated-measures ANOVA was performed to determine if there was a significant difference in FOV values with the different PPE. FOV was significantly different between each PPE (F[3, 42] = 6339.845, p < 0.0005). Post hoc analysis revealed a significant decrease in the FOV from the naked eye (9305.33 ± 406.1 mm2) to blast goggles (2501.91 ± 176.5 mm2) and face shields (92.33 ± 6.4 mm2). There were no significant FOV changes with the safety spectacles (9267.45 ± 410.5 mm2). While operating under a surgical microscope safety spectacles provide favorable FOVs. Face shields increase the eye piece-pupil distance, which causes a severe reduction in FOV.


The Attitudes of Therapists and Physicians on the Use of Sex Robots in Sexual Therapy: Online Survey and Interview Study.
Various types of robots have already been successfully used in medical care, and the use of new technologies is also playing an increasing role in the area of sexuality. Sex robots are marketed as advanced sex toys and sex dolls with artificial intelligence. Only a few considerations about the therapeutic use of sex robots in sexual therapy are debated in expert discussions. The aim of this study was to conduct a first exploratory survey on the attitudes of sex therapists and physicians toward the therapeutic benefits of sex robots. This study comprised a quantitative online survey and a qualitative interview study. A self-constructed questionnaire was used to survey the general attitudes of sex therapists and physicians regarding the benefits of sex robots in therapy. The qualitative study was designed to gain in-depth insight into the participants' beliefs and attitudes. Therefore, semistructured interviews were conducted. The quantitative data were evaluated by statistical analysis, and the interviews were transcribed and analyzed by using a grounded theory approach. A total of 72 sex therapists and physicians completed our self-constructed questionnaire (response rate 15%, 72/480). Only a few respondents (11%, 8/72) said that the use of sex robots was not conceivable for them, and almost half of all therapists and physicians could imagine recommending sex robots in therapy (45%, 33/72). The attitude toward sex robots as a therapeutic tool was very heterogeneous, with gender (P=.006), age (P=.03), and occupational differences (P=.05); female therapists, older therapists, and psychologists (in contrast to physicians) were more critical toward the therapeutic use of sex robots. The analysis of the 5 interviews identified 3 high-level core themes that were representative of the participants' responses: (1) the importance of the personal definition of sex robots for the assessment of their therapeutic benefits, (2) therapeutic benefits and dangers of sex robots, and (3) considerations on the quality of human-robot sexuality. Initial insights into the possible therapeutic use of sex robots in different disorders (eg, sexual dysfunction or pedophilia) and situations were gained from the perspective of sex therapists. The results of this study provide a first overview of the potential therapeutic use of sex robots. Moral, ethical, and treatment-related issues in this context are still unresolved and need to be further researched. We suggest integrating the topic into the training of sex therapists to form opinions beyond media images and to show therapy possibilities. Scientists engaged in sexual research should be involved in the development of sex robots to design robots with positive effects on sexual education, sexual therapy, sexual counseling, and sexual well-being for interested groups.


Impact of STAT5A-CNVs on growth traits in Chinese beef cattle breeds.
CNVs, which are a type of structural variation, make a substantial impact on diverse characteristics in multiple species. Q-PCR and data association analysis were used for STAT5A gene copy in this study. This study aimed to investigate the copy number variation (CNV) of the STAT5A gene in seven Chinese cattle breeds, namely Qingchuan cattle, Xiannan cattle, Yunling cattle, Ji'an cattle, Jiaxian Red cattle, Qaidam cattle, and Guyuan yellow cattle. Blood samples were collected for CNV typing, and the correlation between CNV type and growth traits was analyzed using SPSS 23.0 software and ANOVA. The findings revealed variations in the distribution of different copy number types among the different cattle breeds. Furthermore, association analysis demonstrated a positive impact of CNV in the STAT5A gene on cattle growth: in the JX, individuals with duplication types exhibited superior performance in terms of rump length (P<0.05). Conversely, normal GY cattle demonstrated better body height and abdomen circumference (P<0.05), while QD cattle exhibited a significant correlation between weight and body length with normal individuals (P<0.05). Moreover, QC bovine duplication individuals outperformed other types, with copy number variation significantly associated with chest depth, chest width, and body length (P<0.05). The results validate the correlation between copy number variation (CNV) of the STAT5A gene and growth characteristics in five different cattle breeds, providing a reliable benchmark for the purpose of cattle breeding.


Evolution of activation patterns during long-duration ventricular fibrillation in pigs.
Quantitative analysis has demonstrated five temporal stages of activation during the first 10 min of ventricular fibrillation (VF) in dogs. To determine whether these stages exist in another species, we applied the same analysis to the first 10 min of VF recorded in vivo from two 504-electrode arrays, one each on left anterior and posterior ventricular epicardium in six anesthetized pigs. The following descriptors were continuously quantified: 1) number of wavefronts, 2) wavefront fractionations, 3) wavefront collisions, 4) repeatability, 5) multiplicity index, 6) wavefront conduction velocity, 7) activation rate, 8) mean area activated by the wavefronts, 9) negative peak rate of voltage change, 10) incidence of breakthrough/foci, 11) incidence of block, and 12) incidence of reentry. Cluster analysis of these descriptors divided VF into four stages (stages i-iv). The values of most descriptors increased during stage i (1-22 s after VF induction), changed quickly to values indicating greater organization during stage ii (23-39 s), decreased steadily during stage iii (40-187 s), and remained relatively unchanged during stage iv (188-600 s). The epicardium still activated during stage iv instead of becoming silent as in dogs. In conclusion, during the first 10 min, VF activation can be divided into four stages in pigs instead of five stages as in dogs. Following a 16-s period during the first minute of VF when activation became more organized, all parameters exhibited progressive decreased organization. Further studies are warranted to determine whether these changes, particularly the increased organization of stage ii, have clinical consequences, such as alteration in defibrillation efficacy.


[Initiation of laparoscopic nephrectomy].
This work is reported to encourage experienced urologists to take advantage of a laparoscopic nephrectomy technique that has evolved into a remarkably inexpensive, uncomplicated routine procedure almost comparable with the gallbladder operations of general surgery. The patient is placed in the lumbotomy position. The unsleeved, uncuffed hand is introduced through a mini-McBurney incision in the iliac fossa. The first 12 mm trocar is introduced just above the posterior part of the iliac crest. The second is placed anteriorly some 10 to 12 cm from the first. The kidney is released by extraperitoneal manual dissection. The artery is clipped and sectioned and then, without dissecting the vein, the rest of the pedicle is sectioned en bloc with the endostapler. However, if the artery is not found, then the whole pedicle is sectioned en bloc. Lastly, the ureter is sectioned. The kidney is then introduced into a simple plastic bag (open urine bag) and digitally fragmented for easy removal through the incision. The oblique McBurney incision is also useful in the event reconversion to an open lumbotomy is necessary. As we described in 1994, manual manipulation significantly simplifies the procedure. Operators soon gain confidence when they appreciate in practice the surprising versatility of the technique. Because most of the procedure is done under visual control, operator precision soon increases and successive operation times shorten considerably. Operation costs are lower because an expensive inflatable cuff or sleeve is unnecessary, only two trocars are required and a standard urine bag serves to receive the kidney. We are sure that once urologists experienced in conventional surgery try the procedure, they will wonder why they did not adopt it earlier.


A comprehensive study of the extensor tendons to the medial four digits of the hand.
Awareness of the anatomy and variations of the extensor tendons on the dorsum of the hand is necessary when assessing the traumatized or diseased hand and when considering tendons for repair or transfer. A complete quantitative documentation of the extensor tendons is lacking. The arrangements of extensor tendons to the medical four fingers namely, the extensor digitorum communis (EDC), extensor indicis proprius (EIP) and extensor digiti minimi (EDM) on the dorsum of the hand and the intertendinous connections between them were studied in 100 upper limb specimens. The findings were photographed, tabulated and analyzed statistically. In 98% of the specimens, the EIP was a single tendon with a single insertion, whereas in two right upper limbs there were two EIP tendons with two insertions. In 77% of the specimens the EDC distally had tendons to the middle three fingers (EDC index, EDC longus and EDC ring). The EDC small was present in only 34% of samples and the EDM showed normal anatomy in only 20%. The most common types of juncturae tendinum in the 2nd, 3rd and 4th intermetacarpal spaces were Type 1, 2 and 3r, respectively. Two accessory muscles were seen. One was the extenson medii proprius in 5% of samples and the other, the extensor digitorum brevis manus, was seen in 3%. Variations of the extensor tendons were common in this study, especially for the middle and ring fingers which showed multiple tendons of the EDC.


Longitudinal assessment of hemoglobin oxygen saturation in preterm and term infants in the first six months of life.
To report longitudinal home recordings of hemoglobin O(2) saturation by pulse oximetry (Spo(2)) during unperturbed sleep in preterm and term infants. We recorded continuous pulse oximetry during the first 3 minutes of each hour of monitor use (nonevent epochs) for 103 preterm infants born at <1750 g and ≤ 34 weeks postmenstrual age (PMA), and 99 healthy term infants. Median baseline Spo(2) was approximately 98% for both the preterm and term groups. Episodes of intermittent hypoxemia occurred in 74% of preterm and 62% of term infants. Among infants with intermittent hypoxemia, the number of seconds/hour of monitoring <90% Spo(2) was initially significantly greater in the preterm than the term group and declined with age at a similar rate in both groups. The 75(th) to 95(th) percentiles for seconds/hour of Spo(2) <90% in preterm infants were highest at 36 weeks PMA and progressively decreased until 44 weeks PMA, after which time they did not differ from term infants. Clinically inapparent intermittent hypoxemia occurs in epochs unperturbed by and temporally unrelated to apnea or bradycardia events, especially in preterm infants at 36 to 44 weeks PMA.


Right ventricular function in acute myocardial ischaemia.
A haemodynamic examination of 10 dogs was carried out at rest, during volume loading and after ligation of the right coronary artery in the presence of a closed pericardium. Ligation of the right coronary artery led to haemodynamic signs of depression of right ventricular function--a drop in systolic pressure and an increase in end diastolic pressure, together with a shift of the functional curve to the right and downwards. Overall performance of the heart (cardiac output and the mean systemic pressure, also fell. Our results show that the depression of the systolic function of the myocardium in the presence of right ventricular infarction can be an important factor in the genesis of low cardiac output syndrome observed in clinical situations. Its pathophysiological mechanisms and some of the clinical consequences are discussed.


[ADHD and attachment processes: are they related?].
Attention-deficit/hyperactivity disorder (ADHD) is defined on the basis of developmentally inappropriate inattention, motor activity and impulsivity that emerges early in development and causes impairment in social and academic functioning. ADHD is described as a multifactorial disease, with a well studied genetic vulnerability, and early environmental factors also playing an important role in the development and course of the disorder. Current aetiological models emphasize interaction between genes and environment. The concept of attachment, as proposed by John Bowlby, reflects quality of early interactions, and should therefore be considered as an early developmental factor. First, clinical findings emphasize similitude between both disorders; emotional dysregulation is an important feature in reactive attachment disorder as well as in ADHD. Emotion regulation is highly related to attachment security in young children and could play a part in the development of early attention processes. Moreover, difficult temperament is associated with higher risk for ADHD on the one hand, and can disturb the process of attachment on the other. Parental caregiving - including maternal sensitivity, positive parenting practices - is a main factor involved in the development of attachment, and has shown to be associated with better outcomes in ADHD children, especially with less oppositional/conduct disorders. Second, the aim of our review is to present clinical studies that have looked for a link between ADHD and attachment: the type of attachment could play a part in the course of the disorder: insecure and disorganised attachment types tend to be associated with a higher risk of externalised behaviors in children. For ADHD, this effect seems to be weaker than for other externalised disorders, and has been shown only in populations of at-risk children. Clinical studies also raise the question of possible links between reactive attachment disorder and ADHD. In children suffering severe early deprivon such as institution-rearing, inattention/hyperactivity symptoms were shown to be high, but these findings may not be valid in less severely deprived children. Third, another link could depend on a common vulnerability for ADHD and attachment disorder. Some perinatal factors, such as smoking during pregnancy or prematurity, have been shown to increase the risk of hyperactive symptoms in children. These variables may also be associated with a higher risk of impaired early interactions. Recent animal studies have raised interest in the role of prenatal stress in the emotional and behavioral development of the offspring, particularly as regards vulnerability to stress. Epigenetic mechanisms may be involved in durable alterations of the hypothalamo-pituitary-adrenergic axis. Preliminary findings in humans show that prenatal stress or maternal depression may also influence the development of the child. The understanding of the relationship between attachment and ADHD may help to better target prevention and intervention efforts. As the perinatal period seems to be particularly involved in both ADHD and attachment disorders, early guidance and possibly prenatal interventions should be developed and assessed for mothers and caregivers with risk-factors.


Designated Interpreters: A Model to Promote the Diversity and Inclusion of Deaf Professionals in Academic Medicine.
Deaf professionals who use American Sign Language (ASL) are a growing population in academic medicine. Reasonable accommodations for this group include providing an ASL interpreter. Many institutions contract with external agencies to provide ad hoc interpreters, but this model has hidden costs for deaf professionals and institutions. The University of Rochester School of Medicine and Dentistry (URSMD) uses the designated interpreter model in which interpreters are on staff and embedded with deaf professionals so they can learn both the work environment and the deaf professionals' specialized science and medicine content. This model addresses many of the limitations of the external agency approach and better facilitates the inclusion of deaf professionals in the institution. This model has been in use at URSMD since 1990 but has seen exponential growth recently (increasing from 3 deaf professionals with designated interpreters in 2011 to a peak of 17 in 2016). Designated interpreters have worked in different research and clinical settings from dentistry and nursing to community and global health. This growth highlights the increasing number of deaf professionals in medicine and the need to train more designated interpreters. In response to this growing demand, URSMD is developing an ASL Interpreting in Medicine and Science program, a master's degree-level program to train interpreters who are bilingual in ASL and English to be designated interpreters. The designated interpreter model is one step toward creating an environment that is fully inclusive of deaf professionals to the benefit of the whole institution.


Effects of indoor environmental parameters related to building heating, ventilation, and air conditioning systems on patients' medical outcomes: A review of scientific research on hospital buildings.
The indoor environment of a mechanically ventilated hospital building controls infection rates as well as influences patients' healing processes and overall medical outcomes. This review covers the scientific research that has assessed patients' medical outcomes concerning at least one indoor environmental parameter related to building heating, ventilation, and air conditioning (HVAC) systems, such as indoor air temperature, relative humidity, and indoor air ventilation parameters. Research related to the naturally ventilated hospital buildings was outside the scope of this review article. After 1998, a total of 899 papers were identified that fit the inclusion criteria of this study. Of these, 176 papers have been included in this review to understand the relationship between the health outcomes of a patient and the indoor environment of a mechanically ventilated hospital building. The purpose of this literature review was to summarize how indoor environmental parameters related to mechanical ventilation systems of a hospital building are impacting patients. This review suggests that there is a need for future interdisciplinary collaborative research to quantify the optimum range for HVAC parameters considering airborne exposures and patients' positive medical outcomes.


Individual differences in selective attention predict speech identification at a cocktail party.
Listeners with normal hearing show considerable individual differences in speech understanding when competing speakers are present, as in a crowded restaurant. Here, we show that one source of this variance are individual differences in the ability to focus selective attention on a target stimulus in the presence of distractors. In 50 young normal-hearing listeners, the performance in tasks measuring auditory and visual selective attention was associated with sentence identification in the presence of spatially separated competing speakers. Together, the measures of selective attention explained a similar proportion of variance as the binaural sensitivity for the acoustic temporal fine structure. Working memory span, age, and audiometric thresholds showed no significant association with speech understanding. These results suggest that a reduced ability to focus attention on a target is one reason why some listeners with normal hearing sensitivity have difficulty communicating in situations with background noise.


Atonal, Senseless, and Abdominal-A regulate rhomboid enhancer activity in abdominal sensory organ precursors.
The atonal (ato) proneural gene specifies different numbers of sensory organ precursor (SOP) cells within distinct regions of the Drosophila embryo in an epidermal growth factor-dependent manner through the activation of the rhomboid (rho) protease. How ato activates rho, and why it does so in only a limited number of sensory cells remains unclear. We previously identified a rho enhancer (RhoBAD) that is active within a subset of abdominal SOP cells to induce larval oenocytes and showed that RhoBAD is regulated by an Abdominal-A (Abd-A) Hox complex and the Senseless (Sens) transcription factor. Here, we show that ato is also required for proper RhoBAD activity and oenocyte formation. Transgenic reporter assays reveal RhoBAD contains two conserved regions that drive SOP gene expression: RhoD mediates low levels of expression in both thoracic and abdominal SOP cells, whereas RhoA drives strong expression within abdominal SOP cells. Ato indirectly stimulates both elements and enhances RhoA reporter activity by interfering with the ability of the Sens repressor to bind DNA. As RhoA is also directly regulated by Abd-A, we propose a model for how the Ato and Sens proneural factors are integrated with an abdominal Hox factor to regulate region-specific SOP gene expression.


Plasma Metabolome Normalization in Rheumatoid Arthritis Following Initiation of Methotrexate and the Identification of Metabolic Biomarkers of Efficacy.
Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response. Plasma samples were collected from healthy control subjects (n = 20), and RA patients initiating MTX therapy (n = 20, 15 mg/week) before and after 16 weeks of treatment. The samples were analyzed by a semi-targeted metabolomic analysis, and then analyzed by univariate and multivariate methods, as well as an enrichment analysis. An MTX response was defined as a clinically significant reduction in the disease activity score in 28 joints (DAS-28) of greater than 1.2; achievement of clinical remission, defined as a DAS-28 < 2.6, was also utilized as an additional measure of response. In this study, RA is associated with an altered plasma metabolome that is normalized following initiation of MTX therapy. Metabolite classes found to be altered in RA and corrected by MTX therapy were diverse and included triglycerides (p = 1.1 × 10-16), fatty acids (p = 8.0 × 10-12), and ceramides (p = 9.8 × 10-13). Stratification based on responses to MTX identified various metabolites differentially impacted in responders and non-responders including glucosylceramides (GlcCer), phosphatidylcholines (PC), sphingomyelins (SM), phosphatidylethanolamines (PE), choline, inosine, hypoxanthine, guanosine, nicotinamide, and itaconic acid (p < 0.05). In conclusion, RA is associated with significant alterations to the plasma metabolome displaying at least partial normalization following 16 weeks of MTX therapy. Changes in multiple metabolites were found to be associated with MTX efficacy, including metabolites involved in fatty acid/lipid, nucleotide, and energy metabolism.


Pharmacokinetics of nelfinavir in children: influencing factors and dose implications.
The study describes the pharmacokinetics (PK) of the protease inhibitor nelfinavir and its active metabolite M8 in children and evaluates the influence of patient-related factors on nelfinavir plasma levels. HIV-1-infected children treated with nelfinavir every 8 h (q8h) were eligible for inclusion in this retrospective study. 0-8 h intensive plasma pharmacokinetics (PK) sampling was performed at steady state. Nelfinavir maximum concentration (Cmax), area under the plasma concentration-time curve in 0-8 h (AUC0-8), trough level at the 8 h time point (C8) and relative apparent oral clearance (CI*F/kg) were calculated. Twenty-four children (median age: 4.5 years, median nelfinavir dose: 28 mg/kg q8h) were included. Nelfinavir PK were highly variable: 10/24 children had an AUC0-8 below the value of 12.5 mg/l x h, which has previously been associated with an increased virological failure rate in children. With children aged < 2 years and a dose of 20 mg/kg q8h, a non-significant trend was observed to more AUC0-8 < 12.5 mg/l x h [odds ratio (OR) (95% CI): 2.44 (0.41-14.7) and 8.7 (0.79-95), respectively]. Nelfinavir C8 correlated strongly with AUC0-8 (r = 0.89, P < 0.001). C8 > 0.69 mg/l predicted an AUC0-8 > 12.5 mg/l x h with 71% sensitivity and 80% specificity. Dose of nelfinavir per body surface area was a better predictor of AUC0-8 than dose per body weight. Nelfinavir PK show high interindividual variability in children. Children < 2 years old tend to be at increased risk for low nelfinavir levels. These data show that the nelfinavir dose of 20 mg/kg q8h is inadequate in most children. Also, these data suggest that paediatric dosing of nelfinavir based on body surface area should be considered. Therapeutic drug monitoring (TDM) can detect abnormal plasma levels and is therefore useful in optimizing nelfinavir therapy in HIV-infected children. However, further research is needed to more firmly establish a therapeutic range for nelfinavir in children.


Interactive effects of temperature, organic carbon, and pipe material on microbiota composition and Legionella pneumophila in hot water plumbing systems.
Several biotic and abiotic factors have been reported to influence the proliferation of microbes, including Legionella pneumophila, in hot water premise plumbing systems, but their combined effects have not been systematically evaluated. Here, we utilize simulated household water heaters to examine the effects of stepwise increases in temperature (32-53 °C), pipe material (copper vs. cross-linked polyethylene (PEX)), and influent assimilable organic carbon (0-700 μg/L) on opportunistic pathogen gene copy numbers and the microbiota composition, as determined by quantitative polymerase chain reaction and 16S rRNA gene amplicon sequencing. Temperature had an overarching influence on both the microbiota composition and L. pneumophila numbers. L. pneumophila peaked at 41 °C in the presence of PEX (1.58 × 105 gene copies/mL). At 53 °C, L. pneumophila was not detected. Several operational taxonomic units (OTUs) persisted across all conditions, accounting for 50% of the microbiota composition from 32 to 49 °C and 20% at 53 °C. Pipe material most strongly influenced microbiota composition at lower temperatures, driven by five to six OTUs enriched with each material. Copper pipes supported less L. pneumophila than PEX pipes (mean 2.5 log10 lower) at temperatures ≤ 41 °C, but showed no difference in total bacterial numbers. Differences between pipe materials diminished with elevated temperature, probably resulting from decreased release of copper ions. At temperatures ≤ 45 °C, influent assimilable organic carbon correlated well with total bacterial numbers, but not with L. pneumophila numbers. At 53 °C, PEX pipes leached organic carbon, reducing the importance of dosed organic carbon. L. pneumophila numbers correlated with a Legionella OTU and a Methylophilus OTU identified by amplicon sequencing. Temperature was the most effective factor for the control of L. pneumophila, while microbiota composition shifted with each stepwise temperature increase. While copper pipe may also help shape the microbiota composition and limit L. pneumophila proliferation, its benefits might be constrained at higher temperatures. Influent assimilable organic carbon affected total bacterial numbers, but had minimal influence on opportunistic pathogen gene numbers or microbiota composition. These findings provide guidance among multiple control measures for the growth of opportunistic pathogens in hot water plumbing and insight into the mediating role of microbial ecological factors.


Protecting Labor and Delivery Personnel from COVID-19 during the Second Stage of Labor.
The novel coronavirus disease 2019 (COVID-19) is spreading fast and is affecting the clinical workers at much higher risk than the general population. Little is known about COVID-19 effect on pregnant women; however, the emerging evidence suggests they may be at high risk of asymptomatic disease. In light of projected shortage of personal protective equipment (PPE), there is an aggressive attempt at conservation. In obstetrics, the guidelines on PPE use are controversial and differ among hospitals, globally, as well as nationally. The centers for disease control and prevention (CDC) recommend using N95 respirators, which are respirators that offer a higher level of protection instead of a facemask for when performing or present for an aerosol-generating procedures (AGP). However, the second stage of labor is not considered an AGP. The second stage of labor can last up to 4 hours. During that time, labor and delivery personnel is in close contact to patients, who are exerting extreme effort during and frequently blow out their breath, cough, shout, and vomit, all of which put the health care team at risk, considering that COVID-19 transmission occurs through aerosol generated by coughing and sneezing. The CDC and the American College of Obstetricians and Gynecologists (ACOG) do not provide clarification on the use of N95 during the second stage. We recommend that labor and delivery personnel have the utmost caution and be granted the protection they need to protect themselves and other patients. This includes providing labor and delivery personnel full PPE including N95 for the second stage of labor. This is critical to ensure the adequate protection for health care workers and to prevent spread to other health care workers and patients. KEY POINTS: · Second stage of labor exposes providers to aerosol.. · COVID-19 risk during second stage of labor is high.. · N95 should be used during second stage of labor..


Cognitive and neural consequences of memory suppression in major depressive disorder.
Negative biases in cognition have been documented consistently in major depressive disorder (MDD), including difficulties in the ability to control the processing of negative material. Although negative information-processing biases have been studied using both behavioral and neuroimaging paradigms, relatively little research has been conducted examining the difficulties of depressed persons with inhibiting the retrieval of negative information from long-term memory. In this study, we used the think/no-think paradigm and functional magnetic resonance imaging to assess the cognitive and neural consequences of memory suppression in individuals diagnosed with depression and in healthy controls. The participants showed typical behavioral forgetting effects, but contrary to our hypotheses, there were no differences between the depressed and nondepressed participants or between neutral and negative memories. Relative to controls, depressed individuals exhibited greater activity in right middle frontal gyrus during memory suppression, regardless of the valence of the suppressed stimuli, and differential activity in the amygdala and hippocampus during memory suppression involving negatively valenced stimuli. These findings indicate that depressed individuals are characterized by neural anomalies during the suppression of long-term memories, increasing our understanding of the brain bases of negative cognitive biases in MDD.


Conditional mutator phenotypes in hMSH2-deficient tumor cell lines.
Two human tumor cell lines that are deficient in the mismatch repair protein hMSH2 show little or no increase in mutation rate relative to that of a mismatch repair-proficient cell line when the cells are maintained in culture conditions allowing rapid growth. However, mutations accumulate at a high rate in these cells when they are maintained at high density. Thus the mutator phenotype of some mismatch repair-deficient cell lines is conditional and strongly depends on growth conditions. These observations have implications for tumor development because they suggest that mutations may accumulate in tumor cells when growth is limited.


Observations on oesophageal length.
The subject of oesophageal length is discussed. The great variations in the length of the oesophagus in individual patients is noted, and the practical use of its recognition in oesophageal surgery is stressed. An apprasial of the various methods available for this measurement is made; this includes the use of external chest measurement, endoscopic measurement, and the measurement of the level of the electrical mucosal potential change. Correlative studies of these various methods are made, and these show a very high degree of significance. These studies involved simultaneous measurement of external and internal oesophageal length in 26 patients without a hiatal hernia or gastro-oesophageal length in 26 patients without a hiatal hernia or gastro-oesophageal reflux symptoms, 42 patients with sliding type hiatal hernia, and 17 patients with a peptic stricture in association with hiatal hernia. The method of measuring oesophageal length by the use of the external chest measurement, that is, the distance between the lower incisor teeth and the xiphisternum, measured with the neck fully extended and the patient lying supine, is described in detail, its practical application in oesophageal surgery is illustrated, and its validity tested by internal measurements. The findings of this study demonstrate that the external chest measurement provides a mean of assessing the true static length of the oesophagus, corrected for the size of the individual.


Internet use and stigmatized illness.
People with stigmatized illnesses often avoid seeking health care and education. The internet may be a useful health education and outreach tool for this group. This study examined patterns of internet use for health information among those with and without stigmatized illnesses. A national survey of internet users in the USA was conducted. Respondents who self-reported a stigmatized condition-defined as anxiety, depression, herpes, or urinary incontinence-were compared to respondents who reported having at least one other chronic illness, such as cancer, heart problems, diabetes, and back pain. The analytical sample consisted of 7014 respondents. Cross-sectional associations between stigmatized illness and frequency of internet use for information about health care, use of the internet for communication about health, changes in health care utilization after internet use, and satisfaction with the internet were determined. After controlling for a number of potential confounders, those with stigmatized illnesses were significantly more likely to have used the internet for health information, to have communicated with clinicians about their condition using the internet, and to have increased utilization of health care based on information found on the internet, than those with non-stigmatized conditions. Length of time spent online, frequency of internet use, satisfaction with health information found on the internet, and discussion of internet findings with health care providers did not significantly differ between the two groups. Results from this survey suggest that the internet may be a valuable health communication and education tool for populations who are affected by stigmatized illnesses.


Local Knowledge for Addressing Food Insecurity: The Use of a Goat Meat Drying Technique in a Rural Famine Context in Southern Africa.
Only 30% of households in Bairro Boroma (Boroma neighborhood) have a regular protein intake, mainly due to the lack of a proper cold chain. We analyzed the level of knowledge about a local dried meat called chinkui, examining the relationship between this knowledge and its value for strengthening local food security. Through surveys of Bairro Boroma goat herders (n = 23) about "chinkui awareness" and passive observation of chinkui preparation (n = 5) from local biotype goats, we found that chinkui was known to most goat herders (91.3%), but was used only irregularly, mainly because knowledge transmission has decreased over time. From passive observation, we found that the amount of dried meat obtained from an animal rarely exceeded a yield of 10% and its performance and safety depended on weather conditions and the absence of other animals in the area of preparation. It is, therefore, recommended to strengthen initiatives to increase the amount of chinkui, based on local knowledge, so as to enhance its frequency of consumption and the possibility of using it as a sustainable alternative source of protein.


JAK2 R683S Mutation Resulting in Dual Diagnoses of Chronic Eosinophilic Leukemia and Myelodysplastic/Myeloproliferative Overlap Syndrome.
A 66-year-old male presented with hypereosinophilia, thrombocytosis, extensive thrombosis refractory to direct oral anticoagulant therapy, and evidence of end-organ damage, including rash, splenic infarcts, and pulmonary infiltrates. Bone marrow biopsy revealed myeloid malignancy consistent with both chronic eosinophilic leukemia and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with SF3B1 mutation and thrombocytosis. Next-generation sequencing of the patient's eosinophils and neutrophil compartments revealed pathologic variants in EZH2 and SF3B1 in addition to a noncanonical JAK2 R683S mutation that has not been previously described in myeloproliferative disorders or other chronic myeloid neoplasms. These mutations were not present in the patient's lymphoid cell fraction, suggesting that the hematopoietic malignancy arose in a myeloid-committed progenitor cell. Based on this case and previous work from our group, we propose that noncanonical JAK2 mutations may permit signal transduction that biases toward eosinophilic differentiation in chronic myeloid neoplasms. Although the patient's blood counts initially responded to ruxolitinib and hydroxyurea, the response was not durable. Early referral for allogenic bone marrow transplant appears necessary to prevent long-term complications and disease progression in myeloid neoplasms with clonal hypereosinophilia driven by noncanonical JAK2 mutations.


A preliminary evaluation of efficacy and safety of Wharton's jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus.
Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus (T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton's Jelly-derived mesenchymal stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective phase I/II study to determine efficacy and safety of WJ-MSC transplantation in T2DM. Twenty-two patients with T2DM were enrolled and received WJ-MSC transplantation through one intravenous injection and one intrapancreatic endovascular injection (catheterization). They were followed up for 12 months after transplantation. The primary endpoints were changes in the levels of glycated hemoglobin and C-peptide and the secondary endpoints included insulin dosage, fasting blood glucose (FBG), post-meal blood glucose (PBG), inflammatory markers and T lymphocyte counts. WJ-MSC transplantation significantly decreased the levels of glucose and glycated hemoglobin, improved C-peptide levels and beta cell function, and reduced markers of systemic inflammation and T lymphocyte counts. No major WJ-MSC transplantation-related adverse events occurred, but data suggest a temporary decrease in levels of C-peptide and beta cell function at one month after treatment, possibly related to intrapancreatic endovascular injection. Our data demonstrate that treatment with WJ-MSCs can improve metabolic control and beta cell function in patients with T2DM. The therapeutic mechanism may involve improvements in systemic inflammation and/or immunological regulation. Chinese Clinical Trial Register ChiCTR-ONC-10000985. Registered 23 September 2010.


A dual amylin and calcitonin receptor agonist inhibits pain behavior and reduces cartilage pathology in an osteoarthritis rat model.
Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis. Medial meniscectomy (MNX) was performed in 39 rats, while 10 underwent sham surgery. Rats were treated with KBP and/or naproxen. Nociception was assessed by mechanical and cold allodynia, weight bearing asymmetry, and burrowing behavior. Blood samples were collected for biomarker measurements, and knees for histology. Cartilage histopathology was evaluated according to the advanced Osteoarthritis Research International (OARSI) score and KBPs in vitro antiresorptive effects were assessed using human osteoclasts cultured on bone. The MNX animals displayed an increased nociceptive behavior. Treatment with KBP attenuated the MNX-induced osteoarthritis-associated joint pain. The cartilage histopathology was significantly lower in rats treated with KBP than in MNX animals. Bone and cartilage degradation, assessed by CTX-I and CTX-II plasma levels, were decreased in all KBP-treated groups and KBP potently inhibited bone resorption in vitro. Our study demonstrates the effectiveness of KBP in ameliorating osteoarthritis-associated joint pain and in protecting the articular cartilage, suggesting KBP as a potential drug candidate for osteoarthritis.


Prolactin and growth hormone release by morphine in the rat: different receptor mechanisms.
Concentrations of prolactin and growth hormone in the serum of rats were significantly increased by morphine. Dose response studies demonstrated that maximum prolactin release required lower doses of morphine than those needed for the maximum growth hormone response. Selective blockade of mu 1 (high affinity) opiate receptor with the irreversible antagonist naloxazone reduced morphine-induced peak concentrations of prolactin by 80 percent while increasing peak growth hormone levels by 250 percent. These results suggest different receptor mechanisms for the opiate modulation of the two hormones. The mu 1 (high affinity) receptor sites appear to mediate the morphine-induced release of prolactin but not growth hormone.


Optimal sedation in pediatric intensive care patients: a systematic review.
Sedatives administered to critically ill children should be titrated to effect, because both under- and oversedation may have negative effects. We conducted a systematic review to examine reported incidences of under-, optimal, and oversedation in critically ill children receiving intensive care. A systematic literature search using predefined criteria was performed in PubMed and Embase to identify all articles evaluating level of sedation in PICU patients receiving continuous sedation. Two authors independently recorded: study objective, study design, sample size, age range, details of study intervention (if applicable), sedatives used, length of sedation, sedation scale used, and incidences of optimal, under-, and oversedation as defined in the studies. Twenty-five studies were included. Two studies evaluated sedation level as primary study outcome; the other 23 as secondary outcomes. Together, these studies investigated 1,163 children; age range, 0-18 years. Across studies, children received many different sedative agents and sedation level was assessed with 12 different sedation scales. Optimal sedation was ascertained in 57.6 % of the observations, under sedation in 10.6 %, and oversedation in 31.8 %. This study suggests that sedation in the PICU is often suboptimal and seldom systematically evaluated. Oversedation is more common than undersedation. As oversedation may lead to longer hospitalization, tolerance, and withdrawal, preventing oversedation in pediatric intensive care deserves greater attention.


Off-Pump versus Conventional Coronary Artery Bypass Grafting: A Meta-Analysis and Consensus Statement From The 2004 ISMICS Consensus Conference.
: The purpose of this evidence-based consensus statement is to systematically review and meta-analyze the randomized and nonrandomized evidence comparing off-pump (OPCAB) to conventional coronary artery bypass (CCAB) surgery and to provide consensus on the role of OPCAB in low- and high-risk surgical patients. : This consensus conference was conducted according to the American College of Cardiology (ACC)/American Heart Association (AHA) standards for development of clinical practice guidelines. The Steering Committee collated all published studies of OPCAB versus CCAB through May 2004 and developed six questions central to controversies surrounding OPCAB surgery in mortality, morbidity, and resource utilization. For mixed-risk patient populations, meta-analysis of 37 randomized clinical trials (3,369 patients, Level A) reported across a total of 53 papers, and two meta-analyses of nonrandomized trials (Level B) comparing OPCAB versus CCAB were identified. For high-risk patient populations, we performed a meta-analysis of 3 randomized and 42 nonrandomized trials (26,349 patients, Level B). : Meta-analysis of Level A and B evidence provided the basis for the following consensus statements in patients undergoing surgical myocardial revascularization: (1) OPCAB should be considered a safe alternative to CCAB with respect to risk of mortality [Class I, Level A]; (2) With appropriate use of modern stabilizers, heart positioning devices, and adequate surgeon experience, similar completeness of revascularization and graft patency can be achieved [Class IIa, Level A]; (3) OPCAB is recommended to reduce perioperative morbidity [Class I, Level A]; (4) OPCAB may be recommended to minimize midterm cognitive dysfunction [Class IIa, Level A]; (5) OPCAB should be considered as an equivalent alternative to CCAB in regard to quality of life [Class I, Level A]; (6) OPCAB is recommended to reduce the duration of ventilation, ICU and hospital stay, and resource utilization [Class I, Level A]; (7) OPCAB should be considered in high-risk patients to reduce perioperative mortality, morbidity, and resource utilization [Class IIa, Level B].


Endovascular repair of abdominal aortic aneurysm.
An abnormal dilatation of the abdominal aorta is referred to as an abdominal aortic aneurysm (AAA). Due to the risk of rupture, surgical repair is offered electively to individuals with aneurysms greater than 5.5 cm in size. Traditionally, conventional open surgical repair (OSR) was considered the first choice approach. However, over the past two decades endovascular aneurysm repair (EVAR) has gained popularity as a treatment option. This article intends to review the role of EVAR in the management of elective AAA. To assess the effectiveness of EVAR versus conventional OSR in individuals with AAA considered fit for surgery, and EVAR versus best medical care in those considered unfit for surgery. This was determined by the effect on short, intermediate and long-term mortality, endograft related complications, re-intervention rates and major complications. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12). The TSC also searched trial databases for details of ongoing or unpublished studies. Prospective randomised controlled trials (RCTs) comparing EVAR with OSR in individuals with AAA considered fit for surgery. and comparing EVAR with best medical care in individuals considered unfit for surgery. We excluded studies with inadequate data or using an inadequate randomisation technique. Three reviewers independently evaluated trials for appropriateness for inclusion and extracted data using pro forma designed by the Cochrane PVD Group. We assessed the quality of trials using The Cochrane Collaboration's 'Risk of bias' tool. We entered collected data in to Review Manager (version 5.2.3) for analysis. Where direct comparisons could be made, we determined odds ratios (OR). We tested studies for heterogeneity and, when present, we used a random-effects model; otherwise we used a fixed-effect model. We tabulated data that could not be collated. Four high-quality trials comparing EVAR with OSR (n = 2790) and one high-quality trial comparing EVAR with no intervention (n = 404) fulfilled the inclusion criteria. In individuals considered fit for surgery, a pooled analysis, including 1362 individuals randomised to EVAR and 1361 randomised to OSR, found short-term mortality (including 30-day or inhospital mortality, excluding deaths prior to intervention) with EVAR to be significantly lower than with OSR (1.4% versus 4.2%, OR 0.33, 95% confidence interval (CI) 0.20 to 0.55; P < 0.0001). Using intention-to-treat analysis (ITT) there was no significant difference in mortality at intermediate follow-up (up to four years from randomisation), with 221 (15.8%) and 237 (17%) deaths in the EVAR (n = 1393) and OSR (n = 1390) groups, respectively (OR 0.92, 95% CI 0.75 to 1.12; P = 0.40). There was also no significant difference in long-term mortality (beyond four years), with 464 (37.3%) deaths in the EVAR and 470 (37.8%) deaths in the OSR group (OR 0.98, 95% CI 0.83 to 1.15; P = 0.78). Similarly, there was no significant difference in aneurysm-related mortality between groups, either at the intermediate- or long-term follow up.Studies showed that both EVAR and OSR were associated with similar incidences of cardiac deaths (OR 1.14, 95% CI 0.86 to 1.52; P = 0.36) and fatal stroke rate (OR 0.81, 95% CI 0.42 to 1.55; P = 0.52). The long-term reintervention rate was significantly higher in the EVAR group than in the OSR group (OR 1.98, 95% CI 1.12 to 3.51; P = 0.02; I(2) = 85%). Results of the reintervention analysis should be interpreted with caution due to significant heterogeneity. Operative complications, health-related quality of life and sexual dysfunction were generally comparable between the EVAR and OSR groups. However, there was a slightly higher incidence of pulmonary complications in the OSR group compared with the EVAR group (OR 0.36, 95% CI 0.17 to 0.75; P = 0.006).In individuals considered unfit for conventional OSR, the one included trial found no difference between the EVAR and no-intervention groups with regard to all-cause mortality at final follow up, with 21.0 deaths per 100 person-years in the EVAR group and 22.1 deaths per 100 person years in the no-intervention group (adjusted hazard ratio (HR) with EVAR 0.99, 95% CI 0.78 to 1.27; P = 0.97). Aneurysm-related deaths were, however, significantly higher in the no-intervention group than in the EVAR group (adjusted HR 0.53, 95% CI 0.32 to 0.89; P = 0.02). There was no difference in myocardial events (HR 1.07, 95% CI 0.60 to 1.91) between the groups in this study. In individuals considered fit for conventional surgery, EVAR was associated with lower short-term mortality than OSR. However, this benefit from EVAR did not persist at the intermediate- and long-term follow ups. Individuals undergoing EVAR had a higher reintervention rate than those undergoing OSR. Most of the reinterventions undertaken following EVAR, however, were catheter-based interventions associated with low mortality. Operative complications, health-related quality of life and sexual dysfunction were generally comparable between EVAR and OSR. However, there was a slightly higher incidence of pulmonary complications in the OSR group than in the EVAR group.In individuals considered unfit for open surgery, the results of a single trial found no overall short- or long-term benefits of EVAR over no intervention with regard to all-cause mortality, but individuals may differ and individual preferences should always be taken into account.


Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells.
Endoglin (CD105) is a membrane glycoprotein that is mutated in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and shows increased expression in proliferating endothelial cells during angiogenesis. We investigated the effect of hypoxia on endoglin expression in murine cerebral microvascular endothelial (bEND.3) cells in vitro and the possible involvement of mitogen-activated protein kinase (MAPK) pathways. Hypoxia increased endoglin mRNA and protein expression in bEND.3 cells, which was associated with phosphoactivation of extracellular signal-related kinase (ERK), p38 MAPK, and Jun amino-terminal kinase (JNK). Inhibitors of p38 decreased hypoxic induction of endoglin expression, as did dominant negative MAPK kinase 3 (MKK3), which activates p38. In contrast, constitutively active MKK3 or JNK1 potentiated the hypoxic induction of endoglin. These results indicate that hypoxia induces the expression of endoglin at both the mRNA and protein levels and that induction is regulated by the p38 and perhaps also JNK pathways.


Modeling the obesity epidemic: social contagion and its implications for control.
As an obesity epidemic has grown worldwide, a variety of intervention programs have been considered, but a scientific approach to comparatively assessing the control programs has still to be considered. The present study aims to describe an obesity epidemic by employing a simple mathematical model that accounts for both social contagion and non-contagious hazards of obesity, thereby comparing the effectiveness of different types of interventions. An epidemiological model is devised to describe the time- and age-dependent risk of obesity, the hazard of which is dealt with as both dependent on and independent of obesity prevalence, and parameterizing the model using empirically observed data. The equilibrium prevalence is investigated as our epidemiological outcome, assessing its sensitivity to different parameters that regulate the impact of intervention programs and qualitatively comparing the effectiveness. We compare the effectiveness of different types of interventions, including those directed to never-obese individuals (i.e. primary prevention) and toward obese and ex-obese individuals (i.e. secondary prevention). The optimal choice of intervention programs considerably varies with the transmission coefficient of obesity, and a limited transmissibility led us to favour preventing weight gain among never-obese individuals. An abrupt decline in the prevalence is expected when the hazards of obesity through contagious and non-contagious routes fall into a particular parameter space, with a high sensitivity to the transmission potential of obesity from person to person. When a combination of two control strategies can be selected, primary and secondary preventions yielded similar population impacts and the superiority of the effectiveness depends on the strength of the interventions at an individual level. The optimality of intervention programs depends on the contagiousness of obesity. Filling associated data gaps of obesity transmission would help systematically understand the epidemiological dynamics and consider required control programs.


The most exposed regions of SARS-CoV-2 structural proteins are subject to strong positive selection and gene overlap may locally modify this behavior.
We have analyzed the selection pressure of all severe acute respiratory syndrome coronavirus 2 genes by means of the nonsynonymous (Ka) to synonymous (Ks) substitution rate. We found that protein-coding genes are exposed to strong positive selection, especially in the regions of interaction with other molecules (host receptor and genome of the virus itself). However, overlapping coding regions are more protected and show negative selection. This suggests that this measure could be used to study viral gene function as well as overlapping genes.


Treatment of unstable thoracolumbar burst fractures by indirect reduction and posterior stabilization: short-segment versus long-segment stabilization.
In order to compare short-segment stabilization with long-segment stabilization for treating unstable thoracolumbar fractures, we studied fifty patients suffered from unstable thoracolumbar burst fractures. Thirty of them were managed with long-segment posterior transpedicular instrumentation and twenty patients with short-segment stabilization. The mean follow up period was 5.2 years. Pre-operative and post-operative radiological parameters, like the Cobb angle, the kyphotic deformation and the Beck index were evaluated. A statistically significant difference between the two under study groups was noted for the Cobb angle and the kyphotic deformation, while, as far as the Beck index is concerned, no significant difference was noted. In conclusion, either the long-segment or the short-segment stabilization is able for reducing the segmental kyphosis and the vertebral body deformation postoperatively. However, as time goes by, the long-segment stabilization is associated with better results as far as the radiological parameters, the indexes and the patient's satisfaction are concerned.


Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs.
Tissue factor (TF) is the main activator of the coagulation cascade occurring in physiologic and pathologic conditions. Recent data suggest that human platelets might contain TF that is possibly derived from leukocytes. In this study, we investigated whether intraplatelet TF can be exposed on the membrane by platelet agonists. The modulation of this process by antiplatelet drugs has been evaluated as well. Flow cytometric analysis of unstimulated platelets showed a small amount of membrane-associated immunoreactive TF (irTF) in whole blood, platelet-rich plasma, and washed platelets isolated from healthy subjects. ADP, thrombin receptor-activating peptide, and epinephrine significantly increased functionally active, membrane-associated irTF. ADP induced irTF exposure in a concentration- and time-dependent fashion. Agonist-induced irTF expression was completely inhibited by iloprost but not by aspirin. Interestingly, glycoprotein IIb/IIIa antagonists did not inhibit but rather potentiated the stimulatory effect of ADP on platelet irTF expression. Real-time polymerase chain reaction experiments showed detectable amounts of TF mRNA in unstimulated platelets. These findings indicate that platelet agonists and antiplatelet drugs might modulate platelet-associated irTF expression. Regulated TF expression establishes the potential for a previously unrecognized role for platelets in sustaining thrombus formation and growth via coagulation-mediated mechanisms.


RELMα is Induced in Airway Epithelial Cells by Oncostatin M Without Requirement of STAT6 or IL-6 in Mouse Lungs In Vivo.
Resistin-like molecule alpha (RELMα) and YM-1 are secreted proteins implicated in murine models of alternatively activated macrophage (AA/M2) accumulation and Th2-skewed inflammation. Since the gp130 cytokine Oncostatin M (OSM) induces a Th2-like cytokine and AA/M2 skewed inflammation in mouse lung, we here investigated regulation of RELMα and YM-1. Transient pulmonary overexpression of OSM by Adenovirus vector (AdOSM) markedly induced RELMα and YM-1 protein expression in total lung. In situ hybridization showed that RELMα mRNA was highly induced in airway epithelial cells (AEC) and was co-expressed with CD68 mRNA in some but not all CD68+ cells in parenchyma. IL-6 overexpression (a comparator gp130 cytokine) induced RELMα, but at significantly lower levels. IL-6 (assessing IL-6-/- mice) was not required, nor was STAT6 (IL-4/13 canonical signalling) for AdOSM-induction of RELMα in AEC. AEC responded directly to OSM in vitro as assessed by pSTAT3 activation. RELMα-deficient mice showed similar inflammatory cell infiltration and cytokine responses to wt in response to AdOSM, but showed less accumulation of CD206+ AA/M2 macrophages, reduced induction of extracellular matrix gene mRNAs for COL1A1, COL3A1, MMP13, and TIMP1, and reduced parenchymal alpha smooth muscle actin. Thus, RELMα is regulated by OSM in AEC and contributes to extracellular matrix remodelling in mouse lung.


Considerations for using the 'brown bag' strategy to reconcile medications during routine outpatient office visits.
Among medication reconciliation studies, varying methods are used to determine which medications patients are actually taking. One recommended approach is to ask patients to "brown bag" their medications for routine office visits. To determine if 'brown bag' practices performed during routine office visits improve the accuracy of provider-documented medication lists. This cross-sectional pilot study was conducted in a university affiliated community geriatric clinic. Forty-six cognitively intact elders who managed their own medications enrolled. Participants self-selected into two groups: 'brown-baggers' (BBs) and 'non-brown-baggers' (NBBs). Three medication lists were compared for each patient: provider-documented in patient's chart (chart list); researcher-generated by post-appointment semistructured interview (point-of-care [POC] list); post-appointment semi-structured telephone interview (telephone list, reference standard). Accuracy of chart and POC lists were compared with reference lists among BBs and NBBs. Thirty-three (72%) patients brought some of their medications to scheduled appointments (BBs); of these, 39% bagged all of their medications. Excluding route as a variable, 35% of provider-documented chart lists were complete; only 6.5% were accurate. Some 76% of chart-documented medication lists contained inclusion, omission and/or dosing instruction discrepancies, with no differences between BBs and NBBs. However, POC lists obtained using a semi-structured interview included fewer inclusion and omission discrepancies among BBs than NBBs (42% v 77%, P = 0.05). In subset analyses by medication type, over-the-counter (OTC) medication documentation was more accurate among BBs than NBBs. Overall, chart lists contained two to three times more discrepancies than lists generated at POC. Most BBs do not bag all their medications for office visits. Chart list accuracy is no better among BBs than NBBs, although patients who 'brown bag' their medications for office visits may prompt providers to conduct a more thorough medication history. Lists generated by semistructured interviewing, regardless of BB status, are more accurate than chart lists. Findings challenge benefits of the 'brown bag' unless coupled with in-depth questioning and processes for transferring information to chart lists.


Spatial and temporal immunocytochemical analysis of drosulfakinin (Dsk) gene products in the Drosophila melanogaster central nervous system.
The spatial and temporal distribution of three peptides, DSK I, DSK II, and DSK 0, encoded by the Drosophila melanogaster drosulfakinin (Dsk) gene, have been examined in the central nervous system. DSK I and DSK II have a -RFamide C-terminus and are structurally similar to sulfakinin peptides; in contrast, DSK 0 contains -SFamide and is not structurally similar to sulfakinins. Antisera specificities were determined by the design of the antigens and confirmed by dot blot analysis and preincubation with peptides prior to their use in immunocytochemistry. The distribution of immunoreactivity suggests that all three DSK peptides are processed from the polypeptide precursor and expressed in many of the same cells. Expression was observed at all developmental stages with an increase in the level of staining and the number of immunoreactive cells as development progresses. Cells in the brain lobe, optic lobe, subesophageal ganglion, thoracic ganglia, and the eighth abdominal neuromere contain DSK-immunoreactive materials. Immunoreactive fibers project from some cells and extend into the brain and ventral ganglion with regions of extensive arborization. DSK 0 immunoreactivity provides initial evidence for the presence of a -SFamide peptide in neural tissue. The observed expression of DSK-immunoreactive materials throughout development in numerous cells of the central nervous system suggests that DSK peptides may serve as hormones, modulators, or transmitters involved in several functions.


Tunable picosecond blue and ultraviolet pulses from a diode-pumped laser system seeded by a gain-switched laser diode.
Picosecond pulses emitted from a gain-switched laser diode have been amplified in a Ti:sapphire regenerative amplifier indirectly pumped by a 4-W laser diode. This all-solid-state system produced microjoule pulses tunable from 803 to 840 nm at repetition rates up to 25 kHz with durations of 70-100 ps. By frequency doubling and tripling the output, we generated blue and UV pulses tunable from 401 to 420 nm and from 268 to 280 nm, respectively. Average powers larger than 4 mW were reached in these two wavelength regions.


iPod™ technology for teaching patients about anticoagulation: a pilot study of mobile computer-assisted patient education.
To determine whether an educational strategy using a handheld, multimedia computer (iPod™) is practical and sustainable for routine office-based patient educational tasks. With the limited amount of time allotted to the office encounter and the growing number of patient educational tasks, new strategies are needed to improve the efficiency of patient education. Education of patients anticoagulated with warfarin is considered critical to preventing complications. Despite the dangers associated with the use of warfarin, educational practices are variable and often haphazard. During a four-month period, we examined the implementation of a three-part series of iPod™-based patient educational modules delivered to anticoagulated patients at the time of routine INR (International Normalized Ratio) blood tests for outpatients on the anticoagulation registry at an urban community health center. A total of 141 computer module presentations were delivered to 91 patients during the four-month period. In all, 44 patients on the registry had no INR checkups, and thus no opportunity to view the modules, and 32 patients had at least three INR checkups but no modules were documented. Of the 130 patients with at least one INR performed during the study period, 22 (16.9%) patients completed all three modules, 91 (70.0%) patients received at least one module, and nine (7.6%) patients refused to view at least one module. Neither of the two handheld computers was lost or stolen, and no physician time was used in this routine educational activity. Patients reported that the audio and visual quality was very good, (9.0/10); the educational experience of the patient was helpful (7.4/10) compared with the patient's previous warfarin education (6.3/10), and the computer strategy extended the INR visit duration by 1-5 min at most. The computer-assisted patient educational strategy was well received by patients, and uptake of the intervention by the clinic was successful and durable. The iPod™ strategy standardized the educational message, improved clinic efficiency, and helped this busy clinic meet its educational goals for patient education.


A Drosophila model of combined D-2- and L-2-hydroxyglutaric aciduria reveals a mechanism linking mitochondrial citrate export with oncometabolite accumulation.
The enantiomers of 2-hydroxyglutarate (2HG) are potent regulators of metabolism, chromatin modifications and cell fate decisions. Although these compounds are associated with tumor metabolism and commonly referred to as oncometabolites, both D- and L-2HG are also synthesized by healthy cells and likely serve endogenous functions. The metabolic mechanisms that control 2HG metabolism in vivo are poorly understood. One clue towards how cells regulate 2HG levels has emerged from an inborn error of metabolism known as combined D- and L-2HG aciduria (D-/L-2HGA), which results in elevated D- and L-2HG accumulation. Because this disorder is caused by mutations in the mitochondrial citrate transporter (CIC), citrate must somehow govern 2HG metabolism in healthy cells. The mechanism linking citrate and 2HG, however, remains unknown. Here, we use the fruit fly Drosophila melanogaster to elucidate a metabolic link between citrate transport and L-2HG accumulation. Our study reveals that the Drosophila gene scheggia (sea), which encodes the fly CIC homolog, dampens glycolytic flux and restricts L-2HG accumulation. Moreover, we find that sea mutants accumulate excess L-2HG owing to elevated lactate production, which inhibits L-2HG degradation by interfering with L-2HG dehydrogenase activity. This unexpected result demonstrates that citrate indirectly regulates L-2HG stability and reveals a feedback mechanism that coordinates L-2HG metabolism with glycolysis and the tricarboxylic acid cycle. Finally, our study also suggests a potential strategy for preventing L-2HG accumulation in human patients with CIC deficiency.This article has an associated First Person interview with the first author of the paper.


Supported cell mimetic monolayers and their interaction with blood.
Surface modification using supported monolayers of phosphorylcholine containing phospholipids has been an accepted strategy for developing blood-contacting materials. We present a detailed study of the blood compatibility of the supported monolayers of phospholipid, glycolipid, and cholesterol (Chol) binary and ternary lipid combinations using in vitro techniques. The packing and orientation of these monolayers have been correlated with the blood compatibility. We have used phosphatidylcholine (PTC) for phospholipid, galactocerebroside (Gal) for glycolipid, and Chol based on the headgroup structure to represent the major lipid components of the endothelial luminal cell membrane. The interfacial behavior of various combinations of PTC, Gal, and Chol monolayers have been studied at the air/water interface and deposited on hydrophobic polycarbonate (PC) polymer substrates with the help of the Langmuir-Blodgett trough. The packing and orientation of the supported monolayers have been varied by means of changing the lipid composition rather than the deposition parameters. This approach seems to be more similar to the in vivo conditions. The different supported monolayer surfaces prepared accordingly are (1) a closely packed ordered hydrophobic surface, PC modified with the combination PTC/Chol/Gal (1:0.35:0.125), (2) a loosely packed ordered hydrophobic surface, PC modified with the combination PTC/Chol (1:0.35), and (3) a closely packed ordered hydrophilic surface, PC modified with the combination PTC/Chol (1:0.7). An optimized modified surface (PTC/Chol/Gal, 1:0.35:0.125) has been identified on the basis of the maximum transfer ratio from the air/water interface and characterized by using atomic force microscopy. The concentration of Chol has been found to be an important parameter, which influences the transfer ratio. The Gal improves the monolayer integrity under a reduced Chol concentration. The blood compatibility of these supported monolayers was studied by protein adsorption, blood cell adhesion, and calcification. The tightly packed ordered hydrophobic surface (PTC/Chol/Gal, 1:0.35:0.125), has been found to be more blood compatible because of reduced blood cell adhesion and calcification. This surface also promotes albumin adsorption and may be the reason for the reduced platelet activation, while in the case of the loosely packed ordered hydrophobic surface (PTC/Chol, 1:0.35) the protein adsorption also has been reduced along with the blood cell adhesion and calcification. When the ordered hydrophilic surface (PTC/Chol, 1: 0.7) of the monolayer has been exposed, the blood cell adhesions as well as the overall protein adsorption were significantly reduced. However, the packing of the phosphorylcholine moieties of the polar headgroup has been affecting the calcification on the surface. We have observed an increase in calcification to the surface modified with the loosely packed polar headgroup, from a relative study on chitosan and chitosan modified with the monolayer of PTC. These findings are helpful for the surface modifications for blood-contacting materials using this strategy.


Multi-Institution Validation of an Emergency Ultrasound Image Rating Scale-A Pilot Study.
As bedside ultrasound (BUS) is being increasingly taught and incorporated into emergency medicine practice, measurement of BUS competency is becoming more important. The commonly adopted experiential approach to BUS competency has never been validated on a large scale, and has some limitations by design. Our aim was to introduce and report preliminary testing of a novel emergency BUS image rating scale (URS). Gallbladder BUS was selected as the test case. Twenty anonymous BUS image sets (still images and clips) were forwarded electronically to 16 reviewers (13 attendings, 3 fellows) at six training sites across the United States. Each reviewer rated the BUS sets using the pilot URS that consisted of three components, with numerical values assigned to each of the following aspects: Landmarks, Image Quality, and Annotations. Reviewers also decided whether or not each BUS set would be "Clinically Useful." Kendall τs were calculated as a measure of concordance among the reviewers. Among the 13 attendings, image review experience ranged from 2-15 years, 5-300 scans per week, and averaged 7.8 years and 60 images. Kendall τs for each aspect of the URS were: Landmarks: 0.55; Image Quality: 0.57; Annotation: 0.26; Total Score: 0.63, and Clinical Usefulness: 0.45. All URS elements correlated significantly with clinical usefulness (p < 0.001). The correlation coefficient between each attending reviewer and the entire group ranged from 0.48-0.69, and was independent of image review experience beyond fellowship training. Our novel URS had moderate-to-good inter-rater agreement in this pilot study. Based on these results, the URS will be modified for use in future investigations.


Late life gambling: the attitudes and behaviors of older adults.
For a significant number of retired older adults (aged 65+), gambling has become a new form of recreation and entertainment. While prevalence studies have examined the incidence of problem gambling in other age groups, little research attention has been paid to the impact of gambling on older adults since the increase in availability and accessibility of legalized gambling within the last ten years. This study investigated the prevalence of problem gambling behaviors (SOGS-R), depression (GDS-15), levels of life satisfaction (SWLS), and motivations for gambling among older adults. A total of 315 older adults completed the study questionnaire and were grouped and analyzed according to those sampled from gambling venues and those from within the community. Results of the study found the most frequent accession and spending on several types of gambling occurred among older adults who were sampled at gambling venues. Older adults who were sampled at gambling venues were also found more likely to have higher levels of disordered gambling than older adults from the community, as measured by the SOGS-R. Relaxation, boredom, passing time, and getting away for the day were also the most likely reported motivations for the older adults who were gambling patrons. These findings provide an initial profile of older adults and their attitudes, motivations and gambling behaviors.