The Association of Hispanic Ethnicity with Nonalcoholic Fatty Liver Disease in Polycystic Ovary Syndrome.
Polycystic Ovary Syndrome (PCOS) affects 10-15% of reproductive age women and is a recognized risk factor for nonalcoholic fatty liver disease (NAFLD). The more severe form of NAFLD, known as nonalcoholic steatohepatitis (NASH), results in liver inflammation with or without fibrosis, and is now a leading cause of cirrhosis. Ethnic differences are apparent in NAFLD, with higher prevalence in Hispanics, although the role of Hispanic ethnicity on risk for NAFLD/NASH in women with PCOS is not known. The aim of this study was to evaluate ethnic differences in the prevalence and risk of NAFLD/NASH in women with PCOS. Among PCOS women followed in a large academic medical center the association of Hispanic ethnicity with elevated biomarkers of NASH, including plasma cytokeratin 18 (CK18) M30 fragments and/or ALT levels (n=303), was assessed. Prevalence of hepatic steatosis by Controlled Attenuation Parameter (CAP) imaging was also evaluated in a subset of PCOS women (n=35). The median cohort age (n=303) was 28 years (IQR 8), and 15.5% (n=47) were Hispanic, the majority of whom reported white race (94%). Most Hispanic women had hepatic steatosis on imaging, which was markedly higher than in non-Hispanics (83% vs 24%, p=0.005). Approximately 17% of PCOS women had elevated ALT or elevated CK18, which was more common in Hispanics than non-Hispanics, at 34% vs 14%, respectively, p=0.002. On univariate analysis, Hispanic ethnicity was associated with two-fold higher odds of NASH (OR 2.0, 95% CI 1.0-3.9, p=0.038), and the association persisted after adjustment for HOMA-IR and waist circumference (AOR 3.1, 95% CI 1.1-8.9, p=0.034). NAFLD/NASH is an important condition to be considered by PCOS providers and Hispanic women with PCOS are a particularly high-risk group that may warrant routine screening.


Novel endothelin receptors in the follicular membranes of Xenopus laevis oocytes mediate calcium responses by signal transduction through gap junctions.
Follicular oocytes from Xenopus laevis display saturable and high affinity endothelin (ET)-1 binding sites. Competition binding experiments using unlabeled ET-1, ET-3, and sarafotoxin 6c indicated that these ET receptors belong to the ETA receptor subtype. However, the ETA receptor-selective antagonist BQ123 [cyclo(D-Trp,D-Asp,L-Pro,D-Val,L-Leu)] failed to inhibit 125I-ET-1 binding to these receptors, suggesting that these receptors belong to a novel subtype of ETA receptors (ETAX) distinct from the human ETA receptors. These endogenous receptors are present in the follicular layer, because defolliculated oocytes did not show any 125I-ET-1 binding. Addition of ET-1 to follicular oocytes led to Ca2+ mobilization, which was reversibly blocked by treatments that uncouple gap junctions, suggesting that these ETAX receptors mediate their response by transferring signals through gap junctions. On the other hand, the expressed human ETA receptor-mediated Ca2+ mobilization was not blocked by inhibitors of gap junctions. In agreement with the binding data, the endogenous ETAX receptor-mediated response was not inhibited by BQ123 even at 100 nM, whereas the expressed human ETA receptor-mediated response was inhibited by 50% at concentrations as low as 10 nM. This further confirms that the amphibian ETAX receptors are different from mammalian ETA receptors. Finally, ET-1 enhanced the rate of progesterone-induced maturation of follicular oocytes, implying the involvement of these endogenous ETAX receptors in an in vivo maturation process.


Randomized clinical trial of total extraperitoneal inguinal hernioplasty vs Lichtenstein repair: a long-term follow-up study.
Mesh repair is generally preferred for surgical correction of inguinal hernia, although the merits of endoscopic techniques over open surgery are still debated. Herein, minimally invasive total extraperitoneal inguinal hernioplasty (TEP) was compared with Lichtenstein repair to determine if one is associated with less postoperative pain, hypoesthesia, and hernia recurrence. Prospective multicenter randomized clinical trial. Academic research. Six hundred sixty patients were randomized to TEP or Lichtenstein repair. The primary outcome was postoperative pain. Secondary end points were hernia recurrence, operative complications, operating time, length of hospital stay, time to complete recovery, quality of life, chronic pain, and operative costs. At 5 years after surgery, TEP was associated with less chronic pain (P = .004). Impairment of inguinal sensibility was less frequently seen after TEP vs Lichtenstein repair (1% vs 22%, P < .001). Operative complications were more frequent after TEP vs Lichtenstein repair (6% vs 2%, P < .001), while no difference was noted in length of hospital stay. After TEP, patients had faster time to return to daily activities (P < .002) and less absence from work (P = .001). Although operative costs were higher for TEP, total costs were comparable for the 2 procedures, as were overall hernia recurrences at 5 years after surgery. However, among experienced surgeons, significantly lower hernia recurrence rates were seen after TEP (P < .001). In the short term, TEP was associated with more operative complications, longer operating time, and higher operative costs; however, total costs were comparable for the 2 procedures. Chronic pain and impairment of inguinal sensibility were more frequent after Lichtenstein repair. Although overall hernia recurrence rates were comparable for both procedures, hernia recurrence rates among experienced surgeons were significantly lower after TEP. Patient satisfaction was also significantly higher after TEP. Therefore, TEP should be recommended in experienced hands. Trial Registration clinicaltrials.gov Identifier: NCT00788554.


Variation in early life maternal care predicts later long range frontal cortex synapse development in mice.
Empirical and theoretical work suggests that early postnatal experience may inform later developing synaptic connectivity to adapt the brain to its environment. We hypothesized that early maternal experience may program the development of synaptic density on long range frontal cortex projections. To test this idea, we used maternal separation (MS) to generate environmental variability and examined how MS affected 1) maternal care and 2) synapse density on virally-labeled long range axons of offspring reared in MS or control conditions. We found that MS and variation in maternal care predicted bouton density on dorsal frontal cortex axons that terminated in the basolateral amygdala (BLA) and dorsomedial striatum (DMS) with more, fragmented care associated with higher density. The effects of maternal care on these distinct axonal projections of the frontal cortex were manifest at different ages. Maternal care measures were correlated with frontal cortex → BLA bouton density at mid-adolescence postnatal (P) day 35 and frontal cortex → DMS bouton density in adulthood (P85). Meanwhile, we found no evidence that MS or maternal care affected bouton density on ascending orbitofrontal cortex (OFC) or BLA axons that terminated in the dorsal frontal cortices. Our data show that variation in early experience can alter development in a circuit-specific and age-dependent manner that may be relevant to understanding the effects of early life adversity.


A Pt(0) complex with cyclic (alkyl)(amino)silylene and 1,3-divinyl-1,1,3,3-tetramethyldisiloxane ligands: synthesis, molecular structure, and catalytic hydrosilylation activity.
A platinum(0) complex bearing a cyclic (alkyl)(amino)silylene and a 1,3-divinyl-1,1,3,3-tetramethyldisiloxane (DVTMS) was synthesized and isolated in the form of colorless crystals. The single-crystal X-ray diffraction analysis of this complex in combination with theoretical calculations indicated that the Pt→Si π-back-donation in this complex is weaker than that in the corresponding cyclic-dialkylsilylene-ligated Pt complex. The performance of this complex in the catalytic hydrosilylation of (Me3SiO)2MeSi-H with various terminal alkenes that contain functional groups was comparable to that of the corresponding cyclic dialkylsilylene/DVTMS Pt(0) complex.


Importance of canine distemper virus (CDV) infection in free-ranging Iberian lynxes (Lynx pardinus).
Canine distemper virus (CDV) is a morbillivirus that is the etiological agent of one of the most important viral diseases affecting canids and an expanding range of other carnivores. Using real-time RT-PCR, CDV RNA was detected in organs of an Iberian lynx (Lynx pardinus) found dead in the Doñana National Park, Southwestern Andalusia, Spain. This finding may be of great importance for the conservation of the species; at present the Iberian lynx is the most critically endangered wild felid. The aim of the present study was to elucidate the significance of CDV for the Iberian lynx population. High viral loads were evident in the dead lynx, suggesting an etiological involvement of CDV in its death. When carnivores from the same region were analyzed by CDV RT-PCR, a stone marten (Martes foina) was positive. Phylogenetic analyses demonstrated high identity of the two detected CDVs and a close relationship to the European dog lineage of CDV. Antibodies to CDV were detected in 14.8% of 88 tested free-ranging Iberian lynxes. The sample seroprevalence was significantly higher in lynxes from the Doñana Natural Space (22.9%) than Sierra Morena (5%). The stone marten and a red fox (Vulpes vulpes) also tested seropositive. In conclusion, CDV is present in the Iberian lynx population, especially in the Doñana region, with sporadic cases of disease. To reduce the infectious pressure of CDV on this endangered population, a mass dog vaccination should be considered.


Implementing AACN's Healthy Work Environment Framework in an Intensive Care Unit.
Bedside nurse turnover in the United States is 15.9%, representing a national challenge that has been attributed to poor work environments. Healthy work environments are associated with improved nurse satisfaction and retention as well as positive patient outcomes; unhealthy work environments have the opposite effects. To implement the American Association of Critical-Care Nurses (AACN) healthy work environment (HWE) framework in an intensive care unit and to evaluate staff satisfaction, turnover, and tenure 2 years later. A pre-post study design was used to evaluate implementation of the HWE framework in an intensive care unit in a large academic medical facility. Interventions for each of the 6 HWE standards were performed. The AACN HWE assessment survey was used to measure skilled communication, true collaboration, effective decision-making, appropriate staffing, meaningful recognition, and authentic leadership in 2017 and in 2019. Nurse cohorts (n = 165 in 2017; n = 176 in 2019) had a mean age of 31 (median, 27; range, 23-63) years, were predominantly female (76%), and had a mean of 5 (median, 3) years of intensive care unit nursing experience. Statistically significant improvements were found in all standards except the skilled communication and overall measures. Registered nurse turnover remained stable and tenure increased by 79 days in this 2-year period. Findings from this study suggest that interventions addressing the HWE standards are associated with improved staff satisfaction, turnover, and average tenure, further demonstrating the value of the HWE framework in improving retention.


Paramedic-initiated helivac to tertiary hospital for primary percutaneous coronary intervention: a strategy for improving treatment delivery times.
In regions of New Zealand without coronary catheterisation laboratory (CCL) facilities, patients presenting with ST-elevation myocardial infarction (STEMI) are often subjected to prolonged delays before receiving primary percutaneous coronary intervention (PPCI) if it is the chosen reperfusion strategy. Therefore, we aimed to trial a new process of paramedic-initiated helivac of STEMI patients from the field directly to the CCL. Utilising a prospective observational approach, over a 48-month period, paramedics identified patients with a clinical presentation and electrocardiogram features consistent with STEMI and transported them directly to the regional air ambulance base for helivac to the CCL (flight time 30-35 minutes). These patients were compared to two historic STEMI cohorts either transported by paramedics to the region's local hospital or self-presenting, prior to helivac. The primary outcome measures were: first medical contact-to-balloon (FMCTB) time and accuracy of paramedic diagnosis. Secondary outcome measures were mortality at 30 days and six months, and hospital length of stay (LOS). A total of 92 patients underwent helivac for PPCI (mean age of 64 years, SD ±10.3). Median FMCTB time was 155 minutes (IQR 27) for the historic cohorts (n=57), versus 102 minutes (IQR 16) for the experimental cohort (n=35, P<0.001). Paramedic diagnosis showed a sensitivity of 97% (95% CI: 85 to 99) and a specificity of 100% (95% CI: 84 to 100) with no inappropriate CCL activations. No significant difference was observed between groups in terms of 30 day and 6-month mortality. Hospital LOS was significantly shorter among the experimental cohort (P=0.01). Paramedic-initiated helivac of STEMI patients from the field directly to the CCL for PPCI is safe and feasible and can significantly improve time-to-treatment to within benchmark timeframes, resulting in reduced hospital LOS.


Adipose, Bone, and Myeloma: Contributions from the Microenvironment.
Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90 % of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes, and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.


Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis.
Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Multiple databases from database inception to February 24, 2021. Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.


Chemotherapy synergizes with radioimmunotherapy targeting La autoantigen in tumors.
To date, inefficient delivery of therapeutic doses of radionuclides to solid tumors limits the clinical utility of radioimmunotherapy. We aim to test the therapeutic utility of Yttrium-90 ((90)Y)-radio-conjugates of a monoclonal antibody, which we showed previously to bind specifically to the abundant intracellular La ribonucleoprotein revealed in dead tumor cells after DNA-damaging treatment. Immunoconjugates of the DAB4 clone of the La-specific monoclonal antibody, APOMAB, were prepared using the metal chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and then radiolabeled with (90)Y. Mice bearing established subcutaneous tumors were treated with (90)Y-DOTA-DAB4 alone or after chemotherapy. Non-radiosensitizing cyclophosphamide/etoposide chemotherapy was used for the syngeneic EL4 lymphoma model. Radiosensitizing cisplatin/gemcitabine chemotherapy was used for the syngeneic Lewis Lung carcinoma (LL2) model, and for the xenograft models of LNCaP prostatic carcinoma and Panc-1 pancreatic carcinoma. We demonstrate the safety, specificity, and efficacy of (90)Y-DOTA-DAB4-radioimmunotherapy alone or combined with chemotherapy. EL4 lymphoma-bearing mice either were cured at higher doses of radioimmunotherapy alone or lower doses of radioimmunotherapy in synergy with chemotherapy. Radioimmunotherapy alone was less effective in chemo- and radio-resistant carcinoma models. However, radioimmunotherapy synergized with radiosensitizing chemotherapy to retard significantly tumor regrowth and so prolong the survival of mice bearing LL2, LNCaP, or Panc-1 subcutaneous tumor implants. We report proof-of-concept data supporting a unique form of radioimmunotherapy, which delivers bystander killing to viable cancer cells after targeting the universal cancer antigen, La, created by DNA-damaging treatment in neighboring dead cancer cells. Subsequently we propose that DAB4-targeted ionizing radiation induces additional cycles of tumor cell death, which further augments DAB4 binding to produce a tumor-lethal 'genotoxic chain reaction'. Clinically, this approach may be useful as consolidation treatment after a drug-induced cell death among (small-volume) metastatic deposits, the commonest cause of cancer death. This article is part II of a two-part series providing proof-of-concept for the diagnostic and therapeutic use of the DAB4 clone of the La-specific monoclonal antibody, APOMAB.


Evaluation of obstructive sleep apnea in metabolic syndrome.
Metabolic syndrome has become one of the most important public health problems with a growing prevalence in both developed and developing countries. Obesity is a major risk factor for obstructive sleep apnea (OSA), which is associated with significant cardiorespiratory morbidity. The aims of this study were to find out the prevalence of OSA in patients with metabolic syndrome and to highlight the importance of assessment of OSA in these patients. This cross-sectional analytical study was conducted on 100 subjects aged 30-60 years, comprising 50 cases of metabolic syndrome and 50 controls without metabolic syndrome. Overnight polysomnography was done in all the subjects. Prevalence and severity of OSA were assessed and compared between the two groups. Prevalence of OSA was significantly higher (66%) in patients with metabolic syndrome than in subjects without metabolic syndrome (12%). Out of 33 (66%) OSA patients with metabolic syndrome, 8 (16%) had mild OSA, 11 (22%) had moderate OSA, and 14 (28%) had severe OSA. Increasing severity of OSA was associated with higher mean levels of all the metabolic syndrome parameters except serum high density lipoprotein (HDL). OSA is highly prevalent in patients with metabolic syndrome. Also, the increasing severity of OSA is associated with poorer control of diabetes, hypertension, and dyslipidemia, which are all components of metabolic syndrome. Therefore, effective treatment of metabolic syndrome can prevent and control OSA in these patients. Similarly, reducing the severity of OSA (by early diagnosis and treatment) in patients with metabolic syndrome might help to optimize control of blood sugar, blood pressure, and serum lipids, thereby reducing the risk of cardiovascular disease. Therefore, the need for screening metabolic syndrome patients for OSA has been reinforced by this study.


Optical vortex symmetry breakdown and decomposition of the orbital angular momentum of light beams.
Two forms of the transverse energy circulation within plane-polarized paraxial light beams are specified: one inherent in wave-front singularities (optical vortices) and the other peculiar to astigmatism and asymmetry of beams with a smooth wave front. As quantitative measures of these energy flow components, the concepts of vortex and asymmetry parts of a beam's orbital angular momentum are introduced and their definitions are proposed on the basis of beam intensity moments. The properties and physical meaning of these concepts are analyzed, and their use for the study of transformations of optical vortices is demonstrated.


How to use an article about therapy.
Most surgical interventions have inherent benefits and associated risks. Before implementing a new therapy we should ascertain the benefits and risks of the therapy and assure ourselves that the resources consumed in the intervention will not be exorbitant. We suggest a 3-step approach to using an article from the urological literature to guide patient care. We recommend asking whether the study can provide valid results, reviewing the results and considering how the results can be applied to patient care. Key methodological characteristics that have an impact on the validity of a surgical trial include randomization, allocation concealment, stratification, blinding, completeness of followup and intent to treat analysis. To the extent that the quality is poor inferences from this study are weakened. However, if its quality is acceptable, one must determine the range within which the true treatment effect lies (95% CI). One must then consider whether this result can be generalized to a patient and whether the investigators have provided information about all clinically important outcomes. It is then necessary to compare the relative benefits of the intervention with its risks. If one perceives that the benefits outweigh the risks, the intervention may be of use to the patient. Given the time constraints of busy urological practices and training programs, applying this analysis to every relevant article would be challenging. However, the basics of this process are essentially what we all do hundreds of times each week when treating patients. Making this process explicit with guidelines to assess the strength of the available evidence will serve to improve patient care. It will also allow us to defend therapeutic interventions based on available evidence and not on anecdote.


Application of an elastic biodegradable poly(L-lactide-co-epsilon-caprolactone) scaffold for cartilage tissue regeneration.
In cartilage tissue regeneration, it is important that an implant inserted into a defect site can maintain its mechanical integrity and endure stress loads from the body, in addition to being biocompatible and able to induce tissue growth. These factors are crucial in the design of scaffolds for cartilage tissue engineering. We developed an elastic biodegradable scaffold from poly(L-lactideco-epsilon-caprolactone) (PLCL) for application in cartilage treatment. Biodegradable PLCL co-polymer was synthesized from L-lactide and epsilon-caprolactone in the presence of stannous octoate as a catalyst. A highly elastic PLCL scaffold was fabricated by a gel-pressing method with 80% porosity and 300-500 microm pore size. The tensile mechanical and recovery tests were performed in order to examine mechanical and elastic properties of the PLCL scaffold. They could be easily twisted and bent and exhibited almost complete (over 94%) recoverable extension up to breaking point. For examining cartilaginous tissue formation, rabbit chondrocytes were seeded on scaffolds. They were then cultured in vitro for 5 weeks or implanted in nude mice subcutaneously. From in vitro and in vivo tests, the accumulation of extracellular matrix on the constructs showed that chondrogenic differentiation was sustained onto PLCL scaffolds. Histological analysis showed that cells onto PLCL scaffolds formed mature and well-developed cartilaginous tissue, as evidenced by chondrocytes within lacunae. From these results, we are confident that elastic PLCL scaffolds exhibit biocompatibility and as such would provide an environment where cartilage tissue growth is enhanced and facilitated.


Nurses' contributions to the resolution of ethical dilemmas in practice.
Complex and expensive treatment options have increased the frequency and emphasis of ethical decision-making in healthcare. In order to meet these challenges effectively, we need to identify how nurses contribute the resolution of these dilemmas. To identify the values, beliefs and contextual influences that inform decision-making. To identify the contribution made by nurses in achieving the resolution of ethical dilemmas in practice. An interpretive exploratory study was undertaken, 11 registered acute care nurses working in a district general hospital in England were interviewed, using semi-structured interviews. In-depth content analysis of the data was undertaken via NVivo coding and thematic identification. Participants and context: Participants were interviewed about their contribution to the resolution of ethical dilemmas within the context of working in an acute hospital ward. Participants were recruited from all settings working with patients of any age and any diagnosis. Ethical considerations: Ethical approval was obtained from the local National Research Ethics Committee. Four major themes emerged: 'best for the patient', 'accountability', 'collaboration and conflict' and 'concern for others'. Moral distress was also evident in the literature and findings, with moral dissonance recognised and articulated by more experienced nurses. The relatively small, single-site sample may not account for the effects of organisational culture on the results; the findings suggested that professional relationships were key to resolving ethical dilemmas. Nurses use their moral reasoning based on their beliefs and values when faced with ethical dilemmas. Subsequent actions are mediated though ethical decision-making frames of reference including deontology, consequentialism, the ethics of care and virtue ethics. Nurses use these in contributing to the resolution of these dilemmas. Nurses require the skills to develop and maintain professional relationships for addressing ethical dilemmas and to engage with political and organisational macro- and micro-decision-making. Nurses' professional relationships are central to nurses' contributions to the resolution of ethical dilemmas.


Platelet volume, aggregation, and adenosine triphosphate release in cerebral thrombosis.
We compared whole blood platelet aggregation, adenosine triphosphate release, platelet count, platelet crit (percentage volume of platelets), and mean platelet volume during the acute, subacute, and chronic periods of cerebral thrombosis in 22 patients with value in 29 controls. During the acute and subacute periods, platelet aggregation, platelet count, platelet crit, and mean platelet volume were significantly less in the patients than in the controls (p less than 0.05-0.01) while the adenosine triphosphate release rate per volume of platelets was significantly greater (p less than 0.05). During the acute period, infarct size showed a significant positive correlation with platelet aggregation (r = 0.59, p less than 0.01) and adenosine triphosphate release rate (r = 0.70, p less than 0.001) but a negative correlation with platelet count (r = -0.44, p less than 0.05). Our results suggest that platelet aggregation is reduced during the acute period due to the consumption of platelets during thrombogenesis but that the remaining individual platelets are hyperactive. Platelet consumption during the acute period increases with infarct size. During the chronic period, platelet crit and mean platelet volume were significantly less in the patients than in the controls (p less than 0.01) while the adenosine triphosphate release rate was significantly greater (p less than 0.01), suggesting sustained platelet consumption and chronically enhanced secretion of individual platelets.


Dietary intake of phytoestrogens, estrogen receptor-beta polymorphisms and the risk of prostate cancer.
The causes of prostate cancer are poorly understood, but genetic factors may be more important than for many other malignancies, and dietary phytoestrogens may be protective. Because phytoestrogens bind tightly to the estrogen receptor-beta, we conducted an epidemiologic investigation of synergistic effects between phytoestrogen intake and estrogen receptor-beta gene polymorphisms. We performed a population-based case-control study in Sweden. All participants reported their phytoestrogen intake and donated a blood sample. We identified four haplotype-tagging single nucleotide polymorphisms (htSNPs) and genotyped these htSNPs in 1314 prostate cancer patients and 782 controls. Odds ratios were estimated by multivariate logistic regression. Interactions between phytoestrogen intake and estrogen receptor-beta SNPs on prostate cancer risk were evaluated considering both multiplicative and additive effect scales. We found a significant multiplicative interaction (P = 0.04) between dietary intake of phytoestrogens and a promoter SNP in the estrogen receptor-beta gene (rs 2987983-13950), but not with any of the three other htSNPs (P = 0.11, 0.69, 0.85). Among carriers of the variant promoter alleles, we found strong inverse associations with increasing intake of total phytoestrogens (odds ratio for highest vs. lowest quartile = 0.43; P for trend <0.001), isoflavonoids (odds ratio = 0.63; P for trend = 0.05), and coumestrol (odds ratio = 0.57; P for trend = 0.003). We found no association between phytoestrogens and prostate cancer among carriers homozygous for the wild-type allele (TT). Our study provides strong evidence that high intake of phytoestrogens substantially reduce prostate cancer risk among men with specific polymorphic variation in the promoter region of the estrogen receptor-beta gene.


The Intestinal Mycobiota in Wild Zebrafish Comprises Mainly Dothideomycetes While Saccharomycetes Predominate in Their Laboratory-Reared Counterparts.
As an integral part of the resident microbial community of fish intestinal tract, the mycobiota is expected to play important roles in health and disease resistance of the host. The composition of the diverse fungal communities, which colonize the intestine, is greatly influenced by the host, their diet and geographic origin. Studies of fungal communities are rare and the majority of previous studies have relied on culture-based methods. In particular, fungal communities in fish are also poorly characterized. The aim of this study was to provide an in-depth overview of the intestinal mycobiota in a model fish species (zebrafish, Danio rerio) and to determine differences in fungal composition between wild and captive specimens. We have profiled the intestinal mycobiota of wild-caught (Sharavati River, India), laboratory-reared (Bodø, Norway) and wild-caught-laboratory-kept (Uttara, India) zebrafish by sequencing the fungal internal transcribed spacer 2 region on the Illumina MiSeq platform. Wild fish were exposed to variable environmental factors, whereas both laboratory groups were kept in controlled conditions. There were also differences in husbandry practices at Bodø and Uttara, particularly diet. Zebrafish from Bodø were reared in the laboratory for over 10 generations, while wild-caught-laboratory-kept fish from Uttara were housed in the laboratory for only 2 months before sample collection. The intestine of zebrafish contained members of more than 15 fungal classes belonging to the phyla Ascomycota, Basidiomycota, and Zygomycota. Fungal species richness and diversity distinguished the wild-caught and laboratory-reared zebrafish communities. Wild-caught zebrafish-associated mycobiota comprised mainly Dothideomycetes in contrast to their Saccharomycetes-dominated laboratory-reared counterparts. The predominant Saccharomycetes in laboratory-reared fish belonged to the saprotrophic guild. Another characteristic feature of laboratory-reared fish was the significantly higher abundance of Cryptococcus (Tremellomycetes) compared to wild fish. This pioneer study has shed light into the differences in the intestinal fungal communities of wild-caught and laboratory-reared zebrafish and the baseline data generated will enrich our knowledge on fish mycobiota.


Interstitial glycerol concentration in human skeletal muscle and adipose tissue is close to the concentration in blood.
1. The suggestion that the interstitial glycerol concentration in both adipose tissue and skeletal muscle is around 3 mmol/I (Maggs DG, Jacob R, Rife F, et al. J Clin Invest 1995; 96: 370-7), rather than close to the blood concentration as previously supposed, was tested by independent methods. 2. Free glycerol was infused, as part of a triacylglycerol emulsion, into six normal subjects and the arteriovenous difference for glycerol across the forearm was measured. In addition the relative interstitial glycerol concentration in subcutaneous adipose tissue was assessed simultaneously in four of the subjects by microdialysis. 3. During glycerol infusion the arterialized glycerol concentration rose from 52 +/- 5 mumol/I to 250-300 mumol/I (P < 0.001) in a square wave fashion. The net arteriovenous difference for glycerol across the forearm changed from negative (output) to positive (uptake) (P < 0.01). In subcutaneous adipose tissue the interstitial glycerol concentration rose during glycerol infusion (P < 0.001). 4. These observations are most easily explained by the movement of glycerol from plasma to interstitial fluid down a concentration gradient. We conclude that the interstitial glycerol concentration in skeletal muscle and adipose tissue is closer to the arterial concentration than to 3 mmol/I.


Abeta(1-42) and aluminum induce stress in the endoplasmic reticulum in rabbit hippocampus, involving nuclear translocation of gadd 153 and NF-kappaB.
Apoptosis may represent a prominent form of neuronal death in chronic neurodegenerative disorders, such as Alzheimer's disease. Although apoptosis under mitochondrial control has received considerable attention, mechanisms used within the endoplasmic reticulum (ER) and nucleus in mediating apoptotic signals are not well understood. A growing body of evidence is emerging from different studies which suggests an active role for the ER in regulating apoptosis. Disturbances of ER function have been shown to trigger two different apoptotic pathways; one involves cross-talk with mitochondria and is regulated by the antiapoptotic Bcl-2, and the second is characterized by the activation of caspase-12. Also, stress in the ER has been suggested to result in the activation of a number of proteins, such as gadd 153 and NF-kappa, and in the downregulation of the antiapoptotic protein, Bcl-2. In the present study, the intracisternal injection in aged rabbits of either the neurotoxin aluminum maltolate or of Abeta(1-42), has been found to induce nuclear translocation of gadd 153 and the inducible transcription factor, NF-kappaB. Translocation of these two proteins is accompanied by decreased levels of Bcl-2 in both the ER and the nucleus. Aluminum maltolate, but not Abeta, induces caspase-12 activation which is a mediator of ER-specific apoptosis; this is the first report of the in vivo activation of caspase-12. These findings indicate that the ER may play a role in regulating apoptosis in vivo, and could be of significance in the pathology of neurodegeneration and related disorders.


Oxidoreductases and Reactive Oxygen Species in Conversion of Lignocellulosic Biomass.
Biomass constitutes an appealing alternative to fossil resources for the production of materials and energy. The abundance and attractiveness of vegetal biomass come along with challenges pertaining to the intricacy of its structure, evolved during billions of years to face and resist abiotic and biotic attacks. To achieve the daunting goal of plant cell wall decomposition, microorganisms have developed many (enzymatic) strategies, from which we seek inspiration to develop biotechnological processes. A major breakthrough in the field has been the discovery of enzymes today known as lytic polysaccharide monooxygenases (LPMOs), which, by catalyzing the oxidative cleavage of recalcitrant polysaccharides, allow canonical hydrolytic enzymes to depolymerize the biomass more efficiently. Very recently, it has been shown that LPMOs are not classical monooxygenases in that they can also use hydrogen peroxide (H2O2) as an oxidant. This discovery calls for a revision of our understanding of how lignocellulolytic enzymes are connected since H2O2 is produced and used by several of them. The first part of this review is dedicated to the LPMO paradigm, describing knowns, unknowns, and uncertainties. We then present different lignocellulolytic redox systems, enzymatic or not, that depend on fluxes of reactive oxygen species (ROS). Based on an assessment of these putatively interconnected systems, we suggest that fine-tuning of H2O2 levels and proximity between sites of H2O2 production and consumption are important for fungal biomass conversion. In the last part of this review, we discuss how our evolving understanding of redox processes involved in biomass depolymerization may translate into industrial applications.


A 'Semi-Protected Oligonucleotide Recombination' Assay for DNA Mismatch Repair in vivo Suggests Different Modes of Repair for Lagging Strand Mismatches.
In Escherichia coli, a DNA mismatch repair (MMR) pathway corrects errors that occur during DNA replication by coordinating the excision and re-synthesis of a long tract of the newly-replicated DNA between an epigenetic signal (a hemi-methylated d(GATC) site or a single-stranded nick) and the replication error after the error is identified by protein MutS. Recent observations suggest that this 'long-patch repair' between these sites is coordinated in the same direction of replication by the replisome. Here, we have developed a new assay that uniquely allows us to introduce targeted 'mismatches' directly into the replication fork via oligonucleotide recombination, examine the directionality of MMR, and quantify the nucleotide-dependence, sequence context-dependence, and strand-dependence of their repair in vivo-something otherwise nearly impossible to achieve. We find that repair of genomic lagging strand mismatches occurs bi-directionally in E. coli and that, while all MutS-recognized mismatches had been thought to be repaired in a consistent manner, the directional bias of repair and the effects of mutations in MutS are dependent on the molecular species of the mismatch. Because oligonucleotide recombination is routinely performed in both prokaryotic and eukaryotic cells, we expect this assay will be broadly applicable for investigating mechanisms of MMR in vivo.


Phase-field crystals with elastic interactions.
We report on a novel extension of the recently introduced phase-field crystal (PFC) method [Elder, Phys. Rev. Lett. 88, 245701 (2002)10.1103/PhysRevLett.88.245701], which incorporates elastic interactions as well as crystal plasticity and diffusive dynamics. In our model, elastic interactions are mediated through wave modes that propagate on time scales many orders of magnitude slower than atomic vibrations but still much faster than diffusive time scales. This allows us to preserve the quintessential advantage of the PFC model: the ability to simulate atomic-scale interactions and dynamics on time scales many orders of magnitude longer than characteristic vibrational time scales. We demonstrate the two different modes of propagation in our model and show that simulations of grain growth and elastoplastic deformation are consistent with the microstructural properties of nanocrystals.


Cryogenically cooled octupole ion trap for spectroscopy of biomolecular ions.
We present here the design of a linear octupole ion trap, suitable for collisional cryogenic cooling and spectroscopy of large ions. The performance of this trap has been assessed using ultraviolet (UV) photofragmentation spectroscopy of protonated dipeptides. At the trap temperature of 6.1 K, the vibrational temperature of the ions reaches 9.1 K, although their estimated translational temperature is ~150 K. This observation suggests that, despite the significant translational heating by radio-frequency electrical field, vibrational cooling of heavy ions in the octupole is at least as efficient as in the 22-pole ion traps previously used in our laboratory. In contrast to the 22-pole traps, excellent radial confinement of ions in the octupole makes it convenient for laser spectroscopy and boosts the dissociation yield of the stored ions to 30%. Overlap of the entire ion cloud by the laser beam in the octupole also allows for efficient UV depletion spectroscopy of ion-He clusters. The measured electronic spectra of the dipeptides and the clusters differ drastically, complicating a use of UV tagging spectroscopy for structural determination of large species.


Novel solvates M(BH₄)₃S(CH₃)₂ and properties of halide-free M(BH₄)₃ (M = Y or Gd).
Rare earth metal borohydrides have been proposed as materials for solid-state hydrogen storage because of their reasonably low temperature of decomposition. New synthesis methods, which provide halide-free yttrium and gadolinium borohydride, are presented using dimethyl sulfide and new solvates as intermediates. The solvates M(BH4)3S(CH3)2 (M = Y or Gd) are transformed to α-Y(BH4)3 or Gd(BH4)3 at ~140 °C as verified by thermal analysis. The monoclinic structure of Y(BH4)3S(CH3)2, space group P2₁/c, a = 5.52621(8), b = 22.3255(3), c = 8.0626(1) Å and β = 100.408(1)°, is solved from synchrotron radiation powder X-ray diffraction data and consists of buckled layers of slightly distorted octahedrons of yttrium atoms coordinated to five borohydride groups and one dimethyl sulfide group. Significant hydrogen loss is observed from Y(BH4)3 below 300 °C and rehydrogenation at 300 °C and p(H2) = 1550 bar does not result in the reformation of Y(BH4)3, but instead yields YH3. Moreover, composites systems Y(BH4)3-LiBH4 1 : 1 and Y(BH4)3-LiCl 1 : 1 prepared from as-synthesised Y(BH4)3 are shown to melt at 190 and 220 °C, respectively.


Obstructive sleep apnea in New Zealand adults: prevalence and risk factors among Māori and non-Māori.
Examine the distribution of symptoms and risk factors, and estimate the prevalence of obstructive sleep apnea (OSA) among Māori and non-Māori New Zealanders. Mail-out survey to a stratified random sample from the electoral roll of 10,000 people aged 30-59 y, and overnight MESAM IV monitoring during sleep of a similarly aged stratified random sample of 364 people from the Wellington electoral roll. Nationwide survey of OSA symptoms (71% response rate) and regional home-based measurement of respiratory disturbance index (RDI, 4% oxygen desaturations/h of sleep, plus bursts of snoring or > or = 10/min increase in heart rate). Sample designs aimed for equal numbers of Māori and non-Māori participants, men and women, and participants in each decade of age. N/A. Māori were more likely than non-Māori to report OSAS risk factors and symptoms. After controlling for sex and age, Māori were 4.3 times more likely to have RDI > or = 15 (95% CI = 1.3-13.9). Ethnicity was not an independent risk factor after controlling for body mass index (BMI) and neck circumference. The prevalence of OSAS (RDI > or = 5 and ESS > 10) was conservatively estimated to be 4.4% for Māori men, 4.1% for non-Māori men, 2.0% for Māori women, and 0.7% for non-Māori women. The national survey and the regional monitoring study indicate a higher prevalence of OSA among Māori and among men. The higher prevalence among Māori appears to be attributable to recognized risk factors, notably body habitus. In addition to increased prevention and treatment services, strategies are needed to reduce ethnic disparities in OSAS prevalence.


Beyond sacrificial harm: A two-dimensional model of utilitarian psychology.
[Correction Notice: An Erratum for this article was reported in Vol 125(2) of Psychological Review (see record 2018-15704-001). The copyright attribution was incorrectly listed, and the Creative Commons CC-BY license disclaimer was incorrectly omitted from the author note. The correct copyright is "© 2017 The Author(s)" and the omitted disclaimer is found in the erratum. All versions of this article have been corrected.] Recent research has relied on trolley-type sacrificial moral dilemmas to study utilitarian versus nonutilitarian modes of moral decision-making. This research has generated important insights into people's attitudes toward instrumental harm-that is, the sacrifice of an individual to save a greater number. But this approach also has serious limitations. Most notably, it ignores the positive, altruistic core of utilitarianism, which is characterized by impartial concern for the well-being of everyone, whether near or far. Here, we develop, refine, and validate a new scale-the Oxford Utilitarianism Scale-to dissociate individual differences in the 'negative' (permissive attitude toward instrumental harm) and 'positive' (impartial concern for the greater good) dimensions of utilitarian thinking as manifested in the general population. We show that these are two independent dimensions of proto-utilitarian tendencies in the lay population, each exhibiting a distinct psychological profile. Empathic concern, identification with the whole of humanity, and concern for future generations were positively associated with impartial beneficence but negatively associated with instrumental harm; and although instrumental harm was associated with subclinical psychopathy, impartial beneficence was associated with higher religiosity. Importantly, although these two dimensions were independent in the lay population, they were closely associated in a sample of moral philosophers. Acknowledging this dissociation between the instrumental harm and impartial beneficence components of utilitarian thinking in ordinary people can clarify existing debates about the nature of moral psychology and its relation to moral philosophy as well as generate fruitful avenues for further research. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Occurrence of polychlorinated biphenyls and polybrominated diphenyl ethers in green mussels (Perna viridis) from Singapore, Southeast Asia.
The green mussel, Perna viridis, was used in this study to measure levels of polychlorinated biphenyls (PCBs) and, for the first time, polybrominated diphenyl ethers (PBDE) in the marine environment. Samples were collected from eight different locations in the coastal waters of Singapore between April and May 2002. Forty-one PCB and 21 PBDE congeners were quantified by gas chromatography-mass spectrometry and were all positively detected in the mussel tissues. Total concentrations in green mussel tissues ranged from 6.1 to 82 ng/g and 2.0 to 38 ng/g on a dry-weight basis for PCBs and PBDEs, respectively. Such levels reflect the ubiquity of these persistent organic pollutants in a tropical marine environment. Principal component analysis was applied to the PCB data and revealed similarities in the congener composition of mussel tissues to that of the commercial PCB mixture, Aroclor 1254. The PBDE levels, to date, were approximately one order of magnitude greater than the upper concentrations reported for blue mussel (Mytilus edulis) tissues in Europe. At some sampling sites, the congener composition of PBDEs in P. viridis tissues indicated recent exposure to a commercial pentabrominated flame retardant.


Do healthier foods and diet patterns cost more than less healthy options? A systematic review and meta-analysis.
To conduct a systematic review and meta-analysis of prices of healthier versus less healthy foods/diet patterns while accounting for key sources of heterogeneity. MEDLINE (2000-2011), supplemented with expert consultations and hand reviews of reference lists and related citations. Studies reviewed independently and in duplicate were included if reporting mean retail price of foods or diet patterns stratified by healthfulness. We extracted, in duplicate, mean prices and their uncertainties of healthier and less healthy foods/diet patterns and rated the intensity of health differences for each comparison (range 1-10). Prices were adjusted for inflation and the World Bank purchasing power parity, and standardised to the international dollar (defined as US$1) in 2011. Using random effects models, we quantified price differences of healthier versus less healthy options for specific food types, diet patterns and units of price (serving, day and calorie). Statistical heterogeneity was quantified using I(2) statistics. 27 studies from 10 countries met the inclusion criteria. Among food groups, meats/protein had largest price differences: healthier options cost $0.29/serving (95% CI $0.19 to $0.40) and $0.47/200 kcal ($0.42 to $0.53) more than less healthy options. Price differences per serving for healthier versus less healthy foods were smaller among grains ($0.03), dairy (-$0.004), snacks/sweets ($0.12) and fats/oils ($0.02; p<0.05 each) and not significant for soda/juice ($0.11, p=0.64). Comparing extremes (top vs bottom quantile) of food-based diet patterns, healthier diets cost $1.48/day ($1.01 to $1.95) and $1.54/2000 kcal ($1.15 to $1.94) more. Comparing nutrient-based patterns, price per day was not significantly different (top vs bottom quantile: $0.04; p=0.916), whereas price per 2000 kcal was $1.56 ($0.61 to $2.51) more. Adjustment for intensity of differences in healthfulness yielded similar results. This meta-analysis provides the best evidence until today of price differences of healthier vs less healthy foods/diet patterns, highlighting the challenges and opportunities for reducing financial barriers to healthy eating.


Proliferative response of microglia and macrophages in the adult mouse eye after optic nerve lesion.
The purpose of this in vivo study was to evaluate the proliferative response of immunologic cells during the acute phase after optic nerve (ON) lesion in the neural retina and the ciliary body (CB) in the adult mouse. The number of cells obtained 5 to 10 days after ON crush was compared with that counted after intraorbital ON transection. In addition, after ON crush, the time course of in situ proliferating Ki67(+) microglia and macrophages was analyzed from 6 hours up to 10 days. The number of BrdU(+)F4/80(+) retinal microglia and ciliary macrophages increased over time, reaching the peak number 10 days after ON lesion. In the retina, both ON lesion types resulted in a similar number of BrdU(+)F4/80(+) microglia. Approximately 85% of all BrdU(+) cells were identified as F4/80(+) microglia. However, this cell population represented only 30% of all F4/80(+) microglia. The peak of microglial in situ proliferation was found 2 days after ON crush. In the CB, both ON lesion types induced a significant increase in the number of BrdU(+)F4/80(+) macrophages. Of interest, the number of cells after ON transection further increased over time, whereas those after ON crush did not. ON lesion significantly increased proliferation of F4/80(+) immunologic cells in both the retina and CB. Although no significant differences in cellular response were observed in the retina between both lesion types, ON transection had a more pronounced effect on ciliary macrophages than did ON crush. Therefore, both regions seem not to act in concert during the acute phase after ON lesion.


Multiple behaviors for turning performance of Pacific bluefin tuna (Thunnus orientalis).
Tuna are known for exceptional swimming speeds, which are possible because of their thunniform lift-based propulsion, large muscle mass and rigid fusiform body. A rigid body should restrict maneuverability with regard to turn radius and turn rate. To test if turning maneuvers by the Pacific bluefin tuna (Thunnus orientalis) are constrained by rigidity, captive animals were videorecorded overhead as the animals routinely swam around a large circular tank or during feeding bouts. Turning performance was classified into three different types: (1) glide turns, where the tuna uses the caudal fin as a rudder; (2) powered turns, where the animal uses continuous near symmetrical strokes of the caudal fin through the turn; and (3) ratchet turns, where the overall global turn is completed by a series of small local turns by asymmetrical stokes of the caudal fin. Individual points of the rostrum, peduncle and tip of the caudal fin were tracked and analyzed. Frame-by-frame analysis showed that the ratchet turn had the fastest turn rate for all points with a maximum of 302 deg s-1. During the ratchet turn, the rostrum exhibited a minimum global 0.38 body length turn radius. The local turn radii were only 18.6% of the global ratchet turn. The minimum turn radii ranged from 0.4 to 1.7 body lengths. Compared with the performance of other swimmers, the increased flexion of the peduncle and tail and the mechanics of turning behaviors used by tuna overcomes any constraints to turning performance from the rigidity of the anterior body morphology.


Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion.
Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases.


An atlas on risk factors for type 2 diabetes: a wide-angled Mendelian randomisation study.
The aim of this study was to use Mendelian randomisation (MR) to identify the causal risk factors for type 2 diabetes. We first conducted a review of meta-analyses and review articles to pinpoint possible risk factors for type 2 diabetes. Around 170 possible risk factors were identified of which 97 risk factors with available genetic instrumental variables were included in MR analyses. To reveal more risk factors that were not included in our MR analyses, we conducted a review of published MR studies of type 2 diabetes. For our MR analyses, we used summary-level data from the DIAbetes Genetics Replication And Meta-analysis consortium (74,124 type 2 diabetes cases and 824,006 controls of European ancestry). Potential causal associations were replicated using the FinnGen consortium (11,006 type 2 diabetes cases and 82,655 controls of European ancestry). The inverse-variance weighted method was used as the main analysis. Multivariable MR analysis was used to assess whether the observed associations with type 2 diabetes were mediated by BMI. We used the Benjamini-Hochberg method that controls false discovery rate for multiple testing. We found evidence of causal associations between 34 exposures (19 risk factors and 15 protective factors) and type 2 diabetes. Insomnia was identified as a novel risk factor (OR 1.17 [95% CI 1.11, 1.23]). The other 18 risk factors were depression, systolic BP, smoking initiation, lifetime smoking, coffee (caffeine) consumption, plasma isoleucine, valine and leucine, liver alanine aminotransferase, childhood and adulthood BMI, body fat percentage, visceral fat mass, resting heart rate, and four plasma fatty acids. The 15 exposures associated with a decreased risk of type 2 diabetes were plasma alanine, HDL- and total cholesterol, age at menarche, testosterone levels, sex hormone binding globulin levels (adjusted for BMI), birthweight, adulthood height, lean body mass (for women), four plasma fatty acids, circulating 25-hydroxyvitamin D and education years. Eight associations remained after adjustment for adulthood BMI. We additionally identified 21 suggestive risk factors (p < 0.05), such as alcohol consumption, breakfast skipping, daytime napping, short sleep, urinary sodium, and certain amino acids and inflammatory factors. The present study verified several previously reported risk factors and identified novel potential risk factors for type 2 diabetes. Prevention strategies for type 2 diabetes should be considered from multiple perspectives on obesity, mental health, sleep quality, education level, birthweight and smoking.


Kinetic modeling to optimize pentose fermentation in Zymomonas mobilis.
Zymomonas mobilis engineered to express four heterologous enzymes required for xylose utilization ferments xylose along with glucose. A network of pentose phosphate (PP) pathway enzymatic reactions interacting with the native glycolytic Entner Doudoroff (ED) pathway has been hypothesized. We have investigated this putative reaction network by developing a kinetic model incorporating all of the enzymatic reactions of the PP and ED pathways, including those catalyzed by the heterologous enzymes. Starting with the experimental literature on in vitro characterization of each enzymatic reaction, we have developed a kinetic model to enable dynamic simulation of intracellular metabolite concentrations along the network of interacting PP and ED metabolic pathways. This kinetic model is useful for performing in silico simulations to predict how varying the different enzyme concentrations will affect intracellular metabolite concentrations and ethanol production rate during continuous fermentation of glucose and xylose mixtures. Among the five enzymes whose concentrations were varied as inputs to the model, ethanol production in the continuous fermentor was optimized when xylose isomerase (XI) was present at the highest level, followed by transaldolase (TAL). Predictions of the model that the interconnecting enzyme phosphoglucose isomerase (PGI) does not need to be overexpressed were recently confirmed through experimental investigations. Through such systematic analysis, we can develop efficient strategies for maximizing the fermentation of both glucose and xylose, while minimizing the expression of heterologous enzymes.


Widespread Proteome Remodeling and Aggregation in Aging C. elegans.
Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.


Butyrate enhances disease resistance of chickens by inducing antimicrobial host defense peptide gene expression.
Host defense peptides (HDPs) constitute a large group of natural broad-spectrum antimicrobials and an important first line of immunity in virtually all forms of life. Specific augmentation of synthesis of endogenous HDPs may represent a promising antibiotic-alternative approach to disease control. In this study, we tested the hypothesis that exogenous administration of butyrate, a major type of short-chain fatty acids derived from bacterial fermentation of undigested dietary fiber, is capable of inducing HDPs and enhancing disease resistance in chickens. We have found that butyrate is a potent inducer of several, but not all, chicken HDPs in HD11 macrophages as well as in primary monocytes, bone marrow cells, and jejuna and cecal explants. In addition, butyrate treatment enhanced the antibacterial activity of chicken monocytes against Salmonella enteritidis, with a minimum impact on inflammatory cytokine production, phagocytosis, and oxidative burst capacities of the cells. Furthermore, feed supplementation with 0.1% butyrate led to a significant increase in HDP gene expression in the intestinal tract of chickens. More importantly, such a feeding strategy resulted in a nearly 10-fold reduction in the bacterial titer in the cecum following experimental infections with S. enteritidis. Collectively, the results indicated that butyrate-induced synthesis of endogenous HDPs is a phylogenetically conserved mechanism of innate host defense shared by mammals and aves, and that dietary supplementation of butyrate has potential for further development as a convenient antibiotic-alternative strategy to enhance host innate immunity and disease resistance.


U.S. population profile of time-stamped accelerometer outputs: impact of wear time.
We examined the effects of wear time on a population profile of time-stamped accelerometer outputs using the 2005-2006 National Health and Nutrition Examination Survey (NHANES) data representing 3744 adults ≥ 20 years of age. Outputs included activity counts, steps, and time variables: nonwear (macro-determined), sedentary behavior (<100 activity counts/minute), and time in low (100-499 activity counts/minute), light (500-2019 activity counts/minute), and moderate-to-vigorous physical activity (MVPA; ≥2020 activity counts/minute) intensities. We describe mean values according to a 24-hour clock. Analysis was repeated in a reduced data set with only those who wore the accelerometer for 60 minutes within each considered hour of the day. Between 12:00 and 17:00, U.S. adults spend approximately 31 minutes each hour in sedentary behaviors, and approximately 14 minutes, 10 minutes, and 2 minutes in low, light, and MVPA intensity activity, respectively. Removing the effect of nonwear time, sedentary behaviors are reduced in the morning hours and increase in the evening hours. At either end of the day, nonwear time appears to distort population estimates of all accelerometer time and physical activity volume indicators, but its effects are particularly clear on population estimates of time spent in sedentary behavior.


Preferred pre-stimulus EEG states affect cognitive event-related potentials.
Current views of the genesis of the event-related potential (ERP) emphasize the contribution of ongoing oscillations - the ongoing electroencephalogram (EEG) is recognized as much more than "background noise" to be removed by response averaging to find the ERP. Early work from Başar's group noted that repetitive stimuli led to selective phase re-ordering of activity in the delta and alpha bands, such that enhanced brain negativity occurred at the time of the regular stimulus. Other work related negativity in alpha activity at stimulus onset to improved reaction times and ERP enhancements. These findings led us to begin a program of brain dynamics studies exploring pre-stimulus EEG phase states, their preferential occurrence in paradigms with regularly presented stimuli, and their relation to ERP outcomes. In particular, with very narrow EEG bands, we have repeatedly found that certain phase states preferentially occur at stimulus onset, implying ongoing phase re-ordering driven by stimulus occurrence. Effects are weakened with slightly varying inter-stimulus intervals, but still occur reliably. Further, these preferential phase states are functionally effective in relation to the ERP correlates of efficient stimulus processing. Preferential phase occurrence and their effects were originally reported in auditory oddball tasks, using narrow EEG bands derived by digital filtering. A recent study is presented illustrating generalization of the phenomenon in the auditory Go/NoGo task, using narrow bands derived by FFT techniques. Our current work is extending this research in normal children (to provide a comparative context for research in children with AD/HD), and well-functioning elderly (to provide a context for future work in relation to Alzheimer's disease).


A Modified Delphi Consensus Study of the Screening, Diagnosis, and Treatment of Tardive Dyskinesia.
A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation). Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.


Confirmation of family cancer history reported in a population-based survey.
Knowledge of family cancer history is essential for estimating an individual's cancer risk and making clinical recommendations regarding screening and referral to a specialty cancer genetics clinic. However, it is not clear if reported family cancer history is sufficiently accurate for this purpose. In the population-based 2001 Connecticut Family Health Study, 1019 participants reported on 20 578 first-degree relatives (FDR) and second-degree relatives (SDR). Of those, 2605 relatives were sampled for confirmation of cancer reports on breast, colorectal, prostate, and lung cancer. Confirmation sources included state cancer registries, Medicare databases, the National Death Index, death certificates, and health-care facility records. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for reports on lung, colorectal, breast, and prostate cancer and after stratification by sex, age, education, and degree of relatedness and used to estimate report accuracy. Pairwise t tests were used to evaluate differences between the two strata in each stratified analysis. All statistical tests were two-sided. Overall, sensitivity and positive predictive value were low to moderate and varied by cancer type: 60.2% and 40.0%, respectively, for lung cancer reports, 27.3% and 53.5% for colorectal cancer reports, 61.1% and 61.3% for breast cancer reports, and 32.0% and 53.4% for prostate cancer reports. Specificity and negative predictive value were more than 95% for all four cancer types. Cancer history reports on FDR were more accurate than reports on SDR, with reports on FDR having statistically significantly higher sensitivity for prostate cancer than reports on SDR (58.9% vs 21.5%, P = .002) and higher positive predictive value for lung (78.1% vs 31.7%, P < .001), colorectal (85.8% vs 43.5%, P = .004), and breast cancer (79.9% vs 53.6%, P = .02). General population reports on family history for the four major adult cancers were not highly accurate. Efforts to improve accuracy are needed in primary care and other health-care settings in which family history is collected to ensure appropriate risk assessment and clinical care recommendations.


The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications.
This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti-HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment.


Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study.
Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19. Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death). Postmenopausal women between 50 and 80 years of age with verified COVID-19. Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI). Death following COVID-19. From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16). Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.


Long noncoding RNAs in B-cell development and activation.
Long noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.


The Behavioral Model for Vulnerable Populations: application to medical care use and outcomes for homeless people.
(1) To present the Behavioral Model for Vulnerable Populations, a major revision of a leading model of access to care that is particularly applicable to vulnerable populations; and (2) to test the model in a prospective study designed to define and determine predictors of the course of health services utilization and physical health outcomes within one vulnerable population: homeless adults. We paid particular attention to the effects of mental health, substance use, residential history, competing needs, and victimization. A community-based probability sample of 363 homeless individuals was interviewed and examined for four study conditions (high blood pressure, functional vision impairment, skin/leg/foot problems, and tuberculosis skin test positivity). Persons with at least one study condition were followed longitudinally for up to eight months. Homeless adults had high rates of functional vision impairment (37 percent), skin/leg/foot problems (36 percent), and TB skin test positivity (31 percent), but a rate of high blood pressure similar to that of the general population (14 percent). Utilization was high for high blood pressure (81 percent) and TB skin test positivity (78 percent), but lower for vision impairment (33 percent) and skin/leg/foot problems (44 percent). Health status for high blood pressure, vision impairment, and skin/leg/foot problems improved over time. In general, more severe homeless status, mental health problems, and substance abuse did not deter homeless individuals from obtaining care. Better health outcomes were predicted by a variety of variables, most notably having a community clinic or private physician as a regular source of care. Generally, use of currently available services did not affect health outcomes. Homeless persons are willing to obtain care if they believe it is important. Our findings suggest that case identification and referral for physical health care can be successfully accomplished among homeless persons and can occur concurrently with successful efforts to help them find permanent housing, alleviate their mental illness, and abstain from substance abuse.


An anthrone-based Kv7.2/7.3 channel blocker with improved properties for the investigation of psychiatric and neurodegenerative disorders.
A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (compound 18, JDP-107) with a promising combination of potency (IC50 = 0.16 μM in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.


Stem cell-like properties of the endometrial side population: implication in endometrial regeneration.
The human endometrium undergoes cyclical regeneration throughout a woman's reproductive life. Ectopic implantation of endometrial cells through retrograde menstruation gives rise to endometriotic lesions which affect approximately 10% of reproductive-aged women. The high regenerative capacity of the human endometrium at eutopic and ectopic sites suggests the existence of stem/progenitor cells and a unique angiogenic system. The objective of this study was to isolate and characterize putative endometrial stem/progenitor cells and to address how they might be involved in the physiology of endometrium. We found that approximately 2% of the total cells obtained from human endometrium displayed a side population (SP) phenotype, as determined by flow cytometric analysis of Hoechst-stained cells. The endometrial SP (ESP) cells exhibited preferential expression of several endothelial cell markers compared to endometrial main population (EMP) cells. A medium specific for endothelial cell culture enabled ESP cells to proliferate and differentiate into various types of endometrial cells, including glandular epithelial, stromal and endothelial cells in vitro, whereas in the same medium, EMP cells differentiated only into stromal cells. Furthermore, ESP cells, but not EMP cells, reconstituted organized endometrial tissue with well-delineated glandular structures when transplanted under the kidney capsule of severely immunodeficient mice. Notably, ESP cells generated endothelial cells that migrated into the mouse kidney parenchyma and formed mature blood vessels. This potential for in vivo angiogenesis and endometrial cell regeneration was more prominent in the ESP fraction than in the EMP fraction, as the latter mainly gave rise to stromal cells in vivo. These results indicate that putative endometrial stem cells are highly enriched in the ESP cells. These unique characteristics suggest that ESP cells might drive physiological endometrial regeneration and be involved in the pathogenesis of endometriosis.


Survival and functional outcome of the Birmingham Hip Resurfacing system in patients aged 65 and older at up to ten years of follow-up.
Limited evidence exists regarding the outcomes of hip resurfacing in elderly patients. The primary study aims were to determine the survival and functional outcome following Birmingham Hip Resurfacing (BHR) in patients ≥65 years at up to ten years of follow-up. Secondary aims were to explore factors affecting survival and functional outcome. Between 1997 and 2012, data were prospectively collected on 180 BHR (162 patients; mean age 69.2 years; 62 % male) implanted by one designing surgeon. Mean follow-up was six (range one to 14.4) years with no loss to follow-up. Outcomes of interest were implant survival, functional outcome [Oxford Hip Score (OHS)] and radiological evidence of implant failure. Three hips were revised, giving an overall cumulative survival of 96.4 % [95 % confidence interval (CI) 90.3-100] at ten years. Survival of 111 male BHR was 98.9 % (95 % CI 94.8-100) at ten years (one revision) compared with 91.9 % (95 % CI 77.0-100) in 69 female BHR (two revisions). Survival was affected by age (p = 0.014) and femoral head size (p = 0.024) but not by gender (p = 0.079). Median pre-operative OHS was 50.0 % [interquartile range (IQR) 37.5-68.8], improving to 4.4 % (IQR 0-10.4) postoperatively. Men had significantly better postoperative OHSs compared with women (median male OHS 2.1 % versus 6.3 % female OHS; p = 0.021). Good survival and functional outcomes were achieved with the BHR at ten years in men and women ≥65 years. Despite registry findings to the contrary, age alone should not be a contraindication for hip resurfacing in centres with expertise in this procedure.


Anxiety and chronic couple relationship stress moderate adrenocortical response to couple interaction in expectant parents.
The study examines whether anxiety or chronic relationship stress alter the way that couple conflict affects cortisol levels for women and men during the transition to parenthood. Saliva samples, assayed for cortisol, were collected before and after couple interaction from 128 heterosexual couples expecting their first child. Confirming prior research, expectant mothers had higher cortisol levels than their spouses, and gestational age was linked to women's cortisol level. Negativity during couple interaction was associated with greater cortisol reactivity for men, but not women. Tests of moderation indicated little relation between negativity and cortisol recovery for individuals with a low level of anxiety or little history of chronic arguing with the partner. However, among individuals with elevated levels of either of these two factors, negativity was linked to less cortisol recovery for men, but more cortisol recovery for women. Consistent results were also found for the relation between low warmth in the couple interaction and both reactivity and recovery for men and women high in anxiety. Future research should examine whether pregnancy is responsible for these different gender patterns, or whether the inhibition of negativity is stressful for women with high levels of risk.


Unification of neuronal spikes, seizures, and spreading depression.
The pathological phenomena of seizures and spreading depression have long been considered separate physiological events in the brain. By incorporating conservation of particles and charge, and accounting for the energy required to restore ionic gradients, we extend the classic Hodgkin-Huxley formalism to uncover a unification of neuronal membrane dynamics. By examining the dynamics as a function of potassium and oxygen, we now account for a wide range of neuronal activities, from spikes to seizures, spreading depression (whether high potassium or hypoxia induced), mixed seizure and spreading depression states, and the terminal anoxic "wave of death." Such a unified framework demonstrates that all of these dynamics lie along a continuum of the repertoire of the neuron membrane. Our results demonstrate that unified frameworks for neuronal dynamics are feasible, can be achieved using existing biological structures and universal physical conservation principles, and may be of substantial importance in enabling our understanding of brain activity and in the control of pathological states.


A Case of Epstein-Barr Virus-Associated Leiomyosarcoma Concurrently With Posttransplant Lymphoproliferative Disorders After Renal Transplantation.
Epstein-Barr virus (EBV) infection might induce not only posttransplantation lymphoproliferative disorder (PTLD) but also leiomyosarcoma. We report a case of EBV-associated leiomyosarcoma concurrently with PTLD after renal transplantation. The patient was a 30-year-old woman who underwent living donor kidney transplantation at 27 years of age. Preoperative EBV viral capsid antibody immunoglobulin M, immunoglobulin G (IgG), and EBV nuclear antigen IgG were negative. Multiple lung and liver tumors were detected 1.5 years after transplantation. She was diagnosed with PTLD after tumor biopsy. Her EBV DNA was 110 copies/mL detected by real-time polymerase chain reaction when PTLD was diagnosed. She received dose reduction of immunosuppressive therapy and several chemotherapies. Because her hepatic lesion was still progressive while pulmonary lesion was reduced, a liver tumor biopsy was performed, but the biopsy specimens were necrotic. A left lateral segmentectomy was performed as a third biopsy for treatment-resistant hepatic lesion 2.5 years after her first PTLD diagnosis. Pathologically, she was diagnosed with EBV-associated leiomyosarcoma. She was treated with sirolimus, but died 7 months after the operation. This is the first case of the coincidence of leiomyosarcoma associated with EBV and PTLD. This case was exceedingly rare; however, we must consider the coincidence of leiomyosarcoma associated with EBV and PTLD when encountering treatment-resistant PTLD.


A microprocessor-controlled photon counter for pulsed optically detected magnetic resonance.
In pulsed optically detected magnetic resonance (ODMR) spectroscopy, a lock-in amplifier is used to monitor the signal which is phase-matched to the duty cycle of an applied sequence of pulses. However, since the desired signals reside atop a much larger amplitude-modulated signal, lock-in amplification methods are difficult to use. Commerically available photon counters are of limited use, because the pulsed ODMR method requires sequential counting over several time intervals, often with minimum time delay between the intervals. The multiaccumulator photon counter described here is capable of such sequential counting over as many as four intervals. The microprocessor which controls the counter algebraically manipulates the photon counts during each of the duty cycles. The result is an inexpensive yet versatile photon counter which is suited for pulsed ODMR and other applications in which sequential counting is necessary.


GABA(B) and Trk receptor signaling mediates long-lasting inhibitory synaptic depression.
In many areas of the nervous system, excitatory and inhibitory synapses are reconfigured during early development. We have previously described the anatomical refinement of an inhibitory projection from the medial nucleus of the trapezoid body to the lateral superior olive in the developing gerbil auditory brain stem. Furthermore, these inhibitory synapses display an age-dependent form of long-lasting depression when activated at a low rate, suggesting that this process could support inhibitory synaptic refinement. Since the inhibitory synapses release both glycine and GABA during maturation, we tested whether GABA(B) receptor signaling could initiate the decrease in synaptic strength. When whole cell recordings were made from lateral superior olive neurons in a brain slice preparation, the long-lasting depression of medial nucleus of the trapezoid body-evoked inhibitory potentials was eliminated by the GABA(B) receptor antagonist, SCH-50911. In addition, inhibitory potentials could be depressed by repeated exposure to the GABA(B) receptor agonist, baclofen. Since GABA(B) receptor signaling may not account entirely for inhibitory synaptic depression, we examined the influence of neurotrophin signaling pathways located in the developing superior olive. Bath application of brain-derived neurotrophic factor or neurotrophin-3 depressed evoked inhibitory potentials, and use-dependent depression was blocked by the tyrosine kinase antagonist, K-252a. We suggest that early expression of GABAergic and neurotrophin signaling mediates inhibitory synaptic plasticity, and this mechanism may support the anatomical refinement of inhibitory connections.


Data-Driven Analysis of Bicycle Sharing Systems as Public Transport Systems Based on a Trip Index Classification.
Bicycle Sharing Systems (BSSs) are exponentially increasing in the urban mobility sector. They are traditionally conceived as a last-mile complement to the public transport system. In this paper, we demonstrate that BSSs can be seen as a public transport system in their own right. To do so, we build a mathematical framework for the classification of BSS trips. Using trajectory information, we create the trip index, which characterizes the intrinsic purpose of the use of BSS as transport or leisure. The construction of the trip index required a specific analysis of the BSS shortest path, which cannot be directly calculated from the topology of the network given that cyclists can find shortcuts through traffic lights, pedestrian crossings, etc. to reduce the overall traveled distance. Adding a layer of complication to the problem, these shortcuts have a non-trivial existence in terms of being intermittent, or short lived. We applied the proposed methodology to empirical data from BiciMAD, the public BSS in Madrid (Spain). The obtained results show that the trip index correctly determines transport and leisure categories, which exhibit distinct statistical and operational features. Finally, we inferred the underlying BSS public transport network and show the fundamental trajectories traveled by users. Based on this analysis, we conclude that 90.60% of BiciMAD's use fall in the category of transport, which demonstrates our first statement.


Smartphone-based optical palpation: towards elastography of skin for telehealth applications.
Smartphones are now integral to many telehealth services that provide remote patients with an improved diagnostic standard of care. The ongoing management of burn wounds and scars is one area in which telehealth has been adopted, using video and photography to assess the repair process over time. However, a current limitation is the inability to evaluate scar stiffness objectively and repeatedly: an essential measurement for classifying the degree of inflammation and fibrosis. Optical elastography detects mechanical contrast on a micrometer- to millimeter-scale, however, typically requires expensive optics and bulky imaging systems, making it prohibitive for wide-spread adoption in telehealth. More recently, a new variant of optical elastography, camera-based optical palpation, has demonstrated the capability to perform elastography at low cost using a standard digital camera. In this paper, we propose smartphone-based optical palpation, adapting camera-based optical palpation by utilizing a commercially available smartphone camera to provide sub-millimeter resolution imaging of mechanical contrast in scar tissue in a form factor that is amenable to telehealth. We first validate this technique on a silicone phantom containing a 5 × 5 × 1 mm3 embedded inclusion, demonstrating comparative image quality between mounted and handheld implementations. We then demonstrate preliminary in vivo smartphone-based optical palpation by imaging a region of healthy skin and two scars on a burns patient, showing clear mechanical contrast between regions of scar tissue and healthy tissue. This study represents the first implementation of elastography on a smartphone device, extending the potential application of elastography to telehealth.


The COVID-19 Pandemic Mental Health Questionnaire (CoPaQ): psychometric evaluation and compliance with countermeasures in psychiatric inpatients and non-clinical individuals.
The COVID-19 pandemic has greatly impacted people's lives across a broad spectrum of psychosocial domains. We report the development and psychometric evaluation of the self-report COVID-19 Pandemic Mental Health Questionnaire (CoPaQ), which assesses COVID-19 contamination anxiety, countermeasure necessity and compliance, mental health impact, stressor impact, social media usage, interpersonal conflicts, paranoid ideations, institutional & political trust, conspiracy beliefs, and social cohesion. Further, we illustrate the questionnaire's utility in an applied example investigating if higher SARS-Cov-2 infection rates in psychiatric patients could be explained by reduced compliance with preventive countermeasures. A group of 511 non-clinical individuals completed an initial pool of 111 CoPaQ items (Open Science Framework: https://osf.io/3evn9/ ) and additional scales measuring psychological distress, well-being, and paranoia to assess construct validity and lifetime mental health diagnosis for criterion validity. Factor structure was determined by exploratory factor analyses and validated by conducting confirmatory factor analysis in the accompanying longitudinal sample (n = 318) and an independent psychiatric inpatient sample primarily admitted for major depressive-, substance abuse-, personality-, and anxiety disorders (n = 113). Internal consistency was assessed by Cronbach's Alpha and McDonald's Omega. For the applied research example, Welch t-tests and correlational analyses were conducted. Twelve out of 16 extracted subscales were retained in the final questionnaire version, which provided preliminary evidence for adequate psychometric properties in terms of factor structure, internal consistency, and construct and criterion validity. Our applied research example showed that patients exhibited greater support for COVID-19 countermeasures than non-clinical individuals. However, this requires replication in future studies. We demonstrate that the CoPaQ is a comprehensive and valid measure of the psychosocial impact of the pandemic and could allow to a degree to disentangle the complex psychosocial phenomena of the pandemic as exemplified by our applied analyses.


The surprising negative correlation of gene length and optimal codon use--disentangling translational selection from GC-biased gene conversion in yeast.
Surprisingly, in several multi-cellular eukaryotes optimal codon use correlates negatively with gene length. This contrasts with the expectation under selection for translational accuracy. While suggested explanations focus on variation in strength and efficiency of translational selection, it has rarely been noticed that the negative correlation is reported only in organisms whose optimal codons are biased towards codons that end with G or C (-GC). This raises the question whether forces that affect base composition--such as GC-biased gene conversion--contribute to the negative correlation between optimal codon use and gene length. Yeast is a good organism to study this as equal numbers of optimal codons end in -GC and -AT and one may hence compare frequencies of optimal GC- with optimal AT-ending codons to disentangle the forces. Results of this study demonstrate in yeast frequencies of GC-ending (optimal AND non-optimal) codons decrease with gene length and increase with recombination. A decrease of GC-ending codons along genes contributes to the negative correlation with gene length. Correlations with recombination and gene expression differentiate between GC-ending and optimal codons, and also substitution patterns support effects of GC-biased gene conversion. While the general effect of GC-biased gene conversion is well known, the negative correlation of optimal codon use with gene length has not been considered in this context before. Initiation of gene conversion events in promoter regions and the presence of a gene conversion gradient most likely explain the observed decrease of GC-ending codons with gene length and gene position.