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Ratings of Perceived Exertion (RPE) are frequently used to prescribe exercise intensity. A central assumption of using RPE scales is that the subjective perception of effort maps onto objective performance in a consistent way. However, the degree and shape of how RPE aligns with objective performance is not fully understood. Here, we investigate the degree and shape of alignment, as well as how time (i.e., how frequently an effort needs to be performed) and mental effort (i.e., if one has to invest mental effort and physical effort) correspond with the alignment. In a randomized within-subjects experiment, we used a grip-to-scale method that asked participants (N = 43) to repeatedly squeeze a handgrip dynamometer with four to-be-produced RPE target levels relative to their subjective maximum strength (representing 20%, 40%, 60%, or 80%). We found that the RPE-force alignment was not the same across RPE-levels: Whereas subjective differences from 20-40% and 40-60% were met by comparable differences in produced force, a substantially larger difference was observed for the 60-80% interval. Interestingly, exploratory post-hoc analyses revealed that this was mirrored by an increase in variance at the higher effort levels. In addition, at constant RPE-levels, participants produced less force over time, and this effect was more pronounced at lower RPE target levels. Lastly, anticipating mental effort after the physical effort slightly altered the alignment as a function of the to-be-produced RPE-level and experimental duration. Taken together, our results indicate that the mapping of perceived effort on objective performance is intricate, and several factors affect the degree and shape of how RPE and performance align. Understanding the dynamic adjustment of RPE-performance alignment across different RPE levels is particularly relevant for contexts that use RPE as a tool for training load prescription.

Paleopathology, the study of diseases and injuries from the fossil record, allows for a unique view into the life of prehistoric animals. Pathologies have nowadays been described in nearly all groups of fossil vertebrates, especially dinosaurs. Despite the large number of skeletons, pathologies had never been reported in the sauropodomorph Plateosaurus trossingensis. Here we describe the first pathologies of Plateosaurus using two individuals with pathologies in the chevrons of the tail, from the Upper Triassic of Trossingen, SW Germany. The two specimens each contain three consecutive pathological chevrons. Our results show that the pathologies were caused by external trauma in one individual and potentially tendinous trauma in the other. Healing of the lesions allowed survival of both animals. Using additional pathological specimens found in other collections and from multiple localities, we observe that 14.8% of all individuals of Plateosaurus contain pathologies within their chevrons, suggesting it was a vulnerable bone.

BackgroundResearch on COVID-19 during pregnancy has mainly focused on women hospitalized for COVID-19 or other reasons during their pregnancy. Little is known about COVID-19 in the general population of pregnant women.ObjectiveTo describe the prevalence of COVID-19, symptoms, consequent healthcare use, and possible sources of COVID-19 exposure among a population-based sample of pregnant women residing in Northern California.MethodsWe analyzed data from 19,458 members of Kaiser Permanente Northern California who were pregnant between January 2020 and April 2021 and responded to an online survey about COVID-19 testing, diagnosis, symptoms, and their experiences during the COVID-19 pandemic. Medical diagnosis of COVID-19 during pregnancy was defined separately by self-report and by documentation in electronic health records (EHR). We examined relationships of COVID-19 with sociodemographic factors, underlying comorbidities, and survey measures of COVID-19-like symptoms, consequent healthcare utilization, and possible COVID-19 exposures.ResultsAmong 19,458 respondents, the crude prevalence of COVID-19 was 2.5% (n = 494) according to self-report and 1.4% (n = 276) according to EHR. After adjustment, the prevalence of self-reported COVID-19 was higher among women aged

Viral infections were investigated in American black bears (Ursus americanus) from Nevada and northern California with and without idiopathic encephalitis. Metagenomics analyses of tissue pools revealed novel viruses in the genera Circoviridae, Parvoviridae, Anelloviridae, Polyomaviridae, and Papillomaviridae. The circovirus and parvovirus were of particular interest due to their potential importance as pathogens. We characterized the genomes of these viruses and subsequently screened bears by PCR to determine their prevalence. The circovirus (Ursus americanus circovirus, UaCV) was detected at a high prevalence (10/16, 67%), and the chaphamaparvovirus (Ursus americanus parvovirus, UaPV) was found in a single bear. We showed that UaCV is present in liver, spleen/lymph node, and brain tissue of selected cases by in situ hybridization (ISH) and PCR. Infections were detected in cases of idiopathic encephalitis and in cases without inflammatory brain lesions. Infection status was not clearly correlated with disease, and the significance of these infections remains unclear. Given the known pathogenicity of a closely related mammalian circovirus, and the complex manifestations of circovirus-associated diseases, we suggest that UaCV warrants further study as a possible cause or contributor to disease in American black bears.

The ancient southern Levantine city of Gezer is well-known from Egyptian, Biblical and Assyrian sources, associated with power struggles, conquests, and intriguing tales involving figures such as Milkilu and Amenhotep III, Merneptah, the Philistines, Solomon and his unidentified pharaonic father-in-law, and Shishak / Sheshonq I. Since the identity of Gezer with "Tell Jezer" is quite literally 'set in stone' by some dozen boundary inscriptions, along with impressive Bronze and Iron Age remains, research at this site provides a unique opportunity to compare text and archaeology, as well as bring to light the undocumented everyday lives of the city's inhabitants. In this endeavour, independent scientific dating is crucial for anchoring the remains chronologically. This paper presents the first substantial radiocarbon dataset and Bayesian chronological analysis for Gezer spanning the last part of the Late Bronze Age (LBA; LB IIB) through Iron Age II. The dataset derives from an essentially continuous stratigraphic sequence exposed in recent years by the Tandy expedition along the central-southern edge of the site. The results allow us for the first time to independently determine the site chronology, test the viability (from a chronological perspective) of proposed historical correlations, and contribute to debates on Philistine and Iron Age chronology.

BackgroundSuicide and suicidal behavior during adolescence have been steadily increasing over the past two decades. The preponderance of interventions focuses on crisis intervention, underlying psychiatric disorders, regulating negative affect, and reducing cognitive distortions. However, low positive affectivity may be a mechanism that contributes to adolescent suicidal ideation and behaviors independent of other risk factors. Skills to Enhance Positivity (STEP) is an acceptance-based intervention, designed to increase attention to, and awareness of, positive affect and positive experiences. Results from a pilot RCT demonstrated engagement of the target (positive affect) and a decrease in clinical outcomes (suicidal events; i.e., either a suicide attempt or an emergency intervention for an acute suicidal crisis), providing support to test the clinical effectiveness of STEP in a larger clinical trial with clinical staff implementing the intervention.ObjectiveTo test the effectiveness of STEP, compared to Enhanced Treatment as Usual (ETAU), in reducing suicidal events and ideation in adolescents admitted to inpatient psychiatric care due to suicide risk. We hypothesize that those randomized to STEP, compared to ETAU, will have lower rates of suicide events, active suicidal ideation (SI), and depressed mood over the 6-month follow-up period. We hypothesize that those randomized to STEP, compared to ETAU, will demonstrate greater improvement in the hypothesized mechanisms of attention to positive affect stimuli and gratitude and satisfaction with life.MethodsParticipants will be randomized to either STEP or ETAU. STEP consists of four in-person sessions focused on psychoeducation regarding positive and negative affect, mindfulness meditation, gratitude, and savoring. Mood monitoring prompts and skill reminders will be sent via text messaging daily for the first month post-discharge and every other day for the following two months. The ETAU condition will receive text-delivered reminders to use a safety plan provided at discharge from the hospital and healthy habits messages, matched in frequency to the STEP group. This trial was registered on 6 August 2021 (ClinicalTrials.gov NCT04994873).ResultsThe STEP protocol was approved by the National Institute of Mental Health (NIMH) Data and Safety Monitoring Board on March 4, 2022. The RCT is currently in progress.DiscussionThe STEP protocol is an innovative, adjunctive treatment that has the potential to have positive effects on adolescent suicidal ideation and attempts beyond that found for standard treatment alone.

Opioid use disorder (OUD) represents a public health crisis in the United States. Medication for opioid use disorder (MOUD) with buprenorphine in primary care is a proven OUD treatment strategy. MOUD induction is when patients begin withdrawal and receive the first doses of buprenorphine. Differences between induction methods might influence short-term stabilization, long-term maintenance, and quality of life. This paper describes the protocol for a study designed to: (1) compare short-term stabilization and long-term maintenance treatment engagement in MOUD in patients receiving office, home, or telehealth induction and (2) identify clinically-relevant practice and patient characteristics associated with successful long-term treatment. The study design is a randomized, parallel group, pragmatic comparative effectiveness trial of three care models of MOUD induction in 100 primary care practices in the United States. Eligible patients are at least 16 years old, have been identified by their clinician as having opioid dependence and would benefit from MOUD. Patients will be randomized to one of three induction comparators: office, home, or telehealth induction. Primary outcomes are buprenorphine medication-taking and illicit opioid use at 30, 90, and 270 days post-induction. Secondary outcomes include quality of life and potential mediators of treatment maintenance (intentions, planning, automaticity). Potential moderators include social determinants of health, substance use history and appeal, and executive function. An intent to treat analysis will assess effects of the interventions on long-term treatment, using general/generalized linear mixed models, adjusted for covariates, for the outcomes analysis. Analysis includes practice- and patient-level random effects for hierarchical/longitudinal data. No large-scale, randomized comparative effectiveness research has compared home induction to office or telehealth MOUD induction on long-term outcomes for patients with OUD seen in primary care settings. The results of this study will offer primary care providers evidence and guidance in selecting the most beneficial induction method(s) for specific patients.

Mercury (Hg) is a concerning contaminant due to its widespread distribution and tendency to accumulate to harmful concentrations in biota. We used a machine learning approach called random forest (RF) to test for different predictors of Hg concentrations in three species of Colorado reservoir sport fish. The RF approach indicated that the best predictors of 864 mm northern pike (Esox lucius) Hg concentrations were covariates related to salmonid stocking in each study system, while system-specific metrics related to productivity and forage base were the best predictors of Hg concentrations of 381 mm smallmouth bass (Micropterus dolomieu), and walleye (Sander vitreus). Protecting human and ecological health from Hg contamination requires an understanding of fish Hg concentrations and variability across the landscape and through time. The RF approach could be applied to identify potential areas/systems of concern, and predict whether sport fish Hg concentrations may change as a result of a variety of factors to help prioritize, focus, and streamline monitoring efforts to effectively and efficiently inform human and ecological health.

Providing insights on refusal to participate in research is critical to achieve a better understanding of the non-response bias. Little is known on people who refused to participate, especially in hard-to-reach populations such as detained persons. This study investigated the potential non-response bias among detained persons, comparing participants who accepted or refused to sign a one-time general informed consent. We used data collected in a cross-sectional study primary designed to evaluate a one-time general informed consent for research. A total of 190 participants were included in the study (response rate = 84.7%). The main outcome was the acceptance to sign the informed consent, used as a proxy to evaluate non-response. We collected sociodemographic variables, health literacy, and self-reported clinical information. A total of 83.2% of the participants signed the informed consent. In the multivariable model after lasso selection and according to the relative bias, the most important predictors were the level of education (OR = 2.13, bias = 20.7%), health insurance status (OR = 2.04, bias = 7.8%), need of another study language (OR = 0.21, bias = 39.4%), health literacy (OR = 2.20, bias = 10.0%), and region of origin (not included in the lasso regression model, bias = 9.2%). Clinical characteristics were not significantly associated with the main outcome and had low relative biases (≤ 2.7%). Refusers were more likely to have social vulnerabilities than consenters, but clinical vulnerabilities were similar in both groups. The non-response bias probably occurred in this prison population. Therefore, efforts should be made to reach this vulnerable population, improve participation in research, and ensure a fair and equitable distribution of research benefits.

Microbiome research relies on next-generation sequencing and on downstream data analysis workflows. Several manufacturers have introduced multi-amplicon kits for microbiome characterization, improving speciation, but present unique challenges for analysis. The goal of this methodology study was to develop two analysis pipelines specific to mixed-orientation reads from multi-hypervariable (V) region amplicons. A secondary aim was to assess agreement with expected abundance, considering database and variable region. Mock community sequence data (n = 41) generated using the Ion16S™ Metagenomics Kit and Ion Torrent Sequencing Platform were analyzed using two workflows. Amplicons from V2, V3, V4, V6-7, V8 and V9 were deconvoluted using a specialized plugin based on CutPrimers. A separate workflow using Cutadapt is also presented. Three reference databases (Ribosomal Database Project, Greengenes and Silva) were used for taxonomic assignment. Bray-Curtis, Euclidean and Jensen-Shannon distance measures were used to evaluate overall annotation consistency, and specific taxon agreement was determined by calculating the ratio of observed to expected relative abundance. Reads that mapped to regions V2-V9 varied for both CutPrimers and Cutadapt-based methods. Within the CutPrimers-based pipeline, V3 amplicons had the best agreement with the expected distribution, tested using global distance measures, while V9 amplicons had the worst agreement. Accurate taxonomic annotation varied by genus-level taxon and V region analyzed. For the first time, we present a microbiome analysis pipeline that employs a specialized plugin to allow microbiome researchers to separate multi-amplicon data from the Ion16S Metagenomics Kit into V-specific reads. We also present an additional analysis workflow, modified for Ion Torrent mixed orientation reads. Overall, the global agreement of amplicons with the expected mock community abundances differed across V regions and reference databases. Benchmarking data should be referenced when planning a microbiome study to consider these biases related to sequencing and data analysis for multi-amplicon sequencing kits.

Mycoplasma pneumoniae is a significant cause of respiratory illness worldwide. Despite a minimal and highly conserved genome, genetic diversity within the species may impact disease. We performed whole genome sequencing (WGS) analysis of 107 M. pneumoniae isolates, including 67 newly sequenced using the Pacific BioSciences RS II and/or Illumina MiSeq sequencing platforms. Comparative genomic analysis of 107 genomes revealed >3,000 single nucleotide polymorphisms (SNPs) in total, including 520 type-specific SNPs. Population structure analysis supported the existence of six distinct subgroups, three within each type. We developed a predictive model to classify an isolate based on whole genome SNPs called against the reference genome into the identified subtypes, obviating the need for genome assembly. This study is the most comprehensive WGS analysis for M. pneumoniae to date, underscoring the power of combining complementary sequencing technologies to overcome difficult-to-sequence regions and highlighting potential differential genomic signatures in M. pneumoniae.

[This corrects the article DOI: 10.1371/journal.pone.0174701.].

Ratings of Perceived Exertion (RPE) are frequently used to prescribe exercise intensity. A central assumption of using RPE scales is that the subjective perception of effort maps onto objective performance in a consistent way. However, the degree and shape of how RPE aligns with objective performance is not fully understood. Here, we investigate the degree and shape of alignment, as well as how time (i.e., how frequently an effort needs to be performed) and mental effort (i.e., if one has to invest mental effort and physical effort) correspond with the alignment. In a randomized within-subjects experiment, we used a grip-to-scale method that asked participants (N = 43) to repeatedly squeeze a handgrip dynamometer with four to-be-produced RPE target levels relative to their subjective maximum strength (representing 20%, 40%, 60%, or 80%). We found that the RPE-force alignment was not the same across RPE-levels: Whereas subjective differences from 20–40% and 40–60% were met by comparable differences in produced force, a substantially larger difference was observed for the 60–80% interval. Interestingly, exploratory post-hoc analyses revealed that this was mirrored by an increase in variance at the higher effort levels. In addition, at constant RPE-levels, participants produced less force over time, and this effect was more pronounced at lower RPE target levels. Lastly, anticipating mental effort after the physical effort slightly altered the alignment as a function of the to-be-produced RPE-level and experimental duration. Taken together, our results indicate that the mapping of perceived effort on objective performance is intricate, and several factors affect the degree and shape of how RPE and performance align. Understanding the dynamic adjustment of RPE-performance alignment across different RPE levels is particularly relevant for contexts that use RPE as a tool for training load prescription. [ABSTRACT FROM AUTHOR]

Paleopathology, the study of diseases and injuries from the fossil record, allows for a unique view into the life of prehistoric animals. Pathologies have nowadays been described in nearly all groups of fossil vertebrates, especially dinosaurs. Despite the large number of skeletons, pathologies had never been reported in the sauropodomorph Plateosaurus trossingensis. Here we describe the first pathologies of Plateosaurus using two individuals with pathologies in the chevrons of the tail, from the Upper Triassic of Trossingen, SW Germany. The two specimens each contain three consecutive pathological chevrons. Our results show that the pathologies were caused by external trauma in one individual and potentially tendinous trauma in the other. Healing of the lesions allowed survival of both animals. Using additional pathological specimens found in other collections and from multiple localities, we observe that 14.8% of all individuals of Plateosaurus contain pathologies within their chevrons, suggesting it was a vulnerable bone. [ABSTRACT FROM AUTHOR]

Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality "unpleasantness" delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol-objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and Transvamix® in forward or reversed orders, each for two weeks and separated by a washout. The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal. Trial registration number: Netherlands Trial Register: NL9347 (Acronym: C4EB).

Social science research is key for understanding and for predicting compliance with COVID-19 guidelines, and this research relies on survey data. While much focus is on the survey question stems, less is on the response alternatives presented that both constrain responses and convey information about the assumed expectations of the survey designers. The focus here is on the choice of response alternatives for the types of behavioral frequency questions used in many COVID-19 and other health surveys. We examine issues with two types of response alternatives. The first are vague quantifiers, like "rarely" and "frequently." Using data from 30 countries from the Imperial COVID data hub, we show that the interpretation of these vague quantifiers (and their translations) depends on the norms in that country. If the mean amount of hand washing in a country is high, it is likely "frequently" corresponds to a higher numeric value for hand washing than if the mean in the country is low. The second type are sets of numeric alternatives and they can also be problematic. Using a US survey, respondents were randomly allocated to receive either response alternatives where most of the scale corresponds to low frequencies or where most of the scale corresponds to high frequencies. Those given the low frequency set provided lower estimates of the health behaviors. The choice of response alternatives for behavioral frequency questions can affect the estimates of health behaviors. How the response alternatives mold the responses should be taken into account for epidemiological modeling. We conclude with some recommendations for response alternatives for behavioral frequency questions in surveys.

IntroductionSince the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines.Materials and methodsTo longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses.ResultsA total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate.ConclusionWhile the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Analysis of convalescent plasma derived from individuals has shown that IgG3 has the most important role in binding to SARS-CoV-2 antigens; however, this has not yet been confirmed in large studies, and the link between binding and neutralization has not been confirmed. By analyzing plasma pools consisting of 247–567 individual convalescent donors, we demonstrated the binding of IgG3 and IgM to Spike-1 protein and the receptor-binding domain correlates strongly with viral neutralization in vitro. Furthermore, despite accounting for only approximately 12% of total immunoglobulin mass, collectively IgG3 and IgM account for approximately 80% of the total neutralization. This may have important implications for the development of potent therapies for COVID-19, as it indicates that hyperimmune globulins or convalescent plasma donations with high IgG3 concentrations may be a highly efficacious therapy.

Background Impaired cardiac autonomic control is common among people with type 2 diabetes. The autonomic nervous system and its regulatory influence on the cardiovascular system also play a key role in the physiological response to psychosocial stressors. It is unclear whether the disease-related impairment of cardiac autonomic control in people with type 2 diabetes affects the stress response. The aim of this study was therefore to examine the cardiac autonomic and the psychological stress response of people with type 2 diabetes compared to healthy control participants. Methods We used the trier social stress test to induce stress in n = 51 participants with type 2 diabetes and n = 47 healthy controls. We assessed heart rate (HR) and heart rate variability (HRV) using six ECG samples before, during and after the stress test. We measured participants’ psychological stress response using visual analogue scales. Results Longitudinal multilevel models showed an attenuated HR increase in response to the stress test combined with a slower HR recovery after the stress test, in people with type 2 diabetes. This pattern was accompanied by significantly lower low frequency HRV but no differences in high frequency HRV between the groups. Additionally, people with type 2 diabetes showed an increased level of self-reported psychological tension 45 minutes after the stress test. Conclusions The impairment of the autonomic nervous system found in people with type 2 diabetes is reflected in the HR response to stress—but not in the HRV response—and partially mirrored in the psychological stress response. Our results underline the importance of considering the interplay of psychosocial stress and disease-related changes in the physiological stress response system in research and treatment of type 2 diabetes.

BackgroundGrowing social inequities have made it important for general practitioners to verify if patients can afford treatment and procedures. Incorporating social conditions into clinical decision-making allows general practitioners to address mismatches between patients' health-care needs and financial resources.ObjectivesIdentify a screening question to, indirectly, rule out patients' social risk of forgoing health care for economic reasons, and estimate prevalence of forgoing health care and the influence of physicians' attitudes toward deprivation.DesignMulticenter cross-sectional survey.ParticipantsForty-seven general practitioners working in the French-speaking part of Switzerland enrolled a random sample of patients attending their private practices.Main measuresPatients who had forgone health care were defined as those reporting a household member (including themselves) having forgone treatment for economic reasons during the previous 12 months, through a self-administered questionnaire. Patients were also asked about education and income levels, self-perceived social position, and deprivation levels.Key resultsOverall, 2,026 patients were included in the analysis; 10.7% (CI95% 9.4-12.1) reported a member of their household to have forgone health care during the 12 previous months. The question "Did you have difficulties paying your household bills during the last 12 months" performed better in identifying patients at risk of forgoing health care than a combination of four objective measures of socio-economic status (gender, age, education level, and income) (R(2) = 0.184 vs. 0.083). This question effectively ruled out that patients had forgone health care, with a negative predictive value of 96%. Furthermore, for physicians who felt powerless in the face of deprivation, we observed an increase in the odds of patients forgoing health care of 1.5 times.ConclusionGeneral practitioners should systematically evaluate the socio-economic status of their patients. Asking patients whether they experience any difficulties in paying their bills is an effective means of identifying patients who might forgo health care.

IntroductionIt has been estimated that between 15% and 18% of patients who start antiretroviral therapy (ART) do not achieve a successful immune recovery despite complete virological suppression. In the literature this phenomenom is known as poor immune recovery or immunovirological discordance (IVD). Zinc has an immunomodulatory role associated with T lymphocytes and its supplementation could enhance immune recovery.ObjectiveTo determine if zinc supplementation on IVD patients prevents immune failure after 12 months of supplementation. Secondary objectives were to determine serum zinc levels in HIV patients with and without IVD and the frequency of hypozincemia in discordant patients.MethodWe reviewed the historical record of patients under care at Arriarán Foundation. Following inclusion criteria were defined: 1) age ≥ 18 years, 2) standard ART (three effective drugs) for at least 18 months, 3) virologically suppressed for 12 months, 3) persistence of CD4 count ≤200 cells/mm3 and/or increase ≤ 80 cells/mm3 after one year of viral undetectability. A control group was assigned paired 1:1 by sex, age (± 2 years) that did achieved an increase of CD4> 350 cells/ mm3. In both groups plasma zinc levels were determined. In a later phase, patients with IVD were randomized to receive zinc (15 mg daily) versus placebo. Patients were followed for 12 months with CD4 count, viral load and zinc levels determinations every 4-6 months.ResultsA total of 80 patients, 40 patients with IVD criteria and 40 controls were included. 92.5% were men, and age average was 47.5 years. The median baseline CD4 was 189 cells/mm3 (71-258) in the cases vs. 552.5 cells/ mm3 (317-400) in the control group with a median increase at the end of the study of 39 cell/mm3 and 19 cell/mm3 respectively. There was no difference in baseline plasma zinc levels between both groups (81.7 + 18.1 in cases versus 86.2 + 11.0 in controls). In the 40 patients with IVD, the median absolute increase in CD4 after annual zinc supplementation was 31.5 cells/mm3 in the treated group versus 50 cells/mm3 in the placebo group, this difference being statistically not significant (p = 0.382).ConclusionsPatients with IVD have plasma zinc levels similar to those who achieve adequate immune recovery. Zinc supplementation in IVD patients showed a statistically non-significant difference in in CD4 levels between cases and controls. The results warrant a comparative study with a larger number of patients.

Endurance sports pose a plethora of mental demands that exercisers have to deal with. Unfortunately, investigations of exercise-specific demands and strategies to deal with them are insufficiently researched, leading to a gap in knowledge about athletic requirements and strategies used to deal with them. Here, we investigated which obstacles exercisers experience during an anaerobic (Wingate test) and an aerobic cycling test (incremental exercise test), as well as the strategies they considered helpful for dealing with these obstacles (qualitative analysis). In addition, we examined whether thinking of these obstacles and strategies in terms of if-then plans (or implementation intentions; i.e., “If I encounter obstacle O, then I will apply strategy S!”) improves performance over merely setting performance goals (i.e., goal intentions; quantitative analysis). N = 59 participants (age: M = 23.9 ± 6.5 years) performed both tests twice in a 2-within (Experimental session: 1 vs. 2) × 2-between (Condition: goal vs. implementation intention) design. Exercisers’ obstacles and strategies were assessed using structured interviews in Session 1 and subjected to thematic analysis. In both tests, feelings of exertion were the most frequently stated obstacle. Motivation to do well, self-encouragement, and focus on the body and on cycling were frequently stated strategies in both tests. There were also test-specific obstacles, such as boredom reported in the aerobic test. For session 2, the obstacles and strategies elicited in Session 1 were used to specify if-then plans. Bayesian mixed-factor ANOVA suggests, however, that if-then plans did not help exercisers to improve their performance. These findings shed novel light into the mental processes accompanying endurance exercise and the limits they pose on performance.

Background Transcutaneous vagal nerve stimulation has analgesic potential and might be elicited by abdominally administered low-frequency vibrations. The objective was to study the safety and effect of a combination of music and abdominally administered low-frequency vibrations on pain intensity in elderly patients with chronic musculoskeletal pain. Methods This trial was an international multicenter, randomized controlled pilot study. Patients at age ≥ 65 years with musculoskeletal pain for ≥ 3 months and a daily pain score ≥ 4 out of 10 were recruited at three centers. They were randomized to receive either a combination of music and low-frequency (20–100 Hz) vibrations administered to the abdomen, or a combination with the same music but with higher frequency (200–300 Hz) vibrations administered to the abdomen. Low-frequency vibrations were expected to result in pain reduction measured with a numeric pain rating scale (NRS). Patients in both groups received eight treatments of the music combined with the vibrations in three weeks. Primary outcomes were safety (Serious Adverse Events) and pain intensity measured at baseline, after the last treatment and at six weeks follow-up. Multilevel linear model analyses were performed to study group and time effects. Results A total of 45 patients were analyzed according to intention-to-treat principle. After 344 treatments, 1 Adverse Event was found related to the intervention, while 13 Adverse Events were possibly related. A multilevel linear model showed that the interaction effect of group by time did not predict pain intensity (F[1, 45.93] = 0.002, p = 0.97) when comparing pain intensity at baseline, after the last treatment and at follow-up. Conclusions The combination of music and abdominally administered vibrations was found to be safe and well tolerated by the elderly patients. However, over time, neither the low-frequency treatment group nor the high-frequency treatment group provided clinically meaningful pain relief. There is no evidence that the low-frequency treatment elicited vagal nerve stimulation. Trial registration The trial was prospectively registered in the Netherlands Trial Register (NTR: NL7606) on 21-03-2019.

IntroductionThe aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM).MethodsOur study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019.ResultsThe study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%-25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%-22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41-1.70, severe depression 1.33, 95% CI 1.18-1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27-1.38, PIM 1.18, 95% CI: 1.14-1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11-1.46, PIM 1.27, 95% CI: 1.11-1.44), respectively.ConclusionThis study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.

Altered attentional processing of pain-associated stimuli-which might take the form of either avoidance or enhanced vigilance-is thought to be implicated in the development and maintenance of chronic pain. In contrast to reaction time tasks like the dot probe, eye tracking allows for tracking the time course of visual attention and thus differentiating early and late attentional processes. Our study aimed at investigating visual attention to emotional faces in patients with chronic musculoskeletal pain (N = 20) and matched pain-free controls (N = 20). Emotional faces (pain, angry, happy) were presented in pairs with a neutral face for 2000 ms each. Three parameters were determined: First fixation probabilities, fixation durations (overall and divided in four 500 ms intervals) and a fixation bias score as the relative fixation duration of emotional faces compared to neutral faces. There were no group differences in any of the parameters. First fixation probabilities were lower for pain faces than for angry faces. Overall, we found longer fixation duration on emotional compared to neutral faces ('emotionality bias'), which is in accord with previous research. However, significant longer fixation duration compared to the neutral face was detected only for happy and angry but not for pain faces. In addition, fixation durations as well as bias scores yielded evidence for vigilant-avoidant processing of pain faces in both groups. These results suggest that attentional bias towards pain-associated stimuli might not generally differentiate between healthy individuals and chronic pain patients. Exaggerated attentional bias in patients might occur only under specific circumstances, e.g., towards stimulus material specifically relating to the specific pain of the patients under study or under high emotional distress.

Social interaction requires fast and efficient processing of another person's intentions. In face-to-face interactions, aversive or appetitive actions typically co-occur with emotional expressions, allowing an observer to anticipate action intentions. In the present study, we investigated the influence of facial emotions on the processing of action intentions. Thirty-two participants were presented with video clips showing virtual agents displaying a facial emotion (angry vs. happy) while performing an action (punch vs. fist-bump) directed towards the observer. During each trial, video clips stopped at varying durations of the unfolding action, and participants had to recognize the presented action. Naturally, participants' recognition accuracy improved with increasing duration of the unfolding actions. Interestingly, while facial emotions did not influence accuracy, there was a significant influence on participants' action judgements. Participants were more likely to judge a presented action as a punch when agents showed an angry compared to a happy facial emotion. This effect was more pronounced in short video clips, showing only the beginning of an unfolding action, than in long video clips, showing near-complete actions. These results suggest that facial emotions influence anticipatory processing of action intentions allowing for fast and adaptive responses in social interactions.

ObjectivesComprehensive cost-effectiveness analyses of introducing varicella and/or herpes zoster vaccination in the Swedish national vaccination programme.DesignCost-effectiveness analyses based on epidemiological results from a specifically developed transmission model.SettingNational vaccination programme in Sweden, over an 85- or 20-year time horizon depending on the vaccination strategy.ParticipantsHypothetical cohorts of people aged 12 months and 65-years at baseline.InterventionsFour alternative vaccination strategies; 1, not to vaccinate; 2, varicella vaccination with one dose of the live attenuated vaccine at age 12 months and a second dose at age 18 months; 3, herpes zoster vaccination with one dose of the live attenuated vaccine at 65 years of age; and 4, both vaccine against varicella and herpes zoster with the before-mentioned strategies.Main outcome measuresAccumulated cost and quality-adjusted life years (QALY) for each strategy, and incremental cost-effectiveness ratios (ICER).ResultsIt would be cost-effective to vaccinate against varicella (dominant), but not to vaccinate against herpes zoster (ICER of EUR 200,000), assuming a cost-effectiveness threshold of EUR 50,000 per QALY. The incremental analysis between varicella vaccination only and the combined programme results in a cost per gained QALY of almost EUR 1.6 million.ConclusionsThe results from this study are central components for policy-relevant decision-making, and suggest that it was cost-effective to introduce varicella vaccination in Sweden, whereas herpes zoster vaccination with the live attenuated vaccine for the elderly was not cost-effective-the health effects of the latter vaccination cannot be considered reasonable in relation to its costs. Future observational and surveillance studies are needed to make reasonable predictions on how boosting affects the herpes zoster incidence in the population, and thus the cost-effectiveness of a vaccination programme against varicella. Also, the link between herpes zoster and sequelae need to be studied in more detail to include it suitably in health economic evaluations.

BackgroundResearch on COVID-19 during pregnancy has mainly focused on women hospitalized for COVID-19 or other reasons during their pregnancy. Little is known about COVID-19 in the general population of pregnant women.ObjectiveTo describe the prevalence of COVID-19, symptoms, consequent healthcare use, and possible sources of COVID-19 exposure among a population-based sample of pregnant women residing in Northern California.MethodsWe analyzed data from 19,458 members of Kaiser Permanente Northern California who were pregnant between January 2020 and April 2021 and responded to an online survey about COVID-19 testing, diagnosis, symptoms, and their experiences during the COVID-19 pandemic. Medical diagnosis of COVID-19 during pregnancy was defined separately by self-report and by documentation in electronic health records (EHR). We examined relationships of COVID-19 with sociodemographic factors, underlying comorbidities, and survey measures of COVID-19-like symptoms, consequent healthcare utilization, and possible COVID-19 exposures.ResultsAmong 19,458 respondents, the crude prevalence of COVID-19 was 2.5% (n = 494) according to self-report and 1.4% (n = 276) according to EHR. After adjustment, the prevalence of self-reported COVID-19 was higher among women aged ConclusionsObserved COVID-19 prevalence differences by sociodemographic and socioeconomic factors underscore social and health inequities among reproductive-aged women. Women with COVID-19 reported unique symptoms and low frequency of hospitalization. Many were not aware of an exposure to someone with COVID-19.

ObjectivesTo elicit patterns in pathogenic biofilm composition we characterized the oral microbiome present in patients with dentin caries in comparison to healthy subjects.Methods16S amplicon sequencing was used to analyse a total of 56 patients; 19 samples of carious dentin (pooled from at least three teeth) and 37 supragingival samples (pooled from three healthy tooth surfaces). Oral and periodontal status and socio-demographic parameters were recorded. Group assignment, smoking and further socio-demographic parameters were used as explanatory variables in the microbiome composition analysis.ResultsOverall, a total of 4,110,020 DNA high-quality sequences were yielded. Using a threshold of similarity >97% for assigning operational taxonomic units (OTU), a total of 1,537 OTUs were identified. PERMANOVA showed significant differences in microbiome composition between the groups caries/healthy (p = 0.001), smoking/non-smoking (p = 0.007) and fluoride intake during childhood yes/no (tablets p = 0.003, salt p = 0.023). The healthy microbiome had a significantly higher diversity (alpha diversity, pConclusionsThe healthy microbiome was highly diverse. The advanced caries microbiome was dominated by a set of carious associated bacteria where S. mutans played only a minor role. Smoking and fluoride intake during childhood influenced the microbiome composition significantly.Clinical significanceThe presented investigation adds knowledge to the still not fully comprehended patterns of oral microbiomes in caries compared with oral health. By analysing the genetics of biofilm samples from oral health and severe tooth decay we found distinct discriminating species which could be targets for future therapeutic approaches.

In the Gulf of Maine area (GoMA), as elsewhere in the ocean, the organisms of greatest numerical abundance are microbes. Viruses in GoMA are largely cyanophages and bacteriophages, including podoviruses which lack tails. There is also evidence of Mimivirus and Chlorovirus in the metagenome. Bacteria in GoMA comprise the dominant SAR11 phylotype cluster, and other abundant phylotypes such as SAR86-like cluster, SAR116-like cluster, Roseobacter, Rhodospirillaceae, Acidomicrobidae, Flavobacteriales, Cytophaga, and unclassified Alphaproteobacteria and Gammaproteobacteria clusters. Bacterial epibionts of the dinoflagellate Alexandrium fundyense include Rhodobacteraceae, Flavobacteriaceae, Cytophaga spp., Sulfitobacter spp., Sphingomonas spp., and unclassified Bacteroidetes. Phototrophic prokaryotes in GoMA include cyanobacteria that contain chlorophyll (mainly Synechococcus), aerobic anoxygenic phototrophs that contain bacteriochlorophyll, and bacteria that contain proteorhodopsin. Eukaryotic microalgae in GoMA include Bacillariophyceae, Dinophyceae, Prymnesiophyceae, Prasinophyceae, Trebouxiophyceae, Cryptophyceae, Dictyochophyceae, Chrysophyceae, Eustigmatophyceae, Pelagophyceae, Synurophyceae, and Xanthophyceae. There are no records of Bolidophyceae, Aurearenophyceae, Raphidophyceae, and Synchromophyceae in GoMA. In total, there are records for 665 names and 229 genera of microalgae. Heterotrophic eukaryotic protists in GoMA include Dinophyceae, Alveolata, Apicomplexa, amoeboid organisms, Labrynthulida, and heterotrophic marine stramenopiles (MAST). Ciliates include Strombidium, Lohmaniella, Tontonia, Strobilidium, Strombidinopsis and the mixotrophs Laboea strobila and Myrionecta rubrum (ex Mesodinium rubra). An inventory of selected microbial groups in each of 14 physiographic regions in GoMA is made by combining information on the depth-dependent variation of cell density and the depth-dependent variation of water volume. Across the entire GoMA, an estimate for the minimum abundance of cell-based microbes is 1.7×10(25) organisms. By one account, this number of microbes implies a richness of 10(5) to 10(6) taxa in the entire water volume of GoMA. Morphological diversity in microplankton is well-described but the true extent of taxonomic diversity, especially in the femtoplankton, picoplankton and nanoplankton--whether autotrophic, heterotrophic, or mixotrophic, is unknown.

BACKGROUND:Coinfections of HIV patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) are mayor public health problems, contributing to the emerging burden of HIV-associated hepatic mortality. Coinfection rates vary geographically, depending on various factors such as predominant transmission modes, HBV vaccination rates, and prevalence of HBV and HCV in the general population. In South America, the epidemiology of coinfections is uncertain, since systematic studies are scarce. Our study aimed to analyze rates of HBV and HCV infection in people living with HIV attending centers of the public and private health system in Chile. METHODS:We performed a cross-sectional study including a public university hospital and a private health center in Santiago, Metropolitan Region in Chile. Serum samples were used to determine serological markers of hepatitis B (HBsAg, anti-HBs, anti-HBc total, HBeAg, anti-HBe) and anti-HCV. Demographic, clinical and laboratory data were obtained from medical records. RESULTS:399 patients were included (353 from public, 46 from private health center). Most (92.8%) were male, with a median age of 38.3 years; 99.4% acquired HIV through sexual contact (75.0% MSM); 25.7% had AIDS and 90.4% were on ART. In 78.9%, viral loads were

Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation [CSI] or local radiotherapy [LRT]). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.

Fatigue and cognitive deficits are often co-occurring symptoms reported by patients after radiation therapy for prostate cancer. In this study, we induced fatigue-like behavior in mice using targeted pelvic irradiation to mimic the clinical treatment regimen and assess cognitive behavioral changes. We observed that pelvic irradiation produced a robust fatigue phenotype, a reduced rate of spontaneous alternation in a Y-maze test, and no behavioral change in an open field test. We found that reversal learning for fatigued mice was slower with respect to time, but not with respect to effort put into the test, suggesting that fatigue may impact the ability or motivation to work at a cognitive task without impairing cognitive capabilities. In addition, we found that mice undergoing pelvic irradiation show lower whole-brain levels of mature BDNF, and that whole-brain proBDNF levels also correlate with spontaneous alternation in a Y-maze test. These results suggest that changes in BDNF levels could be both a cause and an effect of fatigue-related changes in behavior.

Why people differ in their susceptibility to external events is essential to our understanding of personality, human development, and mental disorders. Genes explain a substantial portion of these differences. Specifically, genes influencing the serotonin system are hypothesized to be differential susceptibility factors, determining a person's reactivity to both positive and negative environments. We tested whether genetic variation in the serotonin transporter (5-HTTLPR) is a differential susceptibility factor for daily events. Participants (N = 326, 77% female, mean age = 25, range = 17-36) completed smartphone questionnaires four times a day over four to five days, measuring stressors, uplifts, positive and negative affect. Affect was predicted from environment valence in the previous hour on a within-person level using three-level autoregressive linear mixed models. The 5-HTTLPR fulfilled all criteria of a differential susceptibility factor: Positive affect in carriers of the short allele (S) was less reactive to both uplifts and stressors, compared to homozygous carriers of the long allele (L/L). This pattern might reflect relative affective inflexibility in S-allele carriers. Our study provides insight into the serotonin system's general role in susceptibility and highlights the need to assess the whole spectrum of naturalistic experiences.

In this study, we present a novel strategy to the method of finite elements (FEM) of linear elastic problems of very high resolution on graphic processing units (GPU). The approach exploits regularities in the system matrix that occur in regular hexahedral grids to achieve cache-friendly matrix-free FEM. The node-by-node method lies in the class of block-iterative Gauss-Seidel multigrid solvers. Our method significantly improves convergence times in cases where an ordered distribution of distinct materials is present in the dataset. The method was evaluated on three real world datasets: An aluminum-silicon (AlSi) alloy and a dual phase steel material sample, both captured by scanning electron tomography, and a clinical computed tomography (CT) scan of a tibia. The caching scheme leads to a speed-up factor of ×2-×4 compared to the same code without the caching scheme. Additionally, it facilitates the computation of high-resolution problems that cannot be computed otherwise due to memory consumption.

IntroductionEtiology studies of severe acute respiratory infections (SARI) in adults are limited. We studied potential etiologies of SARI among adults in six countries using multi-pathogen diagnostics.MethodsWe enrolled both adults with SARI (acute respiratory illness onset with fever and cough requiring hospitalization) and asymptomatic adults (adults hospitalized with non-infectious illnesses, non-household members accompanying SARI patients, adults enrolled from outpatient departments, and community members) in each country. Demographics, clinical data, and nasopharyngeal and oropharyngeal specimens were collected from both SARI patients and asymptomatic adults. Specimens were tested for presence of 29 pathogens utilizing the Taqman® Array Card platform. We applied a non-parametric Bayesian regression extension of a partially latent class model approach to estimate proportions of SARI caused by specific pathogens.ResultsWe enrolled 2,388 SARI patients and 1,135 asymptomatic adults from October 2013 through October 2015. We detected ≥1 pathogen in 76% of SARI patients and 67% of asymptomatic adults. Haemophilus influenzae and Streptococcus pneumoniae were most commonly detected (≥23% of SARI patients and asymptomatic adults). Through modeling, etiology was attributed to a pathogen in most SARI patients (range among countries: 57.3-93.2%); pathogens commonly attributed to SARI etiology included influenza A (14.4-54.4%), influenza B (1.9-19.1%), rhino/enterovirus (1.8-42.6%), and RSV (3.6-14.6%).ConclusionsUse of multi-pathogen diagnostics and modeling enabled attribution of etiology in most adult SARI patients, despite frequent detection of multiple pathogens in the upper respiratory tract. Seasonal flu vaccination and development of RSV vaccine would likely reduce the burden of SARI in these populations.

BackgroundA growing population of older adults with HIV will increase demands on HIV-related healthcare. Nearly a quarter of people receiving care for HIV in Latin America are currently 50 years or older, yet little is known about the frequency of comorbidities in this population. We estimated the prevalence and incidence of non-communicable diseases (NCDs) among people 50 years of age or older (≥50yo) receiving HIV care during 2000-2015 in six centers affiliated with the Caribbean, Central and South American network for HIV epidemiology (CCASAnet).MethodsWe estimated the annual prevalence, and overall prevalence and incidence of cardiovascular diseases, diabetes, hypertension, dyslipidemia, psychiatric disorders, chronic liver and renal diseases, and non-AIDS-defining cancers, and multimorbidity (more than one NCD) of people ≥50yo receiving care for HIV. Analyses were performed according to age at enrollment into HIV care (ResultsWe included 3,415 patients ≥50yo, of whom 1,487(43%) were enrolled at age ≥50 years. The annual prevalence of NCDs increased from 32% to 68% and multimorbidity from 30% to 40% during 2000-2015. At the last registered visit, 53% of patients enrolled ConclusionsThe prevalence of NCDs and multimorbidity in people ≥50 years receiving care for HIV in CCASAnet centers in Latin America increased substantially in the last 15 years. Our results make evident the need of planning for provision of complex, primary care for aging adults living with HIV.

BackgroundAn increasing body of evidence is indicating that the gut microbiota modulates pulmonary inflammatory responses. This so-called gut-lung axis might be of importance in a whole spectrum of inflammatory pulmonary diseases such as acute respiratory distress syndrome, chronic obstructive pulmonary disease and pneumonia. Here, we investigate the effect of antibiotic disruption of gut microbiota on immune responses in the lung after a intranasal challenge with lipopolysaccharide (LPS).Methods/resultsC57Bl/6 mice were treated for two weeks with broad-spectrum antibiotics supplemented to their drinking water. Afterwards, mice and untreated control mice were inoculated intranasally with LPS. Mice were sacrificed 2 and 6 hours post-challenge, after which bronchoalveolar lavage fluid (BALF) and lung tissues were taken. Gut microbiota analysis showed that antibiotic-treated mice had a pronounced reduction in numbers and diversity of bacteria. A modest, but time consistent, significant increase of interleukin (IL)-6 release was seen in BALF of antibiotic treated mice. Release of tumor necrosis factor alpha (TNFα), however, was not statistically different between groups.ConclusionAntibiotic induced microbiota disruption is associated with alterations in host responses during LPS-induced lung inflammation. Further studies are required to determine the clinical relevance of the gut-lung axis in pulmonary infection and inflammation.

ObjectiveRapid testing is paramount during a pandemic to prevent continued viral spread and excess morbidity and mortality. This study investigates whether testing strategies based on sample pooling can increase the speed and throughput of screening for SARS-CoV-2, especially in resource-limited settings.MethodsIn a mathematical modelling approach conducted in May 2020, six different testing strategies were simulated based on key input parameters such as infection rate, test characteristics, population size, and testing capacity. The situations in five countries were simulated, reflecting a broad variety of population sizes and testing capacities. The primary study outcome measurements were time and number of tests required, number of cases identified, and number of false positives.FindingsThe performance of all tested methods depends on the input parameters, i.e. the specific circumstances of a screening campaign. To screen one tenth of each country's population at an infection rate of 1%, realistic optimised testing strategies enable such a campaign to be completed in ca. 29 days in the US, 71 in the UK, 25 in Singapore, 17 in Italy, and 10 in Germany. This is ca. eight times faster compared to individual testing. When infection rates are lower, or when employing an optimal, yet more complex pooling method, the gains are more pronounced. Pool-based approaches also reduce the number of false positive diagnoses by a factor of up to 100.ConclusionsThe results of this study provide a rationale for adoption of pool-based testing strategies to increase speed and throughput of testing for SARS-CoV-2, hence saving time and resources compared with individual testing.

Viral infections were investigated in American black bears (Ursus americanus) from Nevada and northern California with and without idiopathic encephalitis. Metagenomics analyses of tissue pools revealed novel viruses in the genera Circoviridae, Parvoviridae, Anelloviridae, Polyomaviridae, and Papillomaviridae. The circovirus and parvovirus were of particular interest due to their potential importance as pathogens. We characterized the genomes of these viruses and subsequently screened bears by PCR to determine their prevalence. The circovirus (Ursus americanus circovirus, UaCV) was detected at a high prevalence (10/16, 67%), and the chaphamaparvovirus (Ursus americanus parvovirus, UaPV) was found in a single bear. We showed that UaCV is present in liver, spleen/lymph node, and brain tissue of selected cases by in situ hybridization (ISH) and PCR. Infections were detected in cases of idiopathic encephalitis and in cases without inflammatory brain lesions. Infection status was not clearly correlated with disease, and the significance of these infections remains unclear. Given the known pathogenicity of a closely related mammalian circovirus, and the complex manifestations of circovirus-associated diseases, we suggest that UaCV warrants further study as a possible cause or contributor to disease in American black bears.

Protein domains often recognize short linear protein motifs composed of a core conserved consensus sequence surrounded by less critical, modulatory positions. PTEN, a lipid phosphatase involved in phosphatidylinositol 3-kinase (PI3K) pathway, contains such a short motif located at the extreme C-terminus capable to recognize PDZ domains. It has been shown that the acetylation of this motif could modulate the interaction with several PDZ domains. Here we used an accurate experimental approach combining high-throughput holdup chromatographic assay and competitive fluorescence polarization technique to measure quantitative binding affinity profiles of the PDZ domain-binding motif (PBM) of PTEN. We substantially extended the previous knowledge towards the 266 known human PDZ domains, generating the full PDZome-binding profile of the PTEN PBM. We confirmed that inclusion of N-terminal flanking residues, acetylation or mutation of a lysine at a modulatory position significantly altered the PDZome-binding profile. A numerical specificity index is also introduced as an attempt to quantify the specificity of a given PBM over the complete PDZome. Our results highlight the impact of modulatory residues and post-translational modifications on PBM interactomes and their specificity.

[This corrects the article DOI: 10.1371/journal.pone.0197162.].

Beauty is the single most frequently and most broadly used aesthetic virtue term. The present study aimed at providing higher conceptual resolution to the broader notion of beauty by comparing it with three closely related aesthetically evaluative concepts which are likewise lexicalized across many languages: elegance, grace(fulness), and sexiness. We administered a variety of questionnaires that targeted perceptual qualia, cognitive and affective evaluations, as well as specific object properties that are associated with beauty, elegance, grace, and sexiness in personal looks, movements, objects of design, and other domains. This allowed us to reveal distinct and highly nuanced profiles of how a beautiful, elegant, graceful, and sexy appearance is subjectively perceived. As aesthetics is all about nuances, the fine-grained conceptual analysis of the four target concepts of our study provides crucial distinctions for future research.

Filter feeding zooplankton are a crucial component of limnic food webs. Copepods and cladocerans are important prey organisms for first-level predators like the common and abundant larvae of phantom midges (Chaoborus sp.). The latter possess a complex catching basket built of head appendages specialized to capture small crustaceans. The predator-prey-relationship of Chaoborus (Diptera, Nematocera) and Daphnia (Crustacea, Cladocera) has been studied in particular detail owing to the daphniids' ability to react upon the threat of predation with inducible defenses. Daphnia pulex expresses so-called 'neckteeth' in the presence of Chaoborus larvae that are discussed as a defensive trait that interferes with the larval head appendages and their effectiveness has been shown in several studies. Nonetheless, mode of function of these neckteeth is not understood and the hypothesis that they interfere with the predator's head appendages still has to be confirmed. To clarify the role of neckteeth in Daphnia, an understanding of the Chaoborus capture apparatus is essential. Here, we present a detailed three-dimensional analysis of Chaoborus obscuripes' larval head morphology as well as a kinematic analysis of the attack motion, which revealed an impressive strike velocity (14 ms to prey contact). The movement of the larvae's head appendages is reconstructed in the three-dimensional space using a combination of high-speed videography, micro-computed tomography and computer animation. Furthermore, we provide predation trial data to distinguish between pre- and post-attack defensive effects in D. pulex. Our findings suggest a combination of pre- and post-attack defenses with an average effectiveness of 50% each. With this study, we quantitatively describe prey capture kinematics of C. obscuripes and take a further step to reveal the neckteeth' mode of function in D. pulex.

[This corrects the article DOI: 10.1371/journal.pone.0203788.].

Opioid use disorder (OUD) represents a public health crisis in the United States. Medication for opioid use disorder (MOUD) with buprenorphine in primary care is a proven OUD treatment strategy. MOUD induction is when patients begin withdrawal and receive the first doses of buprenorphine. Differences between induction methods might influence short-term stabilization, long-term maintenance, and quality of life. This paper describes the protocol for a study designed to: (1) compare short-term stabilization and long-term maintenance treatment engagement in MOUD in patients receiving office, home, or telehealth induction and (2) identify clinically-relevant practice and patient characteristics associated with successful long-term treatment. The study design is a randomized, parallel group, pragmatic comparative effectiveness trial of three care models of MOUD induction in 100 primary care practices in the United States. Eligible patients are at least 16 years old, have been identified by their clinician as having opioid dependence and would benefit from MOUD. Patients will be randomized to one of three induction comparators: office, home, or telehealth induction. Primary outcomes are buprenorphine medication-taking and illicit opioid use at 30, 90, and 270 days post-induction. Secondary outcomes include quality of life and potential mediators of treatment maintenance (intentions, planning, automaticity). Potential moderators include social determinants of health, substance use history and appeal, and executive function. An intent to treat analysis will assess effects of the interventions on long-term treatment, using general/generalized linear mixed models, adjusted for covariates, for the outcomes analysis. Analysis includes practice- and patient-level random effects for hierarchical/longitudinal data. No large-scale, randomized comparative effectiveness research has compared home induction to office or telehealth MOUD induction on long-term outcomes for patients with OUD seen in primary care settings. The results of this study will offer primary care providers evidence and guidance in selecting the most beneficial induction method(s) for specific patients. [ABSTRACT FROM AUTHOR]