Remote recruitment for Essential Coaching for Every Mother during COVID-19 BackgroundWith a decrease in in-person support and increase in perinatal mental health concerns during the coronavirus pandemic, innovative strategies, such as mHealth, are more important than ever. However, due to physical distancing recommendations, recruitments for perinatal research needs to shift. The objective of this study is to desire the process evaluation of recruitment and retention of women for an mHealth pre-post intervention study for Essential Coaching for Every Mother.

MethodsThree methods were used for recruitment: social media, posters in hospital, and media outreach. First time mothers were eligible for enrollment antenatally (37+ weeks) and postnatally (<3 weeks). Eligibility screening occurred remotely via text message. Outcomes were days to recruit 75 participants, eligibility vs. ineligibility rates, dropout and exclusion reasons, survey completion rates, perinatal timing of enrollment, and recruitment sources.

ResultsRecruitment ran July 15th-September 19th (67 days) with 200 screened and 88 enrolled, 70% antenatally. It took 50 days to enroll 75 participants. Mothers recruited antenatally (n=53) were more likely to receive all intervention message (68% vs. 19%). Mothers recruited postnatally (n=35) missed more messages on average (13.8 vs. 6.4). Participants heard about the study through family/friends (31%), news (20%), Facebook groups (16%), Facebook ads (14%), posters (12%), or other ways (7%).

ConclusionAntenatal recruitment resulted in participants enrolling earlier and receiving more of the study messages. Word of mouth and media outreach were successful, followed by advertisement on Facebook. Remote recruitment was a feasible way to recruit for Essential Coaching for Every Mother.
Temporal Trends in Racial and Ethnic Disparities in Sleep Duration in the United States, 2004-2018 ImportanceMinoritized racial and ethnic groups are generally more likely to experience sleep deficiencies. It is unclear how these sleep duration disparities have changed over recent years.

ObjectiveTo determine 15-year trends in the racial and ethnic differences in self-reported sleep duration among adults in the US.

DesignSerial cross-sectional study of the National Health Interview Survey from years 2004- 2018. Analyses were performed between July 26, 2021 and February 10, 2022.

SettingUS population-based.

Participants429,195 non-institutionalized adults.

ExposuresSelf-reported race, ethnicity, household income, and sex/gender.

Main OutcomesTemporal trends and racial/ethnic differences in short- and long-sleep duration (<7 and >9 hours in a 24-hour period, respectively), and racial/ethnic differences in the relationship between sleep duration and age.

ResultsThe study sample consisted of 429,195 individuals (mean age 46.5 [SE, 0.08] years; 51.7% female) of which 5.1% identified as Asian, 11.8% as Black, 14.7% as Latino/Hispanic, and 68.5% as White. In 2004, the adjusted estimated prevalence of short-sleep duration and long-sleep duration, respectively, were 31.3% and 2.5% among Asian individuals, 35.3% and 6.4% among Black individuals, 27.0% and 4.6% among Latino/Hispanic individuals, and 27.8% and 3.5% among White individuals. Over the study period, there was a significant increase in the short sleep prevalence among Black, Latino/Hispanic, and White individuals (P[&le;]0.001 for each), whereas prevalence of long sleep changed significantly only among Latino/Hispanic individuals (-1.4 points, P=0.01). In 2018, compared with White individuals, short sleep prevalence among Black and Latino/Hispanic individuals was higher by 10.7 points and 2.4 points, respectively

(P[&le;]0.03 each), and long sleep prevalence was higher only among Black people (+1.4 points; P=0.01). The short-sleep disparities were the greatest among women and among those with middle/high household income. In addition, across age groups, Black individuals had a higher short- and long-sleep duration prevalence compared with White individuals of their same age.

ConclusionsIn this serial cross-sectional study from 2004 to 2018, the prevalence of short and long sleep duration was persistently higher among Black individuals. The Black-White disparities in short-sleep were highest among women, individuals who had middle or high income, and among young or middle-aged adults.

KEY POINTSO_ST_ABSQuestionC_ST_ABSHow have racial and ethnic differences in self-reported sleep duration among US adults changed between 2004 and 2018?

FindingsIn this serial cross-sectional study that included 429,195 adults, the prevalence of both short and long sleep duration were persistently higher among Black individuals over the 15-year study period. The disparities in short sleep duration were highest for Black women, Black individuals with middle or high income, and young and middle-aged Black adults.

MeaningThere were marked racial and ethnic differences in sleep duration that persisted from 2004 to 2018, which may be contributing to health disparities.
Distinct temporal characteristics of circulating alveolar epithelial and endothelial injury markers in ARDS with COVID-19: a preliminary retrospective report The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19. Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and [~]11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed. Longitudinal intronic RNA-Seq analysis of Parkinson Disease patients reveals disease-specific nascent transcription Transcriptomic studies usually focus on either gene or exon-based annotations, and only limited experiments have reported changes in reads mapping to introns. The analysis of intronic reads allows the detection of nascent transcription that is not influenced by steady - state RNA levels and provides information on actively transcribed genes. Here we describe substantial intronic transcriptional changes in Parkinsons Disease (PD) patients compared to healthy controls (CO) at two different timepoints; at the time of diagnosis (BL) and three years later (V08). We used blood RNA-Seq data from the Parkinsons Progression Markers Initiative (PPMI) cohort and identified significantly changed transcription of intronic reads only in PD patients during this follow up period. In CO subjects, only nine transcripts demonstrated differentially expressed introns between visits. However, in PD patients 4,873 transcripts had differentially expressed introns at visit V08 compared to BL, many of them in genes previously associated with neurodegenerative diseases, such as LRRK2, C9orf72, LGALS3, KANSL1AS1 and ALS2. In addition, at the time of diagnosis (BL visit) we identified 836 transcripts (e.g. SNCA, DNAJC19, PRRG4) and at visit V08 2,184 transcripts (e.g. PINK1, GBA, ALS2, PLEKHM1) with differential intronic expression specific to PD patients. In contrast, reads mapping to exonic regions demonstrated little variation indicating highly specific changes only in intronic transcription. Our study demonstrated that Parkinsons disease is characterized by substantial changes in the nascent transcription and description of these changes could help to understand the molecular pathology underpinning this disease.

Impact statementTranscriptomic studies in most cases describe the steady state changes of the cellular RNA combined with signals from newly synthesised RNA or nascent RNA. Nascent RNA reflects dynamic alterations in the cellular transcriptome and improves the resolution of RNA-Seq analysis. In the present study, we describe the changes in nascent RNA transcription in Parkinsons disease by using intronic RNA-Seq analysis. We compared transcriptome changes at the time of diagnosis and 3 years after the initial diagnosis. As a result, we were able to describe disease-specific time-dependent alterations in the nascent transcription in the blood of Parkinsons patients illustrating another layer of the blood-based biomarkers that could be diagnostic of both risk and progression of Parkinsons disease. Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.

MethodsWe used SOMAscan to measure >1300 analytes in sera from healthy controls and patients with sJIA, MAS, sJIA-PAP and other related diseases. We verified selected findings by ELISA and lung immunostaining. Because the proteome of a sample may reflect multiple states (sJIA, MAS, sJIA-PAP), we used regression modeling to identify subsets of altered proteins associated with each state. We tested key findings in a validation cohort.

ResultsProteome alterations in active sJIA and MAS overlapped substantially, including known sJIA biomarkers like SAA and S100A9, and novel elevations of heat shock proteins and glycolytic enzymes. IL-18 was elevated in all sJIA groups, particularly MAS and sJIA-PAP. We also identified an MAS-independent sJIA-PAP signature notable for elevated ICAM5, MMP7, and allergic/eosinophilic chemokines, which were all previously associated with lung damage. Immunohistochemistry localized ICAM5 and MMP7 in sJIA-PAP lung. ICAM5s ability to distinguish sJIA-PAP from sJIA/MAS was independently validated.

ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Longitudinal determination of mRNA-vaccination induced strongly binding SARS-CoV-2 IgG antibodies in a cohort of Romanian healthcare workers Mass vaccination against the disease caused by the novel coronavirus (COVID-19) was a crucial step in slowing the spread of SARS-CoV-2 in 2021. Even in the face of new variants, it still remains extremely important for reducing hospitalizations and COVID-19 deaths. Only limited data exists about the short- and long-term dynamics of humoral immune response. We present a longitudinal analysis of post-vaccination IgG levels in a cohort of 166 healthcare workers vaccinated with BNT162b2 with weekly follow-up until 35 days past the first dose and monthly follow-up up to 6 months post-vaccination. A subset of the patients continued with follow-up after 6 months and either received a booster dose or got infected during the Delta wave in Romania. Tests were carried out on 1697 samples using a CE-marked IgG ELISA assay developed in-house, containing S1 and N antigens of the wild type virus.

Participants infected with SARS-CoV-2 before vaccination mount a quick immune response, reaching peak IgG levels two weeks after the first dose, while IgG levels of previously uninfected participants mount gradually, increasing abruptly after the second dose. Overall higher IgG levels are maintained for the previously infected group 35-70 days after vaccination. The decrease of IgG levels is gradual, with lower overall values in the infection naive cohort even 7-8 months after vaccination, compared to the previously infected cohort. Administration of a booster dose yielded higher average IgG antibody levels than post second dose in the infection naive group and comparable levels in the previously infected group. Combination of Mifepristone and Methotrexate for the Treatment of Ectopic Pregnancy: A Systematic Review Protocol AimThe increase in ectopic pregnancies (EP) in recent years and their impact on female fertility forces physicians to find an effective medical treatment that can avoid surgery as soon as possible. Methotrexate and mifepristone are widely used in conservative treatments, but the effectiveness of this combination is not completely clear. Therefore, the aims in this meta-analysis are to systematically analyze the efficacy of mifepristone combined with methotrexate in the treatment of EP through existing studies and draw a conclusion, to evaluate the advantages and disadvantages of inclusion trials and propose improvement measures and scientific designing schemes.

MethodsSix databases will be searched, including PubMed, Embase, Cochrane Library, the China National Knowledge Infrastructure(CNKI), Chinese Science and Technology Periodical Database (VIP), and Wanfang Database (WF). Randomized controlled trials published up to October 2020 will be selected. Search terms include mifepristone, methotrexate, EP, and random (free word/synonym expansion). We will include trials in which the experimental group was treated with combination of mifepristone and methotrexate, and the control group was treated with mifepristone alone. Revman 5.4 will be used to evaluate the quality of the trials, and the effect model will be selected to analyze the results. Cure rate will be the main outcome index.

ResultOnly when we finish this meta analysis can we get the result.

DiscussionThe results of this study will provide evidence for the efficacy of mifepristone combined with methotrexate therapy in the treatment of EP. The site of onset of pregnancy should be taken into account.

PROSPERO registration numberCRD42021246757 The Australian Parkinson's Genetics Study (APGS) - pilot (N = 1,532) PurposeParkinsons disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinsons Genetics Study (APGS) seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic, and environmental basis of PD susceptibility, symptoms and progression.

ParticipantsIn the pilot phase reported here, 1,819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme (PBS) records. The average age at the time of the questionnaire was 64 {+/-} 6 years. We collected patient-reported PD information and socio-demographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred thirty-two participants (84.2%) met all inclusion criteria, and 1,499 provided a DNA sample via traditional post.

Findings to date65% of participants were male, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions.

Future plansWe plan to recruit sex- and age-matched unaffected controls, genotype all participants, and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.

Article summaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIWe used a time- and cost-effective recruitment method that enabled us to reach out to a random sample of individuals who have been prescribed medications for Parkinsons disease across all over Australia to invite them to participate in this study.
C_LIO_LIThe identities of letter recipients remained private and confidential and were not shared with the researchers. However, those recipients who were interested and willing to participate were directed to a website where they could sign up and provide informed consent.
C_LIO_LIThe source database only captures individuals who have been prescribed medications to treat Parkinsons disease in Australia and who are eligible for Medicare. Those without an official diagnosis, not receiving treatment, or not eligible for government subsidies are not included.
C_LIO_LIWe collected a wide range of patient-reported variables relevant to disease onset, diagnosis, symptoms, medical comorbidities, lifestyle, and family history in a large cohort of participants. However, some variables might not be as accurate as when measured by a specialist clinician.
C_LIO_LIGiven the 9% response rate to our single-letter invitation, there is a substantial risk of self-selection bias. Thus, patient characteristics for this cohort might differ from those of the typical population of individuals with Parkinsons disease in Australia.
C_LI CD19+IgD+CD27- naive B Cells as predictors of humoral response to COVID 19 mRNA vaccination in immunocompromised patients Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naive B cells was strongly associated with antibody levels ({rho}=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-{micro}l increase, 95%CI 1.02-1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at [&ge;]61 naive B cells per {micro}l to discriminate between patients with and without an optimal antibody response. Consequently, measuring naive B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response. Characteristic and Sex Differences in Auditory Function and Cochlear Pathophysiology in a Noise-exposed Cohort: A Cross-sectional Study BackgroundTo determine the characteristics and sex differences of auditory perception and cochlear function in individuals with long-term occupational noise exposure.

MethodsYoung workers with long-term occupational noise exposure from a shipyard were recruited in the current study as the hidden hearing loss (HHL) risk group. Age-matched office workers in the same shipyard who had no occupational noise-exposure history were enrolled in the control group. The auditory processing ability of speech-in-noise (SIN) score and gap detection threshold (GDT) were further examined by sex. The cochlear function of action potential (AP) and summating potential (SP)/AP values were tested and compared by sex and side. The correlation between the SIN score and cochlear function was studied by sex. The correlation between either auditory processing ability or cochlear function and occupational-noise working length (OWL) was also analysed in the HHL risk group.

ResultsSignificantly decreased SIN scores and a higher GDT of the 4 kHz gap marker were only found in men in the HHL risk group. Although the hearing thresholds of the women in the HHL risk group were slightly but significantly worse than those of the women in the control group, no significant defects in auditory processing or temporal resolution were found between the two groups. Significantly decreased cochlear function and increased SP/AP values in the left ear were only found in men in the HHL risk group. Neither the AP amplitude nor the AP latency differed significantly between the two groups by sex. A correlation study indicated that only the correlation between the SIN score and the AP amplitude of the right ear in men was significant. No significant difference was found between the SIN score and cochlear function in women. The AP latency of the right ear was only significantly correlated with OWL in men.

ConclusionIn long-term occupational working exposure individuals with normal hearing, defects in auditory processing, temporal resolution and cochlear function showed sex differences, none of which were significant in women. In men, a weak correlation between the SIN score and the AP amplitude of the right ear was found. There was only a weak correlation between OWL and the AP latency of the right ear in men. Our findings indicate men are more vulnerable to occupational noise than women. Considering the noise-exposure dose differences between the control and HHL risk groups, our measures are insensitive to cochlear synaptopathy in humans. The Acute Treatment of Migraine with Low-Dose Naltrexone/Acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses. Are We There Yet? Big Surveys Significantly Overestimate COVID-19 Vaccination in the US Surveys are a crucial tool for understanding public opinion and behavior, and their accuracy depends on maintaining statistical representativeness of their target populations by minimizing biases from all sources. Increasing data size shrinks confidence intervals but magnifies the impact of survey bias - an instance of the Big Data Paradox 1. Here we demonstrate this paradox in estimates of first-dose COVID-19 vaccine uptake in US adults: Delphi-Facebook 2,3 (about 250,000 responses per week) and Census Household Pulse 4 (about 75,000 per week). By May 2021, Delphi-Facebook overestimated uptake by 17 percentage points and Census Household Pulse by 14, compared to a benchmark from the Centers for Disease Control and Prevention (CDC). Moreover, their large data sizes led to minuscule margins of error on the incorrect estimates. In contrast, an Axios-Ipsos online panel 5 with about 1,000 responses following survey research best practices 6 provided reliable estimates and uncertainty. We decompose observed error using a recent analytic framework 1 to explain the inaccuracy in the three surveys. We then analyze the implications for vaccine hesitancy and willingness. We show how a survey of 250,000 respondents can produce an estimate of the population mean that is no more accurate than an estimate from a simple random sample of size 10. Our central message is that data quality matters far more than data quantity, and compensating the former with the latter is a mathematically provable losing proposition. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

MethodsWe created a cohort of SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We evaluated trials on 3 criteria of informativeness: potential redundancy, design quality and feasibility of patient-participant recruitment. The study protocol was prospectively registered with the Open Science Framework (https://osf.io/fp726/).

ResultsWe included 500 trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.0% (95% Confidence Interval 23.7 - 36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%.

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. The energy balance theory: an unsatisfactory model of body composition fluctuations Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services. Economic evaluation of disease elimination: an extension to the net-benefit framework and application to human African trypanosomiasis The global health community has earmarked a number of diseases for elimination or eradication, and these goals have often been praised on the premise of long-run cost-savings. However, decision-makers must contend with a multitude of demands on health budgets in the short- or medium-term, and costs-per-case often rise as the burden of a disease falls, rendering such efforts beyond the cost-effective use of scarce resources. In addition, these decisions must be made in the presence of substantial uncertainty regarding the feasibility and costs of elimination or eradication efforts. Therefore, analytical frameworks are necessary to consider the additional effort for reaching global goals, like elimination or eradication, that are beyond the cost-effective use of country resources. We propose a modification to the net-benefit framework to consider the implications of switching from an optimal strategy, in terms of cost-per-burden-averted, to a strategy with a higher likelihood of meeting the global target of elimination of transmission by a specified date. We illustrate the properties of our framework by considering the economic case of efforts to eliminate transmission of gambiense human African trypanosomiasis (gHAT), a vector-borne parasitic disease in West and Central Africa, by 2030.

Significance StatementVarious diseases are earmarked for elimination by the global health community. While the health economic implications of elimination have been discussed before, the combination of uncertainty, cost-effectiveness in terms of cases averted, and elimination in the face of rising per-case costs has not been tackled before. We propose an approach that considers the tension between the dual objectives of cost-effectiveness and elimination while incorporating uncertainty in these objectives. We apply our method to strategies against human African trypanosomiasis in three settings, but this method could be directly applied to simulation-based studies of the cost-effectiveness of other disease elimination efforts. The method yields common metrics of efficiency when stakeholders have different objectives. The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. Deep Covid -Covid Diagnosis Using Deep Neural Networks and Transfer Learning Coronavirus is a global emergency as of May 2021. If not acted upon by drugs at the right time, coronavirus may result in the death of individuals. Hence early diagnosis is very important along the progress of the disease. This paper focuses on coronavirus detection using x-ray images, for automating the diagnosis pipeline using convolutional neural networks and transfer learning. This could be deployed in places where radiologists are not easily available in order to detect the disease at very early stages. In this study we propose our deep learning architecture for the classification task, which is trained with modified images, through multiple steps of preprocessing. Our classification method uses convolutional neural networks and transfer learning architecture for classifying the images. Our findings yield an accuracy value of 91.03%, precision of 89.76 %, recall value of 96.67% and F1 score of 93.09%. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Decoding hand and wrist movement intention from chronic stroke survivors with hemiparesis using a user-friendly, wearable EMG-based neural interface Prosthetics and orthotics have been recognized for decades as a potential means to restore hand function and independence to individuals living with impairment due to stroke. However, 75% of stroke survivors, caregivers, and health care professionals (HCP) believe current practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper limb technologies is to infer movement intent non-invasively from surface electromyography (EMG) activity. While this approach has garnered significant attention in the literature, existing technologies are often limited to research settings and struggle to meet stated user needs. To address these limitations, we have developed the NeuroLife(R) EMG System, which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements, including multiple types of grasps from participants with varying levels of chronic impairment from stroke, with an overall accuracy of 77.1{+/-}5.6%. Importantly, we demonstrate the ability to decode a subset of 3 fundamental movements in individuals with severe hand impairment at 85.4{+/-}6.4% accuracy, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeves design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Taken together, the NeuroLife EMG System represents a platform technology to record and decode high-definition EMG for the eventual real-time control of assistive devices in a form factor designed to meet user needs. Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.