A blood-based miRNA signature with prognostic value for overall survival in advanced stage non-small cell lung cancer treated with immunotherapy Immunotherapies have recently gained traction as highly effective therapies in a subset of late-stage cancers. Unfortunately, only a minority of patients experience the remarkable benefits of immunotherapies, whilst others fail to respond or even come to harm through immune related adverse events. For immunotherapies within the PD-1/PD-L1 inhibitor class, patient stratification is currently performed using tumor (tissue-based) PD-L1 expression. However, PD-L1 is an accurate predictor of response in only [~]30% of cases. There is pressing need for more accurate biomarkers for immunotherapy response prediction.

We sought to identify peripheral blood biomarkers, predictive of response to immunotherapies against lung cancer, based on whole blood microRNA profiling. Using three well characterized cohorts consisting of a total of 334 stage IV NSCLC patients, we have defined a 5 microRNA risk score (miRisk) that is predictive of overall survival following immunotherapy in training and independent validation (HR 2.40, 95% CI 1.37-4.19; P < 0.01) cohorts. We have traced the signature to a myeloid origin and performed miRNA target prediction to make a direct mechanistic link to the PD-L1 signalling pathway and PD-L1 itself. The miRisk score offers a potential blood-based companion diagnostic for immunotherapy that outperforms tissue-based PD-L1 staining.
Virtual Trials: Causally-validated treatment effects efficiently learned from an observational cancer registry Randomized controlled trials (RCTs) offer a clear causal interpretation of treatment effects, but are inefficient in terms of information gain per patient. Moreover, because they are intended to test cohort-level effects, RCTs rarely provide information to support precision medicine, which strives to choose the best treatment for an individual patient. If causal information could be efficiently extracted from widely available real-world data, the rapidity of treatment validation could be increased, and its costs reduced. Moreover, inferences could be made across larger, more diverse patient populations. We created a "virtual trial" by fitting a multilevel Bayesian survival model to treatment and outcome records self-reported by 451 brain cancer patients. The model recovers group-level treatment effects comparable to RCTs representing over 3200 patients. The model additionally discovers the feature-treatment interactions needed to make individual-level predictions for precision medicine. By learning from heterogeneous real-world data, virtual trials can generate more causal estimates with fewer patients than RCTs, and they can do so without artificially limiting the patient population. This demonstrates the value of virtual trials as a complement to large randomized controlled trials, especially in highly heterogeneous or rare diseases.
Croup during the COVID-19 Omicron Variant Surge Croup is a common upper respiratory disease usually associated with parainfluenza virus, resulting in stridor, hoarse voice, barky cough, and variable respiratory distress. Here we examine the data at our center confirming a sharp increase in cases of croup associated with the Omicron variant. Data was retrospectively extracted from patient charts among those seen in the Emergency Department at Seattle Childrens Hospital. Inclusion criteria were patients who were assigned a diagnosis containing "croup" during either 5/30/2021-11/30/2021, a time period correlating with predominance of the COVID-19 Delta variant (B.1.617.2), or the initial phase of the Omicron variant surge (12/1/2021-1/15/2022). Contemporaneous publicly available local data on the proportion of SARS-CoV-2 samples in surrounding King County, Washington, with spike gene target failure on TaqPath PCR assays was used as a proxy for the proportion of infections caused by the Omicron variant. A total of 401 patients were diagnosed with croup during the Delta surge and 107 patients were diagnosed with croup during the Omicron surge. Patients who presented during the Omicron surge were more likely to test positive for COVID-19 (48.2% vs 2.8%, p < 0.0001). Children with a clinical diagnosis of croup during the Omicron surge were more likely to be prescribed racemic epinephrine as part of their care (21.5% vs 13.0%, p = 0.032). There were no differences in presenting age, rate of admission, rate of return to the ED within 72 hours, or admission among those who returned within 72 hours. During the Omicron surge, the incidence of croup nearly doubled compared to the rate in prior months, while at the same time the number of cases of parainfluenza virus identified decreased. Consistent with prior case reports, we have identified a sharp rise in cases of croup seen in our pediatric ED in parallel with the replacement of the SARS-CoV-2 Delta variant by Omicron as the dominant variant in our community. The socioeconomic factors that led to unemployment under COVID-19 pandemic among Japanese workers: a prospective cohort study ObjectivesTo examine the relationship between socioeconomic factors and unemployment among workers during COVID-19 pandemic in Japan.

DesignA prospective cohort study, follow-up from December 22-25, 2020 through February 18-19, 2021.

SettingThe panelists registered with an Internet survey company

ParticipantsA cluster random sample of 33,087 workers with stratification by sex, job type, and region among Japans working population

Main outcomes and measuresUnemployment between December 2020 and February 2021

ResultsAmong the 19,941 participants, 725 (3.6%) had experienced unemployment. Multivariate analysis showed that the significant high unemployment for women (compared to men); younger age (compared to older age); being married (spouse not working), bereaved or divorced, and unmarried (compared to married (spouse working)); annual household income less than 6 million yen, (compared to more than 10 million yen); junior high or high school, vocational school, junior college, or technical school (compared to graduate school); and temporary or contract employees, self-employed, agriculture, forestry, or fishing (compared to general employees).

ConclusionsCOVID-19 appears to have created difficulties for the vulnerable groups. This suggests the need for employment and economic support for such individuals.

Strengths and limitations of this studyUnder the pandemic of COVID-19, we found that unemployment was associated with socioeconomic factors such as age, sex, marriage, income, education and occupation.

Our findings suggest that in the event of a major epidemic, resulting in unemployment among vulnerable segments of the labour market, regardless of whether workers themselves are infected.

It was unclear why the participants had experienced unemployment

This study was conducted as an Internet survey, so the generalizability of our results is limited. 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. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiovascular and Renal Outcomes: A Meta-analysis and Meta-regression Analysis AimsCardiovascular and renal effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been inconsistent in cardiovascular outcome trials, and factors associated with the efficacy of GLP-1RAs remain to be clarified. Here, we evaluate the cardiovascular and renal outcomes with GLP-1RAs and associations between these outcomes and HbA1c or weight reduction.

Materials and MethodsWe searched PubMed/MEDLINE, EMBASE, and CENTRAL for randomized, placebo-controlled trials of GLP1-RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes.

ResultsWe extracted data of 60,800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80-0.93; P < 0.001) and secondary outcomes including the composite renal outcome (0.80; 0.73-0.87; P < 0.001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = 0.044; R2 = 0.65) and the composite renal outcome (P = 0.040; R2 = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = 0.390).

ConclusionsThe reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for cardiovascular and renal benefits of treatment with GLP-1RAs. Impact of HIV Infection on COVID-19 Outcomes Among Hospitalized Adults in the U.S. BackgroundWhether HIV infection is associated with differences in clinical outcomes among people hospitalized with COVID-19 is uncertain.

ObjectiveTo evaluate the impact of HIV infection on COVID-19 outcomes among hospitalized patients.

MethodsUsing the American Heart Associations COVID-19 Cardiovascular Disease registry, we used hierarchical mixed effects models to assess the association of HIV with in-hospital mortality accounting for patient demographics and comorbidities and clustering by hospital. Secondary outcomes included major adverse cardiac events (MACE), severity of illness, and length of stay (LOS).

ResultsThe registry included 21,528 hospitalization records of people with confirmed COVID-19 from 107 hospitals in 2020, including 220 people living with HIV (PLWH). PLWH were younger (56.0+/-13.0 versus 61.3+/-17.9 years old) and more likely to be male (72.3% vs 52.7%), Non-Hispanic Black (51.4% vs 25.4%), on Medicaid (44.5% vs 24.5), and active tobacco users (12.7% versus 6.5%).

Of the study population, 36 PLWH (16.4%) had in-hospital mortality compared with 3,290 (15.4%) without HIV (Risk ratio 1.06, 95%CI 0.79-1.43; risk difference 0.9%, 95%CI -4.2 to 6.1%; p=0.71). After adjustment for age, sex, race, and insurance, HIV was not associated with in-hospital mortality (aOR 1.13; 95%CI 0.77-1.6; p 0.54) even after adding body mass index and comorbidities (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91), severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86), or LOS (aOR 1.03; 95% CI 0.76-1.66, p=0.21).

ConclusionHIV was not associated with adverse outcomes of COVID-19 including in-hospital mortality, MACE, or severity of illness.

Condensed AbstractWe studied 21,528 patients hospitalized with COVID-19 at 107 hospitals in AHAs COVID-19 registry to examine the association between HIV and COVID-19 outcomes. More patients with HIV were younger, male, non-Hispanic Black, on Medicaid and current smokers. HIV was not associated with worse COVID-19 in-hospital mortality (Risk ratio 1.06, 95%CI 0.79-1.43; p=0.71) even after adjustment (aOR 1.15; 95%CI 0.78-1.70; p=0.48). HIV was also not associated with MACE (aOR 0.99, 95%CI 0.69-1.44, p=0.91) or severity of illness (aOR 0.96, 95%CI 0.62-1.50, p=0.86. Our findings do not support that HIV is a major risk factor for adverse COVID-19 outcomes. Prevalence and incidence of stress, depression, and anxiety symptoms among Brazilians in quarantine across the early phases of the COVID-19 crisis ObjectiveThe present study aimed to measure the prevalence and incidence of stress, depression, and anxiety symptoms in Brazilians during the COVID-19 pandemic.

MethodWe assessed 103 (54 women, 49 men) participants online in three periods of the pandemic: March 2020 (T1), April 2020 (T2), and June 2020 (T3). Prevalence and incidence were identified when mental health scores were two standard deviations above the mean compared to normative data. Mental health indicators were measured using the Perceived Stress Scale, the Filgueiras Depression Index, and the State-Trait Anxiety Inventory - State Subscale.

ResultsAt T1, 89% of individuals were below cut-off scores for stress, anxiety, and depression, which dropped to 35% by T3. Stress prevalence was 1.9% at T1, 7.8% at T2, and 28.2% at T3. Depression prevalence was 0% at T1, 23.3% at T2, and 25.2% at T3. State anxiety prevalence was 10.7% at T1, 11.7% at T2, and 45.6% at T3. Stress incidence increased by 7.8% from T1 to T2, and 23.3% from T2 to T3. Depression incidence increased by 23.3% from T1 to T2, and 15.5% from T2 to T3. Anxiety incidence increased by 9.7% from T1 to T2, and 39.8% from T2 to T3. Stress severity scores significantly increased from 16.1{+/-}8.7 at T1 to 23.5{+/-}8.4 at T2, and 30.3{+/-}6.0 at T3. Depression severity scores significantly increased from 48.5{+/-}20.5 at T1 to 64.7{+/-}30.2 at T2, and 75.9{+/-}26.1 at T3. Anxiety increased from 49.0{+/-}13.4 at T1 to 53.5{+/-}12.5 at T2 and 62.3{+/-}13.4 at T3. Females had significantly higher anxiety scores than males by T3 (66.7{+/-}11.8 vs. 57.4{+/-}13.5).

ConclusionPrevalence and incidence of stress, depression, and anxiety significantly increased throughout the pandemic. The largest increase in stress and anxiety occurred between T2 and T3, and between T1 and T2 for depression. Severity of stress, depression, and anxiety increased throughout the study. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI S-ketamine in patient-controlled analgesia reduces opioid consumption in a dose-dependent manner after major lumbar fusion surgery: a randomized, double-blind, placebo-controlled clinical trial BACKGROUNDSpinal fusion surgery causes severe pain. Strong opioids, commonly used as postoperative analgesics, may have unwanted side effects. S-ketamine may be an effective analgesic adjuvant in opioid patient-controlled analgesia (PCA). However, the optimal adjunct S-ketamine dose to reduce postoperative opioid consumption is still unknown.

METHODSWe randomized 107 patients at two tertiary hospitals in a double-blinded, placebo-controlled clinical trial of adults undergoing major lumbar spinal fusion surgery. Patients were randomly allocated to four groups in order to compare the effects of three different doses of adjunct S-ketamine (0.25, 0.5, and 0.75 mg ml-1) or placebo on postoperative analgesia in oxycodone PCA. Study drugs were administered for 24 hours postoperative after which oxycodone-PCA was continued for further 48 hours. Our primary outcome was cumulative oxycodone consumption at 24 hours after surgery.

RESULTSOf the 100 patients analyzed, patients receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA needed 25% less oxycodone at 24 h postoperatively (61.2 mg) compared with patients receiving 0.5 mg ml-1 (74.7 mg) or 0.25 mg ml-1 (74.1 mg) S-ketamine in oxycodone or oxycodone alone (81.9 mg) (mean difference: -20.6 mg; 95% confidence interval [CI]: -41 to -0.20; P = 0.048). A beneficial effect in mean change of pain intensity at rest was seen in the group receiving 0.75 mg ml-1 S-ketamine in oxycodone PCA compared with patients receiving lower ketamine doses or oxycodone alone (standardized effect size: 0.17, 95% CI: 0.013-0.32, P = 0.033). The occurrence of adverse events was similar among the groups.

CONCLUSIONSOxycodone PCA containing S-ketamine as an adjunct at a ratio of 1: 0.75 decreased cumulative oxycodone consumption at 24 h after major lumbar spinal fusion surgery without additional adverse effects. Human lipoproteins comprise at least 12 different classes that are lognormally distributed. Lipoproteins in medical samples have been measured by enzymatic methods that coincide with conventional ultracentrifugation. However, the high gravity and time required for ultracentrifugation can cause sample degradation. This study presents the results of HPLC, a gentler and rapid separation method, for 55 human serum samples. The elution patterns were analysed parametrically, and the attribute of each class was confirmed biochemically. Human samples contained 12 classes of lipoproteins, each of which may consist primarily of proteins. There are three classes of VLDLs. The level of each class was distributed lognormally, and the standard amount and the 95% range were estimated. Enzymatic methods measure the levels of several mixed classes. This lognormal character suggests that the levels are controlled by the synergy of multiple factors. 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. External Validation Of A Novel Signature Of Illness In Continuous Cardiorespiratory Monitoring To Detect Early Respiratory Deterioration Of ICU Patients The goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of Intensive Care Unit patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. We calculated the model outputs for more than 8000 patients in the University of California - San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 hours before the event. We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data. Unveiling Sex-based Differences in Parkinson's Disease: A Comprehensive Meta-analysis of Transcriptomic Studies In recent decades, increasing longevity (among other factors) has fostered a rise in Parkinsons disease (PD) incidence. Although not exhaustively studied in this devastating disease, the impact of sex represents a critical variable in PD as epidemiological and clinical features differ between males and females. To study sex bias in PD, we conducted a systematic review, tissue-specific meta-analyses of transcriptomic data from the frontal cortex (FC), striatum tissue (ST), and substantia nigra (SN), and a global meta-analysis of all 3 brain regions. We selected 7 PD studies that included sex information, analyzing 267 samples. The tissue-specific meta-analyses linked PD to the enhanced expression of MED31 in the female FC and the dysregulation of 237 genes in the SN. The global meta-analysis detected 15 genes with sex-differential patterns in PD, which participate in mitochondrial function, oxidative stress, neuronal degeneration, and cell death. Furthermore, functional analyses identified pathways, protein-protein interaction networks, and transcription factors that differed by sex. While male PD patients exhibited changes in oxidative stress based on metal ions, inflammation, and angiogenesis, female PD patients exhibited dysfunctions in mitochondrial and lysosomal activity, antigen processing and presentation functions, and glutamic and purine metabolism. Overall, we believe that our findings will provide new insight into the perspective of sex in PD, thereby underscoring the importance of including sex information in future PD studies. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets 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. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. In depth analysis of patients with severe SARS-CoV-2 in sub-Saharan Africa demonstrates distinct clinical and immunological profiles Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we comprehensively characterise patients hospitalised with suspected or confirmed COVID-19, and healthy community controls. PCR-confirmed COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-/IgG+ and PCR-/IgG-participants. PCR-/IgG+ participants exhibited a nasal and systemic cytokine signature analogous to PCR-confirmed COVID-19 participants, but increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. We did not find evidence that HIV co-infection in COVID-19 participants was associated with mortality or altered cytokine responses. The nasal immune signature in PCR-/IgG+ and PCR-confirmed COVID-19 participants was distinct and predominated by chemokines and neutrophils. In addition, PCR-/IgG+ individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies. Safety and efficacy of Pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID Study): A prospective, randomised, single-blind, controlled trial BackgroundPulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia.

MethodsIn this randomised, single-blind, controlled trial, we enrolled hospitalized, non-intubated patients (18 to 75 years with oxygen saturation (Spo2) in free-air breathing [&le;]90%) with COVID-19 pneumonia at a referral hospital. Participants were randomly assigned (1:1) to receive PPT (six sessions PPT with breathing exercises and airway clearance techniques) or basic care. The primary outcomes were venous blood O2 (pO2) and CO2 (pCO2) pressures, Spo2, and three-minute walking test (3MWT) that were assessed before and end of sixth session. Secondary outcomes included level of dyspnea, venous blood PH, one-month mortality, three-month mortality and short form-36 (SF-36) after one and three months. The assessor was blinded to the assignment. This trial is registered with ClinicalTrials.gov (NCT04357340).

FindingsIn April-May 2020, 40 participants were randomly assigned to PPT or basic care groups. While at the end of intervention, pO2 (adjusted mean difference to baseline measure (AMD) 6.43 mmHg [95%CI 2.8, 10.07], P<0.01), Spo2 (AMD 4.43% [95%CI 2.04, 6.83], P=0.0011), and 3MTW (AMD 91.44 m [95%CI 68.88, 113.99], P<0.01) were higher in PPT group and basic care group, pCO2 was not improved (AMD -2.1 mmHg [95%CI-6.36, 2.21], P=0.33). Mortality rate was 20% (OR adjusted to baseline Spo2 .19 [95%CI .03, 1.30], P=.09) and 25% (OR adjusted to baseline Spo2 .16 [95%CI .26, 1.05], P=.056) lower in the PPT group at three-month at one-month and three-month, respectively. There were no significant differences in most SF-36 domains scores after one and three months. No serious adverse event was observed during PPT sessions.

ConclusionEarly PPT can be considered a safe and effective therapeutic choice for patients with severe COVID-19. Spatial Allocation of Scarce COVID-19 Vaccines The COVID-19 Vaccines Global Access (COVAX) is an initiative led by the World Health Organization (WHO) and other partners that aims for an equitable access of COVID-19 vaccines. Despite a potential heterogeneous disease burden across space, countries receiving allotments of vaccines via COVAX may want to follow WHOs allocation rule and distribute vaccines to their jurisdictions based on the jurisdictions relative population size. Utilizing economic-epidemiological modeling, we benchmark the performance of this ad hoc allocation rule by comparing it to the rule that minimizes the economic damages and expenditures over time, including a penalty cost representing the social costs of deviating from the ad hoc allocation. Under different levels of vaccine scarcity and different demographic characteristics, we consider scenarios where length of immunity and compliance to travel restrictions vary, and consider the robustness of the rules when assumptions regarding these factors are incorrect. The benefits from deviating are especially high when immunity is permanent, when there is compliance to travel restrictions, when the supply of vaccine is low, and when there is heterogeneity in demographic characteristics. Interestingly, a lack of compliance to travel restrictions pushes the optimal allocations of vaccine towards the ad hoc and improves the relative robustness of the ad hoc rule, as the mixing of the populations reduces the spatial heterogeneity in disease burden.

JEL ClassificationC61, H12, H84, I18, Q54 Stability of the stroke code during the COVID-19 pandemic in the region of Madrid: a retrospective cohort study Acute Stroke (AS) is the most common time-dependent disease attended in the Emergency Medicine Service (EMS) of Madrid (SUMMA 112). Community of Madrid has been one of the most affected regions in Spain by the coronavirus disease 2019 (COVID19) pandemic. A significant reduction in AS hospital admissions has been reported during the COVID-19 pandemic compared to the same period one year before. As international clinical practice guidelines support those patients with suspected acute stroke should be accessed via EMS, it is important to know whether the pandemic has jeopardized urgent pre-hospital stroke care, the first medical contact for most patients. We aimed to examine the impact of the COVID-19 in stroke codes (SC) in our EMS among three periods of time: the COVID-19 period, the same period the year before, and the 2019-2020 seasonal influenza period. Methods: We compared the SC frequency among the periods with high cumulative infection rate (above the median of the series) of the first wave of COVID-19, seasonal influenza, and also with the same period of the year before. Results: 1,130 SC were attended during the three periods. No significant reduction in SC was found during the COVID-19 pandemic. The reduction of hospital admissions might be attributable to patients attending the hospital by their means. The maximum SC workload seen during seasonal influenza has not been reached during the pandemic. We detected a non-significant deviation from the SC protocol, with a slight increase in hospitals transfers to hospitals without stroke units. Development of machine learning models for the prediction of complications after colorectal and small intestine surgery in psychiatric and non-psychiatric patient collectives (P-Study) Psychiatric and psychosomatic diseases are an increasingly cumbersome burden for the medical system. Indeed, hospital costs associated with mental health conditions have been constantly on the rise in recent years. Moreover, psychiatric conditions are likely to have a negative effect on the treatment of other medical conditions and surgical outcomes, in addition to their direct effects on the overall quality of life. Our study aims to investigate the impact of preoperative Risk factor, psychiatric and psychosomatic diseases on the outcomes of colorectal surgery and length of hospital stay via predictive modeling techniques.

MethodPatient data will be collected from several participating national and international surgical centers The machine learning models will be calculated and coded, but also published according to the TRIPOD guidelines (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis).

ResultIt is conceivable to arrive at generalizable models predicting the abovementioned endpoints through large amounts of data from several centers. The models will be subsequently deployed as a free-to-use web-based prediction tool using the Shiny environment [47]. The cost for the hosting server and digital infrastructure will be covered by Dr. Anas Taha. The sponsor will store the data for ten years. A protocol for a multicentre observational study across an integrated care system to understand the effect of living with frailty on access to video consultations Risks for digital exclusion include older age, disability, and deprivation. No literature exists examining frailty as an additional possible risk factor. Many studies have shown frailty to be a more accurate predictor of adverse outcome in healthcare than age alone. Understanding risk factors for digital exclusion may help healthcare services appropriately tailor interventions. The Healthier Together integrated care system (HTICS) in Bristol is developing video consultations for clinics. The aim of this prospective observational cross-sectional study is to identify whether living with frailty is a risk factor of digital exclusion from video consultation. Data will be collected using a structured survey including patients from three sites across the Heal secondary care services at North Bristol Trust, and then two subsequent sites will be included across HTICS. Data will be collected on known risk factors for digital exclusion, frailty using the Clinical Frailty Scale, and will cover four domains for digital exclusion as defined by NHS Digital: access, skill, motivation, and confidence. Data will be presented with descriptive statistics. The association between frailty and outcomes will be analysed with a multivariable logistic regression.

Key Study Contacts

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org.highwire.dtl.DTLVardef@134f5d7org.highwire.dtl.DTLVardef@1f8149forg.highwire.dtl.DTLVardef@11dbf0org.highwire.dtl.DTLVardef@7e854borg.highwire.dtl.DTLVardef@61272f_HPS_FORMAT_FIGEXP  M_TBL C_TBL Study Summary

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org.highwire.dtl.DTLVardef@53a9f0org.highwire.dtl.DTLVardef@b9e76dorg.highwire.dtl.DTLVardef@108bd12org.highwire.dtl.DTLVardef@b500ddorg.highwire.dtl.DTLVardef@14be1d8_HPS_FORMAT_FIGEXP  M_TBL C_TBL Funding and Support in Kind

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org.highwire.dtl.DTLVardef@d86811org.highwire.dtl.DTLVardef@1985973org.highwire.dtl.DTLVardef@118ca5corg.highwire.dtl.DTLVardef@8d7839org.highwire.dtl.DTLVardef@1cff6e1_HPS_FORMAT_FIGEXP  M_TBL C_TBL Role of Study Sponsor and FunderThe pilot at North Bristol Trust (NBT) is overseen by Neuromusculoskeletal (NMSK) Division governance. NBT NMSK Division takes responsibility for ensuring that the design of the study meets appropriate standards and that arrangements are in place to ensure appropriate conduct and reporting. Governance oversight for Hospital at Home was registered with NBT NMSK, and for primary care with Horfield Health Centre.

Roles and Responsibilities

Study Flow Chart

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org.highwire.dtl.DTLVardef@594232org.highwire.dtl.DTLVardef@904b3org.highwire.dtl.DTLVardef@138af7org.highwire.dtl.DTLVardef@10898a3org.highwire.dtl.DTLVardef@15d2719_HPS_FORMAT_FIGEXP  M_TBL C_TBL