Association of COVID-19 vaccination with risks of hospitalization due to cardiovascular and other diseases: A study of the UK Biobank BackgroundVaccines for COVID-19 represent a breakthrough in the fight against the pandemic. However, worries about adverse effects led to vaccine hesitancy in some people. On the other hand, as COVID-19 may be associated with various sequelae, the vaccine may protect against these diseases.

MethodsWe leveraged a large prospective cohort, the UK-Biobank(UKBB), and studied associations of at least one dose of COVID-19 vaccination(BioNTech-BNT162b2 or Oxford-AstraZeneca-ChAdOx1) with hospitalization from cardiovascular and other diseases (N=393,544; median follow-up of 54 days in vaccinated). Multivariable Cox and Poisson regression was conducted controlling for main confounders. Besides all hospitalizations, we also conducted separate analysis for new-onset and recurrent cases. We also performed other sensitivity analyses, including adjustment for prior event rate ratio (PERR) to reduce residual confounding.

ResultsWe observed that COVID-19 vaccination(at least one dose) was associated with lower risks of hospitalizations from stroke (hazard ratio[HR]=0.178, 95% CI: 0.127-0.250, p=1.50e-23), VTE (HR=0.426, 95% CI: 0.270-0.673, p=2.51e-4), dementia (HR=0.114, 95% CI 0.060-0.216; p=2.24e-11), non-COVID-19 pneumonia (NCP) (HR=0.108, 95% CI 0.0.080-0.145; p=2.20e-49), CAD (HR=0.563, 95% CI: 0.416-0.762; p=2.05e-4), COPD (HR=0.212, 95% CI 0.126-0.357; p=4.92e-9), T2DM (HR= 0.216, 95% CI: 0.096 - 0.486, p=2.12e-4), heart failure (HR=0.174, 95% CI, 0.118-0.256, p=1.34e-18) and renal failure (HR=0.415, 0.255-0.677, p=4.19e-4).

After adjusting for HRs of hospitalization between the two groups before the introduction of vaccination, COVID-19 vaccination was still significantly associated with reduced hazards of hospitalization due to CAD (HR=0.517, 95% CI: 0.327-0.817; p=4.70e-03), COPD (HR=0.317, 95% CI: 0.138-0.726; p=6.60e-03), dementia (HR=0.406, 95% CI: 0.180-0.919; p=3.06e-02), heart failure (HR=0.305, 95% CI: 0.179-0.519; p=1.18e-05), NCP (HR=0.191, 95% CI: 0.123-0.295; p=1.02e-13) and stroke (HR=0.222, 95% CI: 0.130-0.382; p=4.94e-08), although the estimated protective effects were weaker.

ConclusionsTaken together, this study provides further support to the safety and benefits of COVID-19 vaccination, and such benefits may extend beyond reduction of infection risk or severity per se. As an observational study, causal relationship cannot be concluded and further studies are required to verify the findings.
Proxalutamide Improves Lung Injury in Hospitalized COVID-19 Patients - an Analysis of the Radiological Findings of the Proxa-Rescue AndroCoV Trial IntroductionAntiandrogens are candidates against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) due to host cell entry inhibition by the suppression of TMPRSS2. Proxalutamide is a nonsteroidal anti-androgen (NSAA) with strong antagonism on androgen receptor (AR) and angiotensin-converting enzyme 2 (ACE2). Efficacy of proxalutamide was previously demonstrated for early COVID-19 outpatients, and also reduction of deaths in hospitalized COVID-19 patients. Whether radiological changes would follow the improvement in clinical outcomes with proxalutamide is not established. The present post-hoc analysis aims to evaluate whether proxalutamide improves lung injury observed through chest computerized tomography (CT) scans.

MethodsThis is a post-hoc analysis of the radiological findings of The Proxa-Rescue AndroCoV Trial with all enrolled patients from the three participating institutions of the city of Manaus, Brazil, that had at least two chest CT scans during hospitalization. The quantification of lung parenchyma involvement was performed by blinded radiologists with expertise in analysis of COVID-19 images. A first chest CT scan was performed upon randomization and a second CT scan was performed approximately five days later, whenever feasible. Improvement rate was the first endpoint, and relative and absolute changes between the first and second CT scans were the second endpoints.

ResultsOf the 395 patients initially evaluated, 77 and 169 patients from the proxalutamide and placebo arms, respectively, were included (n=246). Baseline characteristics and percentage of lung parenchyma affected in the baseline chest CT scan were similar between groups. In the second chest CT scan, the percentage of lungs affected (Median - IQR) was 35.0% (25.0-57.5%) in the proxalutamide group versus 67.5% (50.0-80.0%) in the placebo group (p < 0.001). The absolute and relative change between the second and first chest CT scans (Median - IQR) were -15.0 percent points (p.p.) (-30.0 - 0.0p.p.) and -25.0% (-50.0 - 0.0%) in the proxalutamide group, respectively, and +15.0p.p. (0.0 - +30.0p.p.) and +32.7% (0.0 - +80.0%) in the placebo group, respectively (p < 0.001 for both absolute and relative changes). The improvement rate, i.e., the percentage of subjects that had improvement from the first to the second CT scan, was 72.3% in the proxalutamide group and 23.1% in the placebo group (p < 0.0001), with an improvement rate ratio (95%CI) of 3.15 (2.32 - 4.28).

ConclusionProxalutamide improves lung opacities in hospitalized COVID-19 patients when compared to placebo. (NCT04728802)
The kidney releases a non-polymerizing form of Uromodulin in the urine and circulation that retains the external hydrophobic patch domain Uromodulin (Tamm-Horsfall protein, THP) is a glycoprotein uniquely produced in the kidney. It is released by cells of the thick ascending limbs (TAL) apically in the urine, and basolaterally in the renal interstitium and systemic circulation. Processing of mature urinary THP, which polymerizes into supra-molecular filaments, requires cleavage of an external hydrophobic patch (EHP) at the C terminus. However, THP in the circulation is not polymerized, and it remains unclear if non-aggregated forms of THP exist natively in the urine. We propose that an alternative processing path, which retains the EHP domain, can lead to a non-polymerizing form of THP. We generated an antibody that specifically recognizes THP with retained EHP (THP+EHP) and established its presence in the urine in a non-polymerized native state. Proteomic characterization of urinary THP+EHP revealed its C-terminus to end at F617. In the human kidney, THP+EHP was not only detected in TAL cells, but also diffusely in the renal parenchyma. Using immunoprecipitation followed by proteomic sequencing and immunoblotting, we then demonstrated that serum THP has also retained EHP. In a small cohort of patients at risk for acute kidney injury (AKI), admission urinary THP+EHP was significantly lower in patients who subsequently developed AKI during hospitalization. Our findings uncover novel insights into uromodulin biology by establishing the presence of an alternative path for cellular processing, which could explain the release of non-polymerizing THP in the circulation. Larger studies are needed to establish the utility of urinary THP+EHP as a sensitive biomarker of kidney health and susceptibility to injury. Why one size fits all is not enough when designing covid-19 immunity certificates for domestic use: a UK wide cross-sectional online survey ObjectivesThe present study explored publics willingness to use COVID-19 immunity certificates across six different domestic scenarios.

DesignCross-sectional online survey.

SettingUK representative survey conducted on the 3rd of August 2021.

Participants534 UK residents over 18 years old.

InterventionsParticipants replied to the same set of questions.

Primary and secondary outcome measuresThe primary outcome measure was willingness to use immunity certificates across three different domestic settings (1. Visiting the GP for a non-urgent health issue, 2. Dining in a restaurant, and 3. Attending a performance in a theatre). For each setting two options, one prioritising convenience (option A) and the other privacy (option B), were offered. Our secondary outcome measures were computed indices from items adapted from the Health Belief Model; Attitudes towards sharing immunity status with service providers; Prior to COVID-19 lifestyle. In addition, we recorded data about respondents socio-demographic characteristics.

ResultsRespondents were more willing to use immunity certificates that prioritised convenience, rather than privacy, when visiting their GP (92%). However, privacy was more favorable (84%) in the other two settings (dining in a restaurant and going to a theatre) compared to convenience (39%). Personal beliefs about COVID-19 and immunity certificates were associated with variations in willingness to use these across all scenarios. No variations were observed across socio-demographics and lifestyle.

ConclusionsThe findings of this survey suggest that there is not one size fits all solution for designing immunity certificates. Immunity certificates are complex socio-technical systems, any attempt to implement these for domestic use should be tailored to different settings and user needs. The design of certification services requires a more evidence-based approach and further research is needed to understand how different settings, design elements (like convenience or privacy) and personal beliefs about the pandemic should inform their design.

Strengths and limitations of this studyO_LIThis study presents unique knowledge about the publics willingness to use immunity certificates for domestic purposes where there is very little published research at the moment.
C_LIO_LIThe study reports knowledge about the interaction between individual characteristics, domestic settings, and types of immunity certificate design on willingness to use these certificates.
C_LIO_LIUK nationally representative sample for age, gender, and ethnic background, but limited to people who have the means and capacity to use digital technologies (survey administered using Prolific.co).
C_LIO_LIWe present evidence-based recommendations for Public Health services and policy makers about the use of immunity certificates in different domestic settings.
C_LIO_LISince, as to the writing of this paper, COVID-19 certification has not been mandated in the UK, the scenarios used in the survey were hypothetical.
C_LI Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI Declines and pronounced state disparities in prescription opioid distribution in the United States BackgroundThe United States (US) opioid epidemic is a persistent and pervasive public health emergency as it continues to claim the lives of Americans through addiction and overdose. There have been sustained efforts to reverse this iatrogenic crisis over the past decade. This study analyzed the changes in prescription opioid distribution for pain and identified regional differences between 2010 and 2019.

Methods and FindingsOpioid production data was obtained from the DEAs annual production quotas. Total opioid production has decreased 41.5% from 2013 (87.6 morphine mg equivalent metric tons) to 2019 (51.3). Opioid distribution from 2010 to 2019 was collected for ten prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) from the US Drug Enforcement Administrations Automation of Reports and Consolidated Orders System. Regional variance was expressed as the ratio of the 95th to 5th percentiles of opioid distribution per state, corrected for population. The peak year for all ten prescription opioids was identified, individually, as between 2010 and 2013, except for codeine (2015). There was a 51.96% overall decrease in opioid distribution per capita with the largest decrease in Florida (-61.61%) and smallest in Texas (-18.64%). The largest quantities of opioid distribution were observed in Tennessee (520.70 morphine mg equivalent or MME per person) and Delaware (251.45) in 2011 and 2019. The smallest was Nebraska (153.39) in 2011 and Minnesota (90.49) in 2019. The highest to lowest state ratio of total opioid use, corrected for population, was sizable in 2011 (5.25) and 2019 (2.78). Similarly, the mean 95th/5th ratio was relatively stable in from 2011 (4.78 +0.70) and 2019 (5.64+0.98). The 95th/5th ratio in 2019 was greatest for methadone (10.23) and oxymorphone (10.09) and smallest for morphine (2.20) and fentanyl (2.12). Southern states (e.g MS, TN, AL, AK, DE, and NC) had the highest per capita distribution for eight of the ten opioids in 2019. The strength of the correlation between per capita hydrocodone and codeine, and hydromorphone and codeine increased significantly from 2011 to 2019

ConclusionsThis study found a decline in total production and distribution for ten prescription opioids during the last half-decade. However, distribution was non-homogeneous at a state level. Analysis of regional differences revealed a three-fold difference in the 95th:5th percentile ratio between states which was unchanged over the past decade. Future research focused on identifying factors contributing to the observed regional variability could prove valuable to understanding, and potentially remediating, the pronounced disparities in prescription opioid use in the US. Echocardiographic characterisation in critical Covid19 - an observational study ObjectiveWe aimed to investigate the acute cardiac effects of severe SARS-CoV-2.

MethodsThis is an observational study generated from the first 79 patients admitted to Uppsala intensive care due to respiratory failure with SARS-CoV-2 infection. 34 underwent echocardiography of which 25 were included in the study and compared to 44 non-echo patients. Exclusion was based on absence of normofrequent sinus rhythm and mechanical respiratory support. Biomarker analysis was carried out on all patients.

ResultsMortality was increased in the echo compared to non-echo group (44 % vs. 16%, p<0.05). Right sided dimensions and functional parameters were not affected. Tricuspid regurgitation velocity indicated how increased pulmonary artery pressure was associated with mortality (survivors (n=5): 2.51 {+/-} 0.01 m/s vs. non-survivors (n=5): 3.06 {+/-} 0.11 m/s, p<0.05). Cardiac markers and D-dimer correlated to initiation of echocardiography (hs-TnI (ng/L): echo (n=23): 133 {+/-} 45 vs. non-echo (n=41): 81.3 {+/-} 45, p<0.01; NTproBNP (ng/L): echo (n=25): 2959 {+/-} 573 vs. non-echo (n=42): 1641 {+/-} 420, p<0.001; D-dimer (mg/L): echo (n=25): 16.1 {+/-} 3.7 vs. non-echo (n=43: 6.1 {+/-} 1.5, p<0.01) and mortality (hs-TnI (ng/L): survivors (n=48): 59.1 {+/-} 21 vs. non-survivors (n=17): 211 {+/-} 105, p<0.0001; NT-proBNP (ng/L): survivors (n=47): 1310 {+/-} 314 vs. non-survivors (n=20): 4065 {+/-} 740, p<0.0001; D-dimer (mg/L): survivors (n=50): 7.2 {+/-} 1.5 vs. non-survivors (n=18): 17.1 {+/-} 4.8, p<0.01). All intervals refer to standard error of the mean. Tricuspid regurgitation velocity was correlated with troponin I (r=0.93, r2=0.74, p<0.001, n=10).

ConclusionsThese results suggest that there is no clear negative effect on cardiac function in critical SARS-CoV-2. There are indications that pulmonary pressure elevation carries a negative predictive outcome suggesting pulmonary disease as the driver of mortality. Cardiac biomarkers as well as D-dimer carry predictive value.

Trial registration numberPatients were included in "Clinical trials NCT04316884"

Article summaryO_ST_ABSStrength and limitations of this studyC_ST_ABS- The patient body is recruited from all patients admitted to ICU in need of mechanical respiratory support independent of background which makes it relevant to clinical practice.
- The echocardiographic image acquisition was carried out by hospital assigned agents on clinical indication, which makes the results applicable in a clinical setting.
- Since the image acquisition was carried out on a clinical indication, the results may be skewed towards the false positive if applied to all Covid19 patients. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Impact of COVID-19-related disruptions to measles, meningococcal A, and yellow fever vaccination in 10 countries BackgroundChildhood immunisation services have been disrupted by COVID-19. WHO recommends considering outbreak risk using epidemiological criteria when deciding whether to conduct preventive vaccination campaigns during the pandemic.

MethodsWe used 2-3 models per infection to estimate the health impact of 50% reduced routine vaccination coverage and delaying campaign vaccination for measles, meningococcal A and yellow fever vaccination in 3-6 high burden countries per infection.

ResultsReduced routine coverage in 2020 without catch-up vaccination may increase measles and yellow fever disease burden in the modelled countries. Delaying planned campaigns may lead to measles outbreaks and increases in yellow fever burden in some countries. For meningococcal A vaccination, short term disruptions in 2020 are unlikely to have a significant impact.

ConclusionThe impact of COVID-19-related disruption to vaccination programs varies between infections and countries.

FundingBill & Melinda Gates Foundation and Gavi, the Vaccine Alliance

Impact statementRoutine and campaign vaccination disruption in 2020 may lead to measles outbreaks and yellow fever burden increases in some countries, but is unlikely to greatly increase meningococcal A burden.

SummaryO_ST_ABSBackgroundC_ST_ABSChildhood immunisation services have been disrupted by the COVID-19 pandemic. WHO recommends considering outbreak risk using epidemiological criteria when deciding whether to conduct preventive vaccination campaigns during the pandemic.

MethodsWe used 2-3 models per infection to estimate the health impact of 50% reduced routine vaccination coverage in 2020 and delay of campaign vaccination from 2020 to 2021 for measles vaccination in Bangladesh, Chad, Ethiopia, Kenya, Nigeria, and South Sudan, for meningococcal A vaccination in Burkina Faso, Chad, Niger, and Nigeria, and for yellow fever vaccination in the Democratic Republic of Congo, Ghana, and Nigeria. Our counterfactual comparative scenario was sustaining immunisation services at coverage projections made prior to COVID-19 (i.e. without any disruption).

FindingsReduced routine vaccination coverage in 2020 without catch-up vaccination may lead to an increase in measles and yellow fever disease burden in the modelled countries. Delaying planned campaigns in Ethiopia and Nigeria by a year may significantly increase the risk of measles outbreaks (both countries did complete their supplementary immunisation activities (SIAs) planned for 2020). For yellow fever vaccination, delay in campaigns leads to a potential disease burden rise of >1 death per 100,000 people per year until the campaigns are implemented. For meningococcal A vaccination, short term disruptions in 2020 are unlikely to have a significant impact due to the persistence of direct and indirect benefits from past introductory campaigns of the 1 to 29-year-old population, bolstered by inclusion of the vaccine into the routine immunisation schedule accompanied by further catch-up campaigns.

InterpretationThe impact of COVID-19-related disruption to vaccination programs varies between infections and countries. Planning and implementation of campaigns should consider country and infection-specific epidemiological factors and local immunity gaps worsened by the COVID-19 pandemic when prioritising vaccines and strategies for catch-up vaccination.

FundingBill & Melinda Gates Foundation and Gavi, the Vaccine Alliance Short Practical Regimen of Acupuncture for Melasma: A Prospective Cohort Study in a Tertiary Hospital in Thailand BackgroundMelasma is a common skin pigmentation disorder. Acupuncture shows benefits for patients with melasma, although no standardized method or optimal number of sessions have been determined.

ObjectiveTo comparatively assess clinical outcomes of melasma between five vs ten standard acupuncture sessions.

MethodsWe performed a prospective observational cohort study in all melasma patients at the Acupuncture Clinic, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. All patients were treated with standard acupuncture procedure twice a week and were evaluated after the fifth and the tenth sessions of acupuncture, with a follow-up one week after the last session. Participants were divided into two treatment groups: Groups A and B received five and ten acupuncture sessions respectively. Melasma outcomes were assessed by using the Melanin Index (MI), Melasma Area and Severity Index (MASI), patient-reported improvement scores and acupuncture-related adverse events.

ResultsOf 113 participants, 67 received five sessions of acupuncture treatment while 39 received ten sessions. 7 participants did not finish treatment. After five sessions of acupuncture in Group A, the mean MI decreased by 28.7 (95%CI -38.5 to -18.8), whereas the median MASI decreased by 3.4 (-6.9, -1.2) points. After ten sessions of acupuncture in Group B, the mean MI decreased by 31.3 (95%CI -45.0 to -17.6), whereas the median MASI decreased by 5.4 (-9.9, - 3.0) points. The first five sessions of acupuncture had a higher effect on the change in magnitude than the last five sessions, although there was no statistically significant difference. However, ten-session of acupuncture, had not reached the peak benefit on melasma yet. Further studies should be done with a higher number of sessions to determine the optimal rounds of treatment. Twenty-nine participants reported minor side effects, mostly consisting of persistent pain and small hematoma. Group B had RR of having adverse events 1.8 times (95% CI 1.0-3.4) compared to group A.

ConclusionAcupuncture has a potential dose-response effect on clinical and patient-reported melasma outcomes with minor side effects. Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

Materials and MethodsA cross-sectional study was conducted on 179 patients with knee OA aged [&ge;] 65 years. The six-item short form of the Pain Catastrophizing Scale (PCS-6), the four-item short form of the Pain Self-Efficacy Questionnaire (PSEQ-4), and the fifteen-item Geriatric Depression Scale (GDS-15) were used to assess psychological factors. IADL status was assessed using eight activity items. Participants were divided into IADL-disabled and non-disabled groups. Binary logistic regression analyses were performed with the IADL disability status as the dependent variable. The PCS-6, PSEQ-4, and GDS-15 tools were included as independent variables in the logistic regression model. Demographics, motor functions, and pain intensity were also included as confounders.

ResultsOf the total participants, 88 (49.1%) showed disability in conducting IADL. PSEQ-4 (odds ratio =0.90, 95%; confidence interval=0.82-0.99, p=0.02) was a significant independent variable among all psychological factors.

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. Psychological Distress Before and During the COVID-19 Pandemic Among Adults in the United Kingdom: Coordinated Analyses of 11 Longitudinal Studies ImportanceHow population mental health has evolved across the COVID-19 pandemic under varied lockdown measures is poorly understood, with impacts on health inequalities unclear.

ObjectiveWe investigated changes in mental health and sociodemographic inequalities from before and across the first year of the COVID-19 pandemic in 11 longitudinal studies.

Design, Setting and ParticipantsData from 11 UK longitudinal population-based studies with pre-pandemic measures of psychological distress were jointly analysed and estimates pooled. Multi-level regression was used to examine changes in psychological distress from pre-pandemic to during the first year of the COVID-19 pandemic.

ExposuresTrends in the prevalence of poor mental health were assessed pre-pandemic (TP0) and at three pandemic time periods: initial lockdown (TP1, Mar-June 20); easing of restrictions (TP2, July-Oct 20); and a subsequent lockdown (TP3, Nov 20-Mar 21). We stratified analyses by sex, ethnicity, education, age, and UK country.

Main Outcomes and MeasuresPsychological distress was assessed using the General Health Questionnaire 12 (GHQ-12), Kessler-6, 9-item Malaise Inventory, Short Mood and Feelings Questionnaire (SMFQ), Patient Health Questionnaire-8 and 9 (PHQ-8/9), Hospital Anxiety and Depression Scale (HADS) and Centre for Epidemiological Studies - Depression (CES-D), across different studies.

ResultsIn total, 49,993 adult participants (61.2% female; 8.7% Non-White) were analysed. Across the 11 studies, mental health deteriorated from pre-pandemic scores across all three pandemic time periods, but with considerable heterogeneity across the study-specific effect sizes estimated (pooled estimate TP1 Standardised Mean Difference (SMD): 0.15 (95% CI: 0.06, 0.25); TP2 SMD: 0.18 (0.09, 0.27); TP3 SMD: 0.21 (0.10, 0.32)). Changes in psychological distress across the pandemic were higher in females (TP3 SMD: 0.23 (0.11, 0.35)) than males (TP3 SMD: 0.16 (0.06, 0.26)), and lower in below-degree level educated persons at TP3 (SMD: 0.18 (0.06, 0.30)) compared to those who held degrees (SMD: 0.26 (0.14, 0.38)). Increased psychological distress was most prominent amongst adults aged 25-34 and 35-44 years compared to other age groups. We did not find evidence of changes in distress differing by ethnicity or UK country.

Conclusions and RelevanceThe substantial deterioration in mental health seen in the UK during the first lockdown did not reverse when lockdown lifted, and a sustained worsening was observed across the pandemic. Mental health declines have been unequal across the population, with females, those with higher degrees, and those aged 25-44 years more affected. 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. 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 Predictors of bovine Schistosoma japonicum infection in rural China In China, bovines are believed to be the most common animal source of human schistosomiasis infections, though little is known about what factors promote bovine infections. The current body of literature features inconsistent, and sometimes contradictory results, and to date, few studies have looked beyond physical characteristics to identify the broader environmental conditions that predict bovine schistosomiasis. Because schistosomiasis is a sanitation-related, water-borne disease transmitted by many animals, we hypothesized that several environmental factors - such as the lack of improved sanitation systems, or participation in agricultural production that is water-intensive - could promote schistosomiasis infection in bovines. Using data collected as a part of a repeat cross-sectional study conducted in rural villages in Sichuan, China from 2007 to 2016, we used a Random Forests, machine learning approach to identify the best physical and environmental predictors of bovine S. japonicum infection. Candidate predictors included: 1) physical/biological characteristics of bovines, 2) human sources of environmental schistosomes, 3) socio-economic indicators, 4) animal reservoirs, and 5) agricultural practices. The density of bovines in a village and agricultural practices such as the area of rice and dry summer crops planted and the use of night soil as an agricultural fertilizer, were among the top predictors of bovine S. japonicum infection in all collection years. Additionally, human infection prevalence, pig ownership and bovine age were found to be strong predictors of bovine infection in at least one year. Our findings highlight that presumptively treating bovines in villages with high bovine density or human infection prevalence may help to interrupt transmission. Furthermore, village-level predictors were stronger predictors of bovine infection than household-level predictors, suggesting future investigations may need to apply a broad ecological lens to identify potential underlying sources of persistent transmission. 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. Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Cohort Study BackgroundAnti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease

MethodsA nationwide multicenter retrospective cohort study was conducted by evaluating patients charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).

ResultsIn the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.

ConclusionIn patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed. A collaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic.

MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random  signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [&le;] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests.

Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976).

Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne.
 It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern.
 The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period.
 Data from private maternity hospitals, containing 25% of Melbourne births, are not available.
 This resource will support data-informed hospital pandemic responses through to the end of 2022. COVID-19 vaccine-associated cerebral venous thrombosis in Germany ObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.

MethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States.

ResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable.

ConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women. 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. 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. 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. 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. 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. Dental biofilm microbiota dysbiosis is associated with the risk of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Acute graft-versus-host disease (aGVHD) is one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, aGVHD onset was linked to intestinal microbiota (IM) dysbiosis. However, other bacterial-rich gastrointestinal sites, such as the mouth, which hosts several distinctive microbiotas, may also impact the risk of GVHD. The dental biofilm microbiota (DBM) is highly diverse and, like the IM, interacts with host cells and modulates immune homeostasis. We characterized changes in the DBM of patients during allo-HSCT and evaluated whether the DBM could be associated with the risk of aGVHD. DBM dysbiosis during allo-HSCT was marked by a gradual loss of bacterial diversity and changes in DBM genera composition, with commensal genera reductions and potentially pathogenic bacteria overgrowths. High Streptococcus and high Corynebacterium relative abundance at preconditioning were associated with a higher risk of aGVHD (67% vs. 33%; HR = 2.89, P = 0.04 and 73% vs. 37%; HR = 2.74, P = 0.04, respectively), while high Veillonella relative abundance was associated with a lower risk of aGVHD (27% vs. 73%; HR = 0.24, P < 0.01). Enterococcus faecalis bloom during allo-HSCT was observed in 20% of allo-HSCT recipients and was associated with a higher risk of aGVHD (100% vs. 40%; HR = 4.07, P < 0.001) and severe aGVHD (60% vs. 12%; HR = 6.82, P = 0.01). To the best of our knowledge, this is the first study demonstrating that DBM dysbiosis is associated with the aGVHD risk after allo-HSCT. The antibody response to SARS-CoV-2 infection persists over at least 8 months in symptomatic patients The factors involved in the persistence of antibodies to SARS-CoV-2 are unknown. We evaluated the antibody response to SARS-CoV-2 in personnel from 10 healthcare facilities and its association with individuals characteristics and COVID-19 symptoms in an observational study. We enrolled 4735 subjects (corresponding to 80% of all personnel) for three time points over a period of 8-10 months. For each participant, we determined the rate of antibody increase or decrease over time in relation to 93 features analyzed in univariate and multivariate analyses through a machine learning approach. In individuals positive for IgG ([&ge;] 12 AU/mL) at the beginning of the study, we found an increase [p= 0.0002] in antibody response in symptomatic subjects, particularly with anosmia/dysgeusia (OR 2.75, 95% CI 1.753 - 4.301), in a multivariate logistic regression analysis. This may be linked to the lingering of SARS-CoV-2 in the olfactory bulb.