Effectiveness of mRNA COVID-19 Booster Vaccines against Omicron and Delta Variants among US Veterans BackgroundWe estimated vaccine effectiveness (VE) of mRNA vaccines among US Veterans during periods of Delta and Omicron variant dominance. Patients included in this study were largely 65 years or older (62,834, 55%), male (101,259, 88%), and non-Hispanic white (66,986, 58%).

MethodsWe used SARS-CoV-2 laboratory test results to conduct a matched test-negative case-control study to estimate VE of three and two doses of mRNA vaccines against infection (regardless of symptoms), and a matched case-control study to estimate VE against COVID-19-related hospitalization and death. We estimated VE as (1-odds ratio) x 100%. Severity of disease was measured using hospital length of stay (LOS) and admission to an intensive care unit (ICU).

ResultsAgainst infection, booster doses had 7-times higher VE - 59% (95% confidence interval [CI], 57 to 61) - than 2-dose VE (7%; 95% CI, 3 to 10) during the Omicron period. For the Delta period, estimated VE against infection was 90% (95% CI, 88 to 92) among boosted vaccinees, 64% higher than VE among 2-dose vaccinees [55% (95% CI, 51 to 58)]. Against hospitalization, booster dose VE was 87% (95% CI, 80 to 91) during Omicron and 95% (95% CI, 91 to 97) during Delta; the 2-dose VE was 44% (95% CI, 26 to 58) during Omicron and 75% (95% CI, 70 to 80) during Delta. Against death, estimated VE with a booster dose was 94% (95% CI, 85 to 98) during Omicron and 96% (95% CI, 88 to 99) during Delta, while the 2-dose VE was 75% (95% CI, 52 to 87) during Omicron and 93% (95% CI, 85 to 97) during Delta. During the Omicron period, average hospital LOS was 4 days shorter [3 days (95%CI, 3 to 4 days)] than during the Delta period.

ConclusionsA mRNA vaccine booster is more effective against infection, hospitalization, and death than 2-dose vaccination among an older male population with comorbidities.
Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study Heterologous prime-boost vaccination is of increasing interest for COVID-19 vaccines. Evidence of rare thrombotic events associated with ChAdOx1-nCoV19 (Vaxzevria, ChAdOx) has lead several European countries to recommend a heterologous booster with mRNA vaccines for certain age groups (e.g. persons <60years in Germany), who have already received one dose of ChAdOx, although data on reactogenicity and safety of this vaccination regimen are still missing. Here we report reactogenicity data of homologous BNT162b2 (Comirnaty, BNT) or heterologous ChAdOx/BNT prime-boost immunisations in a prospective observational cohort study of 326 healthcare workers.

Reactogenicity of heterologous ChAdOx/BNT booster vaccination was largely comparable to homologous BNT/BNT vaccination and overall well-tolerated. No major differences were observed in the frequency or severity of local reactions after either of the vaccinations. In contrast, notable differences between the regimens were observed for systemic reactions, which were most frequent after prime immunisation with ChAdOx (86%, 95CI: 79-91), and less frequent after homologous BNT/BNT (65%, 95CI: 56-72), or heterologous ChAdOx/BNT boosters (48%, 95CI: 36-59).

This interim analysis supports the safety of currently recommended heterologous ChAdOx/BNT prime-boost immunisations with 12-week intervals.
Decreased Diastolic Hydraulic Forces Incrementally Associate With Survival Beyond Conventional Measures of Diastolic Dysfunction AIMSDecreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this study was to determine the association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival.

METHODS AND RESULTSPatients (n=11,734, median [interquartile range] 3.9 [2.4-5.0] years follow-up, 1,213 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) [&ge;]50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e, left atrial volume index, and LVEF (multivariable global R2=0.15, p<0.001), and not associated with e and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic [95% confidence interval] 0.645 [0.629-0.662] vs 0.607 [0.592-0.623], p<0.001) and E/e (0.639 [0.623-0.655] vs 0.621 [0.604-0.637], p<0.001), respectively.

CONCLUSIONDecreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction. 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. Quantifying phenotype and genotype distributions in single muscle fibres from patients carrying the pathogenic mtDNA variant m.3243A>G Cells are thought to tolerate the presence of heteroplasmic pathogenic mitochondrial (mt)DNA variants, up to a threshold proportion with little or no functional consequence, only developing a detectable oxidative phosphorylation (OXPHOS) defect once this threshold is exceeded. We hypothesised that, given the highly variable phenotypic presentation and severity of disease caused by the most common heteroplasmic pathogenic mtDNA variant m.3243A>G, this threshold may vary between patients. To estimate this threshold we examined the relationship between m.3243A>G level and deficiency of respiratory complexes I and IV in hundreds of single skeletal muscle fibres captured by laser microdissection from 17 patients carrying the m.3243A>G variant. We confirmed that tissue homogenate m.3243A>G level is a poor surrogate for the broad and complex distributions of m.3243A>G level in single cells from individual patients. We used unsupervised machine learning to characterise the biochemical status of muscle fibres, based on immunocytochemical measurements and estimate that the m.3243A>G threshold proportion above which myofibres develop a respiratory complex defect is 82.8% (IQR:2.7%). We do not find any significant difference in threshold between individuals, however we demonstrate that the pattern of respiratory complex defect and the distribution of m.3243A>G varies considerably between patients. This observation suggests that the pathogenesis of m.3243A>G is more diverse than previously thought. 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

O_TBL View this table:
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

O_TBL View this table:
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 The Association of Opening K-12 Schools with the Spread of COVID-19 in the United States: County-Level Panel Data Analysis AO_SCPLOWBSTRACTC_SCPLOWThis paper empirically examines how the opening of K-12 schools and colleges is associated with the spread of COVID-19 using county-level panel data in the United States. Using data on foot traffic and K-12 school opening plans, we analyze how an increase in visits to schools and opening schools with different teaching methods (in-person, hybrid, and remote) is related to the 2-weeks forward growth rate of confirmed COVID-19 cases. Our debiased panel data regression analysis with a set of county dummies, interactions of state and week dummies, and other controls shows that an increase in visits to both K-12 schools and colleges is associated with a subsequent increase in case growth rates. The estimates indicate that fully opening K-12 schools with in-person learning is associated with a 5 (SE = 2) percentage points increase in the growth rate of cases. We also find that the positive association of K-12 school visits or in-person school openings with case growth is stronger for counties that do not require staff to wear masks at schools. These results have a causal interpretation in a structural model with unobserved county and time confounders. Sensitivity analysis shows that the baseline results are robust to timing assumptions and alternative specifications. Covid-19 Associated Hepatitis in children (CAHC) during the second wave of SARS-CoV-2 infections in Central India: Is it a complication or transient phenomenon. Objective: While pediatric population has largely remained free of severe COVID-19, in some cases SARS-CoV-2 infection has been associated with complications like Multiple Inflammatory Syndrome in children (MIS-C). We mention another unique presentation subsequent to asymptomatic infection of SARS-CoV-2, a unique form of hepatitis designated by us as COVID-19 Associated Hepatitis in Children (CAH-C). The contrasting clinical presentations, temporal association and viral parameters of CAH-C cases, to the MIS-C cases are presented here. Methods: As a retrospective and follow-up observational study we reviewed all children testing positive for SARS-CoV-2 during study period. Children presenting with sudden onset of hepatitis, elevated transaminases, non-obstructive jaundice, lacking marked inflammatory responses and without evidence of (a) other known causes of acute hepatitis or previous underlying liver disease (b) multi-system involvement were classified as CAH-C, are described here. Results: Among 475 children who tested positive, 47 patients presented with hepatitis, 37 patients who had features of CAH-C, having symptoms of hepatitis only, with un-elevated inflammatory markers and uneventful recovery following supportive treatment. Whereas remaining 10 MIS-C hepatitis had protracted illness, multiple system involvement, required admission to critical care, and had mortality of 30%. Conclusion: With the emergence of newer variants of concern (VOC) including the Delta variant which predominated the second wave of infections in India and has now spread to more than 142 countries with changing presentations, CAH-C might be one of them. Cases of such new entities need to be identified early and differentiated from other emerging syndromes in children during the ongoing pandemic for preventing adversities by timely intervention. 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. Epithelial-to-mesenchymal transition lowers the cholesterol pathway, which influences colon tumors differentiation. Colorectal cancer (CRC) is the second cause of death worldwide. Up to 70% of CRC patients will metastasize. Identify new biomarkers of progression to prevent/delay disease evolution is urgent. Epithelial-to-mesenchymal transition (EMT) is a major program engaged during metastasis. We aim at identifying a combination of new genes that further identify signs of EMT in cancer tissues. We treated HT-29 cells grown in 3D with an EMT Inducing cocktail, and collect them before during and after treatment. For each condition, pan-transcriptomic analyses were done. Genes that were both induced upon EMT induction and inhibited upon EMT release (mesenchymal-to-epithelial transition or MET) were selected. We identified new genes for EMT-MET programs. These genes were used to build a metagene that, when applied to a database of transcriptomic data from primary colorectal tumors (n= 2,239), had an independent prognosis value. Finally, we submitted this metagene to CMap and identified drugs that might affect EMT-MET programs. Statins, well-known inhibitors of cholesterol synthesis, were among them and effectively delayed MET. These data show that cholesterol and EMT pathways are opposite regulators and impact differently tumor differentiation and outcome.

TRANSLATIONAL RELEVANCEMetastases are the main cause of death of colorectal cancer (CRC) and the major issue in CRC management. Understanding the chain of events that lead to metastasis occurrence is urgent to identify new biomarkers of progression and/or new potential targets. Epithelial to mesenchymal transition (EMT) is a major player in cancer dissemination that remains non-targetable due to its broad involvement in tissue homeostasis. Here, we used a relevant in vitro dynamic model to identify the pathways triggered during EMT in CRC and how this might improve tumors classification, prognosis and open therapeutic avenue for this deadly disease. The cholesterol pathway surprisingly popped-out from this model and turned out to be a good prognosis factor of disease-free survival for CRC. Altogether, our results showed that an active EMT program lowers the cholesterol pathway, which further influence the differentiation of colon tumor toward the most aggressive subtypes. 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. Epicardial adipose tissue thickness is associated with increased COVID-19 severity and mortality BACKGROUNDIncreased adiposity and visceral obesity have been linked to adverse COVID-19 outcomes. The amount of epicardial adipose tissue (EAT) may have relevant implications given its proximity to the heart and lungs. Here, we explored the role of EAT in increasing the risk for COVID-19 adverse outcomes.

METHODSWe included 748 patients with COVID-19 attending a reference center in Mexico City. EAT thickness, sub-thoracic and extra-pericardial fat were measured using thoracic CT scans. We explored the association of each thoracic adipose tissue compartment with COVID-19 mortality and severe COVID-19 (defined as mortality and need for invasive mechanical ventilation), according to the presence or absence of obesity. Mediation analyses evaluated the role of EAT in facilitating the effect of age, body mass index and cardiac troponin levels with COVID-19 outcomes.

RESULTSEAT thickness was associated with increased risk of COVID-19 mortality (HR 1.18, 95%CI 1.01-1.39) independent of age, gender, comorbid conditions and BMI. Increased EAT was associated with lower SpO2 and PaFi index and higher levels of cardiac troponins, D-dimer, fibrinogen, C-reactive protein, and 4C severity score, independent of obesity. EAT mediated 13.1% (95%CI 3.67-28.0%) and 5.1% (95%CI 0.19-14.0%) of the effect of age and 19.4% (95%CI 4.67-63.0%) and 12.8% (95%CI 0.03-46.0%) of the effect of BMI on requirement for intubation and mortality, respectively. EAT also mediated the effect of increased cardiac troponins on myocardial infarction during COVID-19.

CONCLUSIONEAT is an independent risk factor for severe COVID-19 and mortality independent of obesity. EAT partly mediates the effect of age and BMI and increased cardiac troponins on adverse COVID-19 outcomes. 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. "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. RELATIONSHIP BETWEEN ADVERSE EVENTS PREVALENCE, PATIENT SAFETY CULTURE AND PATIENT SAFETY PERCEPTION IN A SINGLE SAMPLE OF PATIENTS: A CROSS-SECTIONAL AND CORRELATIONAL STUDY ObjectiveTo assess the relationship between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception.

DesignCross-sectional, ex post facto comparative study on a single sample of patients.

SettingFour medium-high-level hospitals were included in the study -- two public and two private from Zulia State in Venezuela.

Participants556 medical records and patients were studied for the prevalence and patient safety perception study, and 397 of the healthcare providers involved in the care of these patients were surveyed for the patient safety culture study, at two public and two private hospitals.

Outcome measurementThe primary outcome of this study was the Association between Adverse Events Prevalence, Patient Safety Culture and Patient Safety Perception, and according to hospital funding type, private and public.

ResultsAn inverse association was observed between Adverse Events Prevalence and its severity and Patient Safety Culture Index (PSCI: rho=-0.8 p=0.5) (95% CI=0.26-0.10) and Patient Safety Perception Index (PSPI: rho=-0.6 p=0.18) (95% CI=0.10-0.28), which were protective factors for patient safety. No association was identified between Patient Safety Culture and Patient Safety Perception (rho=0.0001). No statistical differences were identified by hospital type (p=0.93) (95% CI=0.70-1.2).

ConclusionsThe analysis of the variable correlations studied (AEP, PSC and PSP) within the same sample offers an interesting and useful perspective. In this sample, although no correlation was observed between the three variables as an interacting set, some correlation patterns were observed between pairs of variables that could guide further studies.

Strengths and limitations of this studyO_LIThe association analysis of the three main variables (adverse events prevalence, patient safety culture and patient safety perception) in the same sample of patients and health professionals and over the same time period during which the care process and, consequently, the adverse events took place is an unprecedented and innovative approach, which contributes to the body of knowledge on this field of study.
C_LIO_LIThe relational theoretical framework produced provides a "map" that can facilitate decision-taking and which establishes the variables that should be considered a priority. As a result, it is highly likely to have an impact on the clinical efficiency and safety of healthcare institutions and services.
C_LIO_LIThe study was carried out at both private and public hospitals, enabling the behaviour of the aforementioned variables to be compared and analysed at each type of institution. The literature to date on this approach is scarce and offers little information.
C_LIO_LIAlthough the sample of hospitals selected is not representative of Venezuela, it is representative of the hospitals of one of the most productive and populated states in the country.
C_LIO_LIDuring stages 1 and 2, some resistance to collaborating with and completing the evaluation instruments was identified among the health professionals.
C_LI Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

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

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

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Humoral immune responses to COVID-19 vaccination in people living with HIV receiving suppressive antiretroviral therapy Humoral responses to COVID-19 vaccines in people living with HIV (PLWH) remain incompletely understood. We measured circulating antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, ACE2 displacement and live viral neutralization activities one month following the first and second COVID-19 vaccine doses in 100 adult PLWH and 152 controls. All PLWH were receiving suppressive antiretroviral therapy, with median CD4+ T-cell counts of 710 (IQR 525-935) cells/mm3. Nadir CD4+ T-cell counts ranged as low as <10 (median 280; IQR 120-490) cells/mm3. After adjustment for sociodemographic, health and vaccine-related variables, HIV infection was significantly associated with 0.2 log10 lower anti-RBD antibody concentrations (p=0.03) and [~]11% lower ACE2 displacement activity (p=0.02), but not lower viral neutralization (p=0.1) after one vaccine dose. Following two doses however, HIV was no longer significantly associated with the magnitude of any response measured. Rather, older age, a higher burden of chronic health conditions, and having received two ChAdOx1 doses (versus a heterologous or dual mRNA vaccine regimen) were independently associated with lower responses. After two vaccine doses, no significant correlation was observed between the most recent or nadir CD4+ T-cell counts and vaccine responses in PLWH. These results suggest that PLWH with well-controlled viral loads on antiretroviral therapy and CD4+ T-cell counts in a healthy range will generally not require a third COVID-19 vaccine dose as part of their initial immunization series, though other factors such as older age, co-morbidities, vaccine regimen type, and durability of vaccine responses will influence when this group may benefit from additional doses. Further studies of PLWH who are not receiving antiretroviral treatment and/or who have low CD4+ T-cell counts are needed. Inflammasome-related markers at the ICU admission are not associated with outcome in the critically ill COVID-19 patients. PurposeDevelopment of targeted biological therapies for COVID-19 requires reliable biomarkers that could help indicate the responding patients. Hyperactivation of the inflammasome by SARS-CoV2 virus is hypothesized to contribute to severe course of the COVID-19 disease. Therefore, we aimed to evaluate the prognostic value of several inflammasome-related cytokines and proteins at the admission to the intensive care unit (ICU).

Patients and methodsPlasma samples were obtained from 45 critically ill COVID-19 patients and from 10 patients any without any signs of infection (TBI, traumatic brain injury) on admission to the ICU. The concentration of IL-1, IL-1{beta}, IL-18, IL-1RA, galectin-1, ASC, LDH, ferritin, and gasdermin D were analyzed. A novel cell-free caspase-1 plasma assay was developed by inhibitor-based immunoprecipitation followed by Western Blot. Demographic and clinical characteristics were recorded.

ResultsIn-hospital mortality in COVID-19 patients reached 62%. Galectin-1 was 1.8-fold lower in COVID-19 than in TBI patients (17101.84 vs. 30764.20 pg/ml, p=0.007), but other inflammasome-related biomarkers were at similar concentrations. Patients with SOFA score of >9 on admission who were at high risk of death had significantly higher galectin-1 but lower IL-1RA in comparison to low-risk patients (25551.3 pg/ml vs 16302.7 pg/ml, p=0.014; 14.5 pg/ml vs 39.4 pg/ml, p=0.04, respectively). Statistically significant correlations were observed between: IL-1 and platelets (r=-0.37), IL-1{beta} and platelets (r=-0.36), ferritin and INR (r=0.39). Activated caspase-1 p35 was detectable in 12/22 COVID-19 patients but in none of the TBI patients. Its presence was related with higher fibrinogen and lower D-dimers. Moreover, the densitometric analysis showed a significantly higher amount of p35 in patients with SOFA> 9.

ConclusionOur results indicate that the systemic markers of activation of the inflammasome in critically ill COVID-19 patients is not directly related with outcome. Therefore, potential interventions aimed at the inflammasome pathway in this group of patients may be of limited effectiveness and should be biomarker-guided. Correlates of patient-reported cognitive performance with regard to disability ObjectivesThe patient-reported Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) is inconsistently related to objective cognitive tests in multiple sclerosis (MS), while being strongly correlated with depression. In this study we test whether the relation between subjective and objective cognitive performance is moderated by physical disability, assessed by the Expanded Disability Status Scale (EDSS).

Materials & MethodsFrom 275 MS patients who completed the patient-report MSNQ and the two-question screening tool for depression, we collected Symbol Digit Modalities Test (SDMT) and EDSS scores, indicators of respectively objective cognitive performance and physical disability. We analysed correlations between these variables in the total group and in three EDSS subgroups: Low 0.0 - 3.0, Medium 3.5 - 6.0 and High 6.5 - 9.0. We also investigated the use of a composite measure of cognitive impairment and depression.

ResultsWe found no significant correlations between patient-reported MSNQ and SDMT scores in the total group or the EDSS subgroups. MSNQ scores correlated significantly with depression in all subgroups. After correcting for several variables, MSNQ scores contributed adversely to SDMT scores in the total group, not in any subgroup. MSNQ scores contributed significantly to the prediction of the composite measure of impairment in the total group and in all EDSS subgroups.

ConclusionsThe relationship between measures of subjective and objective cognitive performance is not influenced by the patients level of physical disability. MSNQ scores are substantially influenced by depression, and reflect cognitive function to some degree. The patient-report MSNQ can be useful to identify patients requiring further (neuro)psychological assessment. 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. Grey and white matter micro-structure is associated with polygenic risk for schizophrenia BackgroundRecent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition.

MethodsWe used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons.

ResultsPolygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures and 14 white matter tracts. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia.

ConclusionsRisk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical and white matter micro-structure may be linked to the genetic mechanisms of schizophrenia. The effects of modifiable maternal pregnancy exposures on offspring molar-incisor hypomineralisation: A negative control study ObjectivesO_LITo explore the associations between modifiable maternal pregnancy exposures: pre-pregnancy body mass index (BMI), pregnancy smoking and alcohol consumption with offspring molar-incisor hypomineralisation (MIH).
C_LIO_LITo explore for the presence of residual confounding using negative control analyses.
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MethodsThis study used data from Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective birth cohort. We defined offspring MIH using prospectively collected questionnaire data. We used logistic regression to explore confounder adjusted associations between maternal pre-pregnancy BMI and smoking and alcohol consumption during pregnancy with MIH. We included negative control exposure (paternal BMI, smoking and alcohol around the time of pregnancy) and outcome (offspring dental trauma) analyses to explore for the presence of residual confounding.

Results5536 mother/offspring pairs were included (297 MIH cases [5.4%]). We found a positive association between maternal mean BMI and offspring MIH (OR per 1-kg/m2 difference in maternal BMI: 1.04, 95% CI: 1.00, 1.08). In subsequent analyses, we found evidence that this effect was non-linear and being driven by women in the highest BMI quintiles. In negative control analyses, we found no evidence of association between paternal BMI and offspring MIH (OR: 0.94, 95% CI: 0.89, 1.00) and maternal BMI and offspring dental trauma (OR: 0.99, 95% CI: 0.96, 1.02). There was no clear evidence of an association for maternal pregnancy smoking (OR: 0.76, 95%CI: 0.46, 1.22) and alcohol consumption (OR: 0.79, 95% CI: 0.56, 1.21) with offspring MIH with results imprecisely estimated.

ConclusionIn summary we found evidence of a possible intrauterine effect of high maternal pre-pregnancy BMI on offspring MIH. We did not find robust evidence for an intrauterine effect of maternal pregnancy smoking or alcohol consumption on offspring MIH. Our findings provide further support for women of reproductive age to maintain a healthy weight. Future studies are warranted to explore possible mechanisms on how the pregnancy environment may relate to offspring MIH. 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
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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
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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 Detection of COVID-19 and age-dependent dysosmia with paired crushable odorant ampules BackgroundSigns of anosmia can help detect COVID-19 infection when testing for viral positivity is not available. Inexpensive mass-produced disposable olfactory sensitivity tests suitable for worldwide use might serve not only as a screening tool for potential infection but also to identify cases at elevated risk of severe disease as anosmic COVID-19 patients have a better prognosis.

Methods and FindingsWe adopted paired crushable ampules with two concentrations of a standard test odorant (n-butanol) as standard of care in several clinics as community prevalence of COVID-19 infection waxed and waned. This was not a clinical trial; a chart review was undertaken to evaluate the operating characteristics and potential utility of the test device as RT-PCR testing became routine. The risk of anosmia was greater in COVID-19 patients. Olfactory sensitivity was concentration-dependent and decreased with aging. Hyposmia was detected across a wider age range than expected from the literature, and tests can be optimized to characterize different age groups.

Conclusionsn-Butanol at 0.32 and 3.2% in crushable ampules can be used to characterize olfactory function quickly and inexpensively and thus has potential benefits in pandemic screening, epidemiology, and clinical decision-making. Serum proteome analysis of systemic JIA and related pulmonary alveolar proteinosis identifies distinct inflammatory programs and biomarkers ObjectivesRecent observations in systemic Juvenile Idiopathic Arthritis (sJIA) suggest an increasing incidence of high-mortality interstitial lung disease, characterized by a variant of pulmonary alveolar proteinosis (PAP). Co-occurrence of macrophage activation syndrome (MAS) and PAP in sJIA suggested a shared pathology, but sJIA-PAP patients also commonly experience features of drug reaction such as atypical rashes and eosinophilia. We sought to investigate immunopathology and identify biomarkers in sJIA, MAS, and sJIA-PAP.

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

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

ConclusionsSerum proteins support an sJIA-to-MAS continuum, help distinguish sJIA, sJIA/MAS, and sJIA-PAP, and suggest etiologic hypotheses. Select biomarkers, such as ICAM5, could aid in early detection and management of sJIA-PAP.