Can individuals with low antibody responses to conventional antiviral vaccines acquire adequate antibody by the SARS-CoV-2 mRNA vaccine? ObjectiveIn Japan, healthcare workers (HCWs) are vaccinated against contagious viruses (measles, rubella, chickenpox, mumps, and hepatitis B) to prevent nosocomial infection; however, some do not produce sufficient antibodies (suboptimal responders). Whether suboptimal responders to live attenuated viruses or inactivated viruses vaccines can produce adequate antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines remains to be elucidated.

MethodsIn this prospective cohort study, SARS-CoV-2 anti-spike antibodies were measured 11 times, from before the first BNT162b2 vaccination to 5 months after the second vaccination. Antibody titers of suboptimal and normal responders were compared. SARS-CoV-2 neutralizing antibody activity was measured twice in suboptimal responders, 1 week to 1 month, and 5 months after the second vaccination.

PatientsThis study included 50 HCWs who received two doses of mRNA BNT162b2 vaccine 3 weeks apart.

ResultsAfter vaccination, the SARS-CoV-2 anti-spike antibody was detectable in the samples from suboptimal and normal responders at each timepoint. The median SARS-CoV-2 anti-spike antibody titer was higher in suboptimal responders than in normal responders 1 week after receiving the second dose of BNT162b2 vaccine (3721.0 vs. 2251.5, P=0.029). Suboptimal responders had SARS-CoV-2 neutralizing antibody activity 1 week to 1 month, and 5 months after the second vaccination, which exceeded the positive threshold 5 months after the second vaccination.

ConclusionAfter BNT162b2 vaccination, suboptimal responders acquired adequate SARS-CoV-2 anti-spike and SARS-CoV-2 neutralizing antibodies to prevent SARS-CoV-2. These results suggest that vaccination with mRNA vaccine against SARS-CoV-2 should also be recommended for suboptimal responders to conventional vaccines.
Nationwide surveillance of methicillin-resistant Staphylococcus aureus isolated from bloodstream infections in Japan in 2019 SynopsisO_ST_ABSObjectivesC_ST_ABSSome single-centre studies have reported that MRSA carrying the staphylococcal cassette chromosome mec (SCCmec) type IV has been increasing in bloodstream infections (BSIs) in Japan. Therefore, we conducted nationwide surveillance for MRSA BSI to investigate the extent of such change across Japan.

MethodsWe recruited 51 Japanese hospitals from the Japanese Association for Infectious Diseases. MRSA isolates detected in two or more sets of blood cultures were collected between January and September 2019 and subjected to antimicrobial susceptibility testing. Whole-genome sequencing was also performed to determine SCCmec typing and multilocus typing and detect drug-resistance and virulence genes.

ResultsTwo hundred seventy MRSA isolates were collected from 45 hospitals. The major combination types were ST8 with SCCmec type IV (ST8-IV) (30.7%), ST1-IV (29.6%), ST2725-IV (9.5%), ST764-II (8.1%), and ST5-II (7.8%). However, there were regional differences among the most major types. The most common types in western, eastern, and northern Japan were ST1-IV, ST8-IV, and ST5-II, respectively. ST8-IV, ST1-IV, and ST2725-IV exhibited greater susceptibility to clindamycin and minocycline than ST764-II and ST5-II, but erm(A) was detected in 93.8% and 100% of ST1-IV and ST2725-IV, respectively. Based on drug-resistance and virulence genes, characteristics of ST8-IV were different from those of ST1-IV and ST2725-IV. In addition, there were two major ST8-IV types with different characteristics.

ConclusionsThis study revealed that SCCmec type IV replaced SCCmec type II in MRSA BSI. In addition, SCCmec type IV was divided into several types with different characteristics.
Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology and clinical severity and disease course. A comprehensive genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 862 symptomatic patients with infections caused by Omicron from late November 2021 through December 18, 2021. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with decreased disease severity. Although the number of Omicron patients we studied is relatively small, in the aggregate the data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and provide information about disease character. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patients characteristics and pharmacogenetics on dexmedetomidine clearance.

MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 - 31.1 L/hr) for total clearance (CL), 161 L (139 - 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 - 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 - 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 - 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 - 7.08). Genotype was not statistically or clinically significant.

ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

What is already known about this subject{circ} Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.
{circ}Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.


What this study adds{circ} We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.
{circ}xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population. Structural disconnectome mapping of cognitive function in post-stroke patients Sequalae following stroke represents a significant challenge in current rehabilitation. The location and size of focal lesions are only moderately predictive of the diverse cognitive outcome after stroke. One explanation building on recent work on brain networks proposes that the cognitive consequences of focal lesions are caused by damages to anatomically distributed brain networks supporting cognition rather than specific lesion locations. To investigate the association between post-stroke structural disconnectivity and cognitive performance, we estimated individual level whole-brain disconnectivity probability maps based on lesion maps from 102 stroke patients using normative data from healthy controls. Cognitive performance was assessed in the whole sample using Montreal Cognitive Assessment, and a more comprehensive computerized test protocol was performed on a subset (n=82). Multivariate analysis using Partial Least Squares on the disconnectome maps revealed that higher disconnectivity in right insular and frontal operculum, superior temporal gyrus and putamen was associated with poorer MoCA performance, indicating that lesions in regions connected with these brain regions are more likely to cause cognitive impairment. Furthermore, our results indicated that disconnectivity within these clusters was associated with poorer performance across multiple cognitive domains. These findings demonstrate that the extent and distribution of structural disconnectivity following stroke are sensitive to cognitive deficits and may provide important clinical information predicting post stroke cognitive sequalae. 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. Adjunctive Ketamine for Sedation in Critically Ill Mechanically Ventilated Patients: An Active-Controlled, Pilot, Feasibility Clinical Trial ObjectiveKetamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot clinical trial to evaluate the feasibility of using ketamine as an adjunct analgosedative compared with standard of care (SOC) alone and determine preliminary effect size on 28-day mechanical ventilation (MV) duration and ventilator-free days (VFDs).

DesignPilot, single-center, active-controlled, open-label, randomized clinical trial.

SettingMedical, surgical, and transplant ICUs at King Faisal Specialist Hospital and Research Center, Saudi Arabia.

Patients and MethodsAdult patients who were intubated within 24 hours, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated.

InterventionAdjunct ketamine infusion 1-2 g/kg/min for 48 hours versus SOC.

Measurements and Main ResultsTotal of 83 patients (43 in SOC and 40 in ketamine) were included. Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3-9.25 days) in ketamine and 5 (IQR 2-8 days) in SOC, p= 0.15. Median VFDs was 19 (IQR 0-24.75 days) in ketamine and 19 (IQR 0-24 days) in the SOC (p=0.70). More patients attained goal RASS score at 24 and 48 hours in ketamine (67.5% and 73.5%, respectively) compared with SOC (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative doses, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6-21.2 days) in ketamine, compared with 12 (IQR 5.5-23 days) in SOC, p=0.89. Consent and protocol adherence rate were adequate. No serious adverse events were observed in either group.

ConclusionsUse of ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. The protocol of this pilot trial could be improved by modifying ketamine dosing regimen. These findings provide a basis for future, adequately powered, multicenter trial to investigate its association with patient-centered outcomes further. Emergence and Evolution of Big Data Science in HIV Research: Bibliometric Analysis of Federally Sponsored Studies 2000-2019 BackgroundThe rapid growth of inherently complex and heterogeneous data in HIV/AIDS research underscores the importance of Big Data Science. Recently, there have been increasing uptakes of Big Data techniques in basic, clinical, and public health fields of HIV/AIDS research. However, no studies have systematically elaborated on the evolving applications of Big Data in HIV/AIDS research. We sought to explore the emergence and evolution of Big Data Science in HIV/AIDS-related publications that were funded by the US federal agencies.

MethodsWe identified HIV/AIDS and Big Data related publications that were funded by seven federal agencies from 2000 to 2019 by integrating data from National Institutes of Health (NIH) ExPORTER, MEDLINE, and MeSH. Building on bibliometrics and Natural Language Processing (NLP) methods, we constructed co-occurrence networks using bibliographic metadata (e.g., countries, institutes, MeSH terms, and keywords) of the retrieved publications. We then detected clusters among the networks as well as the temporal dynamics of clusters, followed by expert evaluation and clinical implications.

ResultsWe harnessed nearly 600 thousand publications related to HIV/AIDS, of which 19,528 publications relating to Big Data were included in bibliometric analysis. Results showed that (1) the number of Big Data publications has been increasing since 2000, (2) US institutes have been in close collaborations with China, Canada, and Germany, (3) some institutes (e.g., University of California system, MD Anderson Cancer Center, and Harvard Medical School) are among the most productive institutes and started using Big Data in HIV/AIDS research early, (4) Big Data research was not active in public health disciplines until 2015, (5) research topics such as genomics, HIV comorbidities, population-based studies, Electronic Health Records (EHR), social media, precision medicine, and methodologies such as machine learning, Deep Learning, radiomics, and data mining emerge quickly in recent years.

ConclusionsWe identified a rapid growth in the cross-disciplinary research of HIV/AIDS and Big Data over the past two decades. Our findings demonstrated patterns and trends of prevailing research topics and Big Data applications in HIV/AIDS research and suggested a number of fast-evolving areas of Big Data Science in HIV/AIDS research including secondary analysis of EHR, machine learning, Deep Learning, predictive analysis, and NLP. 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. Impacts of Teaching Modality on U.S. COVID-19 Spread in Fall 2020 Semester We study the impact of college reopening in Fall 2020 on county-level COVID-19 cases and deaths using the information of 1,076 U.S. colleges. We match college and county characteristics using several methods and calculate the average treatment effects of three teaching modalities: in-person, online, and hybrid on COVID-19 outcomes up to two months after college reopening. In pairwise comparison, colleges reopened with in-person teaching mode were found to have about 36% point more cases within 15 days of reopening, compared to those reopened online, and the gap widens over time at a decreasing rate. Death rates follow the pattern with a time lag. However, colleges with hybrid mode catch the pattern of in-person mode after some time. We also find that greater endowment and student population, and fewer republican votes in the county are major predictors of choosing remote teaching modes over in-person.

JEL codesA23, I18, I23. 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. 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 Waning of Vaccine Effectiveness for the COVID-19 vaccine in Japan BackgroundAs of the end of 2021 year, the rate of completion for second-dose administration was almost 80% in Japan.

ObjectWe evaluated waning of vaccine effectiveness for COVID-19 in Japan, controlling for mutated strains, the Olympic Games, and countermeasures.

MethodThe effective reproduction number R(t) was regressed on current vaccine coverage and data of a certain number of days prior, as well as shares of mutated strains, and an Olympic Games dummy variable along with data of temperature, humidity, mobility, and countermeasures. The study period was February, 2020 through December 7, as of December 28, 2021.

ResultsEstimation results indicate that the past vaccine coverage of older than 60 days prior raises R(t) significantly and cancelled vaccine effectiveness completely.

Discussion and ConclusionResults indicate significant waning of vaccine effectiveness from 60 days after the second dose. Safety and efficacy of Pulmonary physiotherapy in hospitalized patients with severe COVID-19 pneumonia (PPTCOVID Study): A prospective, randomised, single-blind, controlled trial BackgroundPulmonary physiotherapy (PPT) is an important treatment in the management of patients with different types of pulmonary disorders. We aimed to evaluate safety and efficacy of PPT in hospitalized patients with severe COVID-19 pneumonia.

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

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

ConclusionEarly PPT can be considered a safe and effective therapeutic choice for patients with severe COVID-19. 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. The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. Testing Black-White disparities in biological aging in older adults in the United States: analysis of DNA-methylation and blood-chemistry methods Biological aging is a proposed mechanism through which social determinants drive health disparities. We conducted proof-of-concept testing of eight DNA-methylation and blood-chemistry quantifications of biological aging as mediators of disparities in healthspan between Black and White participants in the United States Health and Retirement Study (HRS; n=9005). We quantified biological aging from four DNA-methylation "clocks" (Horvath, Hannum, PhenoAge, and GrimAge), a DNA-methylation Pace of Aging (DunedinPoAm), and three blood-chemistry measures (PhenoAge, Klemera-Doubal method Biological Age, and homeostatic dysregulation). We quantified Black-White disparities in healthspan from cross-sectional and longitudinal data on physical-performance tests, self-reported activities of daily living (ADL) limitations and physician-diagnosed chronic diseases, self-rated health, and survival. DNA-methylation and blood-chemistry quantifications of biological aging were moderately correlated (Pearson-r range 0.1-0.4). GrimAge, DunedinPoAm and all three blood-chemistry measures were associated with healthspan characteristics (e.g. mortality effect-size range 1.71-2.32) and showed evidence of more advanced/faster biological aging in Black compared with White participants (Cohens d=.4-.5). These measures accounted for 13-95% of Black-White differences in healthspan-related characteristics. Findings that Black Americans are biologically older and aging more rapidly than White Americans of the same chronological age suggest that eliminating disparities in the pace of aging can contribute building to aging health equity. Clinical impact of the rapid molecular detection of RSV and influenza A and B viruses in the emergency department IntroductionUsing respiratory viruses rapid diagnostic tests in the emergency room (ER) could allow a better and faster clinical management. Point-of-care PCR instruments provide now results in less than 30 minutes. The objective of this study was to assess the impact of the use of the cobas(R) Influenza A/B & RSV Assay for use on Roches cobas(R) Liat(R) instrument on the clinical management of ER patients.

MethodsPatients (adults and children) requiring admission or suffering from an underlying condition at risk of respiratory complication were prospectively recruited in the ER of four hospitals in the Brussels region. Physicians intentions regarding admission, isolation, antibiotic and antiviral use were collected before and after performing a cobas(R) Influenza A/B & RSV molecular test. Additionally, a comparison of the analytical performance of this test against antigen rapid tests and viral culture was performed as well as a time-to-result evaluation.

ResultsPCR yielded twice more positive results than antigen rapid diagnostic tests. It allowed a decrease in the overall need for isolation and treatment by limiting the isolation of negative patients and the antibiotic use for positive patients. Meanwhile, antiviral treatments better targeted patients with a positive influenza PCR.

ConclusionThe use of a rapid influenza and RSV molecular test improves the clinical management of patients admitted to the ER by providing a fast and reliable result. Their additional cost compared to antigen tests should be balanced with the benefit of their analytical performance, leading to efficient reductions in the need of isolation and antibiotic use. "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. Complementary frailty and mortality prediction models on older patients as a tool for assessing palliative care needs BackgroundPalliative care (PC) has demonstrated benefits for life-limiting illnesses. Cancer patients have mainly accessed these services, but there is growing consensus about the importance of promoting access for patients with non-malignant disease. Bad survival prognosis and patients frailty are usual dimensions to decide PC inclusion.

ObjectivesThe main aim of this work is to design and evaluate three quantitative models based on machine learning approaches to predict frailty and mortality on older patients in the context of supporting PC decision making: one-year mortality, survival regression and one-year frailty classification.

MethodsThe dataset used in this study is composed of 39,310 hospital admissions for 19,753 older patients (age >= 65) from January 1st, 2011 to December 30th, 2018. All prediction models were based on Gradient Boosting Machines. From the initial pool of variables at hospital admission, 20 were selected by a recursive feature elimination algorithm based on the random forests GINI importance criterion. Besides, we run an independent grid search to find the best hyperparameters in each model. The evaluation was performed by 10-fold cross-validation and area under the receiver operating characteristic curve and mean absolute error were reported. The Cox proportional-hazards model was used to compare our proposed approach with classical survival methods.

ResultsThe one-year mortality model achieved an AUC ROC of 0.87 {+/-} 0.01; the mortality regression model achieved an MAE of 329.97 {+/-} 5.24 days. The one-year frailty classification reported an AUC ROC of 0.9 {+/-} 0.01. The Spearmans correlation between the admission frailty index and the survival time was -0.1, while the point-biserial correlation between one-year frailty index and survival time was -0.16.

ConclusionsOne-year mortality model performance is at a state-of-the-art level. Frailty Index used in this study behaves coherently with other works in the literature. One-year frailty classifier demonstrated that frailty status within the year could be predicted accurately. To our knowledge, this is the first study predicting one-year frailty status based on a frailty index. We found mortality and frailty as two weakly correlated and complementary PC needs assessment criteria. Predictive models are available online at http://demoiapc.upv.es. Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume BackgroundPast exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear.

ObjectiveTo determine contribution of cardiovascular mechanisms to SHS-associated exercise limitation.

MethodsWe examined the cardiovascular responses to maximum effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic (SBP) and diastolic blood pressures (DBP) and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables.

ResultsAt peak exercise (highest workload completed [WattsPeak]=156{+/-}46 watts [135{+/-}33 %predicted]), oxygen consumption (VO2Peak) and oxygen-pulse (O2-PulsePeak) were 1,557{+/-}476 mL/min (100{+/-}24 %predicted) and 11.0{+/-}3.0 mL/beat (116{+/-}25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98{+/-}1% and remained >93% in all participants. Sixty-six percent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak, and SBPPeak and inversely with SHS, air trapping (RV/TLC), and rise of SBP over workload (all P<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (P<0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (P=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score [&ge;]1) was associated with steeper rise in SBP over workload (P<0.01).

ConclusionIn a never-smoker population with remote exposure to SHS, abnormal escalation of afterload and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Key messagesO_ST_ABSWhat is the key question?C_ST_ABSWhat are the cardiovascular health effects of past exposure to secondhand tobacco smoke in never-smokers? How do pulmonary and cardiovascular systems interact in this setting?

What is the bottom line?Healthy never-smokers with history of remote past exposure to secondhand tobacco smoke have an abnormal cardiovascular response to exercise, which is characterized by a stroke volume and thus an exercise capacity that are reduced proportional to their years of exposure to secondhand tobacco smoke.

Why read on?The abnormal cardiovascular response to exercise in this population reveals the presence of an occult or subclinical pathology that impairs the cardiopulmonary functional reserve and reduces the efficiency of bodys oxygen delivery machinery, which could be disadvantageous during the times of increased cardiopulmonary output demands as in physiological distress or disease. Development of machine learning models for the prediction of complications after colonic, colorectal and small intestine anastomosis in psychiatric and non-psychiatric patient collectives (PSTUDY) 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. Impact of COVID 19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional "SHIELDING" measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients pain impact, hurts, management, treatments, communication with their caregivers and their Guardians perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patients quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria.