Health-related quality of life of female sex workers living with HIV in South Africa: a cross-sectional study IntroductionHealth-related quality of life (HRQoL) is an important HIV outcome beyond viral suppression. However, there are limited data characterizing HRQoL of key populations including female sex workers (FSW) living with HIV.

MethodsWe used baseline data (June 22, 2018-March 23, 2020) of FSW who were diagnosed with HIV and enrolled into a randomized trial in Durban, South Africa. HRQoL information was collected by a generic preference-accompanied tool with five domains (EQ-5D), and summarized into a single score (range 0-1) which represents health utility. We employed multivariable beta regression models to identify determinants of HRQoL and to estimate subgroup-specific HRQoL score. Using external estimates of life expectancy and population size, we estimated the number of quality adjusted life years reduced among FSW living with HIV in South Africa associated with violence and drug use.

ResultsOf 1363 individuals (mean age: 32.4 years; mean HRQoL score: 0.857) in our analysis, 62.6% used drugs, 61.3% experienced physical or sexual violence, and 64.6% self-reported taking antiretroviral treatment (ART). The following were associated with a reduction in the average marginal HRQoL score: older age (per decade: 0.018 [95% confidence interval (CI): 0.008, 0.027]), drug use (0.022 [0.007, 0.036]), experience of violence (0.024 [0.010, 0.038]), and moderate (vs. no) level of internalized stigma (0.023 [0.004, 0.041]). Current ART use was associated with a 0.015-point (-0.001, 0.031) increase in the HRQoL score. The estimated mean (95%CI) HRQoL scores ranged from 0.838 (0.816, 0.860) for FSW who used drugs, experienced violence, and were not on ART; to 0.899 (0.883, 0.916) for FSW who did not use drugs nor experience violence and were on ART. Our results can be translated into a reduction in 37,184 and 39,722 quality adjusted life years related to drug use and experience of violence, respectively in South Africa.

ConclusionsThese results demonstrate the association of ART with higher HRQoL among FSW and the need to further address structural risks including drug use, violence, and stigma. Population-specific estimates of HRQoL score can be further used to calculate quality-adjusted life years in economic evaluations of individual and structural interventions addressing the needs of FSW living with HIV.

Clinical Trial RegistrationNCT03500172 (April 17, 2018)
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.
Psychological factors associated with instrumental activities of daily living disability in older adults with knee osteoarthritis PurposeThe population of older adults with knee osteoarthritis (OA)-related disabilities is increasing globally. This study aimed to investigate the psychological factors associated with instrumental activities of daily living (IADL) disability in older adults with knee OA.

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

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

ConclusionOur study showed the importance of assessing self-efficacy using the PSEQ-4 in relation to IADL disability in older adults with knee OA. "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. EDUCATIONAL NEEDS OF MEDICAL PRACTITIONERS ABOUT MEDICAL BILLING: A SCOPING REVIEW OF THE LITERATURE. IntroductionThe World Health Organization has suggested the solution to health system waste caused by incorrect billing and fraud is policing and prosecution. However, a growing body of evidence suggests leakage may not always be fraudulent or corrupt, with researchers suggesting medical practitioners may sometimes struggle to understand increasingly complex legal requirements around health financing and billing transactions, which may be improved through education. To explore this phenomenon further, we undertook a scoping review of the literature to identify the medical billing education needs of medical practitioners and whether those needs are being met.

MethodsEligible records included English language materials published between 1 January 2000 and 4 May 2020. Searches were conducted on MEDLINE, PubMed, Google Scholar, CINAHL, LexisNexis and Heinonline.

ResultsWe identified 74 records as directly relevant to the search criteria. Despite undertaking a comprehensive, English language search, with no country restrictions, studies meeting the inclusion criteria were limited to three countries (Australia, Canada, U.S), indicating a need for further work internationally. The literature suggests the education needs of medical practitioners in relation to medical billing compliance are not being met and medical practitioners desire more education on this topic. Evidence suggests education may be effective in improving medical billing compliance and reducing waste in health systems. There is broad agreement amongst medical education stakeholders in multiple jurisdictions that medical billing should be viewed as a core competency of medical education, though there is an apparent inertia to include this competency in medical education curricula. Penalties for non-compliant medical billing are serious and medical practitioners are at risk of random audits and investigations for breaches of sometimes incomprehensible, and highly interpretive regulations they may never have been taught.

ConclusionDespite acknowledged significance of waste in health systems due to poor practitioner knowledge of billing practices, there has been very little research to date on education interventions to improve health system efficiency at a practitioner level. The role of classroom volume, occupancy, voice reduction and ffp2 masks in transmission risk of SARS-CoV2 in schools Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms. 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. 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. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

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

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

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

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

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

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

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Normative cognitive scores in western India, stratified by age, rurality, cognitive domains, and psychiatric comorbidity. Background and objectivesIndian ethnic and educational diversities necessitate obtaining normative cognitive data in different populations. We aimed to evaluate cognitive scores using a Marathi translation of the Kolkata Cognitive Battery (KCB), and to study the association of KCB components with depression and socio-demographic variables.

MethodologyWe studied 2651 individuals aged [&ge;]40 years, without pre-existing neuropsychiatric conditions, from urban (Mumbai) and rural districts of Maharashtra. For each component of KCB, the lowest 10th percentile score was used to define cognitive impairment.

ResultsWe studied 1435 (54%) rural and 1216 (46%) urban residents equally divided by gender (1316 women, 1335 men), average age 54 years. KCB scores were significantly lower with female sex, older age, illiteracy and depression. The largest effect sizes attributable to these factors were in the domains of calculation (gender), visuo-constructional ability (VCA; rurality) and verbal fluency (VF; depression). Scores remained significantly lower in rural residents after controlling for age, sex and education, particularly for VCA, immediate recall and calculation.

ConclusionThis Marathi KCB having been validated on large urban as well as rural samples, may be used to study cognition in Marathi speaking populations with appropriate cut-offs tailored to the degree of urbanization of the population. Hemodynamic Differences Between Women and Men with Elevated Blood Pressure in China: A Non-Invasive Assessment of 45,082 Adults Using Impedance Cardiography BackgroundWhether there are sex differences in hemodynamic profiles among people with elevated blood pressure is not well understood and could guide personalization of treatment.

Methods and resultsWe described the clinical and hemodynamic characteristics of adults with elevated blood pressure in China using impedance cardiography. We included 45,082 individuals with elevated blood pressure (defined as systolic blood pressure of [&ge;]130 mmHg or a diastolic blood pressure of [&ge;]80 mmHg), of which 35.2% were women. Overall, women had a higher mean systolic blood pressure than men (139.0 [{+/-}15.7] mmHg vs 136.8 [{+/-}13.8] mmHg, P<0.001), but a lower mean diastolic blood pressure (82.6 [{+/-}9.0] mmHg vs 85.6 [{+/-}8.9] mmHg, P<0.001). After adjusting for age, region, and body mass index, women <50 years old had lower systemic vascular resistance index (beta-coefficient [{beta}] -31.7; 95% CI: -51.2, -12.2) and higher cardiac index ({beta} 0.07; 95% CI: 0.04, 0.09) than men of their same age group, whereas among those [&ge;]50 years old women had higher systemic vascular resistance index ({beta} 120.4; 95% CI: 102.4, 138.5) but lower cardiac index ({beta} -0.15; 95% CI: -0.16, -0.13). Results were consistent with a propensity score matching sensitivity analysis, although the magnitude of the SVRI difference was lower and non-significant. However, there was substantial overlap between women and men in the distribution plots of these variables, with overlapping areas ranging from 78% to 88%.

ConclusionsOur findings indicate that there are sex differences in hypertension phenotype, but that sex alone is insufficient to infer an individuals profile. 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. Comparing SARS-CoV-2 case rates between pupils, teachers and the general population: results from Germany Given the inconsistent state of research regarding the role of pupils and teachers during the SARS-CoV-2 pandemic in Germany, statewide and nationwide data of infection case rates were analyzed to contribute to the discourse. Infection data from official sources ranging from mid to late 2020 were collected, prepared and analyzed to answer the question if pupils, teachers and general population differed in active case rates or not. The data showed that pupils and teachers case rates didnt exceeded those of the general population. In conclusion, it seems appropriate to appraise school-related measures to mitigate the SARS-CoV-2 pandemic sufficiently. Data-quality is a yet to overcome obstacle to provide good evidence-based recommendations regarding the management around infection cases in schools. Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

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

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

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

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2x2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after six weeks of treatment, versus 2 of 11 non-pretreated patients (odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer. 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. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. The Acute Treatment of Migraine with Low-Dose Naltrexone and acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses. Hepatic resection versus transarterial chemoembolization for the intermediate stage hepatocellular carcinoma：A cohort study BackgroundThe selection criterion for hepatic resection(HR) in intermediate-stage(IM) hepatocellular carcinoma(HCC) is still controversial. We used real-world data to evaluate the overall survival (OS) treated with HR or TACE.

MethodsIn all, 942 patients with IM-HCC were categorized in HR and TACE groups. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score- matched (PSM) analyses. The smooth curve was performed through the generalized additive model. The interaction test was performed to evaluate the HR impact on OS concerning risk factors. Also, we used multiple imputation to deal with the missing data.

ResultsTotally, 23.0% (n=225) of patients received HR. At a median overall survival of 23.7 months, HR was associated with the improved OS on multivariate analysis (hazard ratio, 0.45; 95%CI: 0.35, 0.58; after PSM: 0.56; 95%CI: 0.41, 0.77). Landmark analyses limited to long-term survivors of [&ge;] 6 months, [&ge;] 1, and [&ge;] 2 years demonstrated better OS with HR in all subsets (all P<0.05). After PSM analysis, however, HR increased 20% risk of death (HR, 1.20; 95%CI: 0.67, 2.15) in the subgroup of LDH [&le;]192 U/L (P for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and the HR with respect to 1-, 3-, and 5-year observed survival rate (all P<0.05).

ConclusionHepatic resection was superior to TACE for intermediate-stage HCC in the range of LDH level > 192 U/L. Moreover, TACE might be suitable for patients with LDH level [&le;] 192 U/L.

SynopsisO_LIHepatectomy was superior to TACE for BCLC-B HCC.
C_LIO_LIHepatectomy increased 20% risk of death for LDH < 192 U/L after matching.
C_LIO_LIA significant interaction was robust between LDH and with respect to hepatectomy the 1-, 3-, and 5-year observed survival rate.
C_LI The Addiction Risk Factor: A Unitary Genetic Vulnerability Characterizes Substance Use Disorders and Their Associations with Common Correlates Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individuals of European ancestry (Total N = 1,019,521; substance specific Ns range: 82,707-435,563), while adjusting for the genetics of substance use (Ns = 184,765-632,802). We also tested whether shared liability across SUDs is associated with behavioral constructs (risk taking, executive function, neuroticism; Ns = 328,339-427,037) and non-substance use psychopathology (psychotic, compulsive, and early neurodevelopmental disorders). Shared genetic liability to PAU, PTU, CUD, and OUD was characterized by a unidimensional addiction risk factor (termed The Addiction-Risk-Factor, independent of substance use. OUD and CUD demonstrated the largest loadings, while problematic tobacco use showed the lowest loading. The Addiction-Risk-Factor was associated with risk taking, neuroticism, executive function, and non-substance psychopathology, but retained specific variance before and after accounting for genetics of substance use. Thus, a common genetic factor partly explains susceptibility for alcohol, tobacco, cannabis, and opioid use disorder. The Addiction-Risk-Factor has a unique genetic architecture that is not shared with normative substance use or non-substance psychopathology, suggesting that addiction is not the linear combination of substance use and psychopathology. 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

O_TBL View this table:
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

O_TBL View this table:
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 Prospectively validated disease-agnostic predictive medicine with augmented intelligence Despite numerous superhuman achievements in complex challenges1,2, standalone AI does not free life science from the long-term bottleneck of linearly extracting new knowledge from exponentially growing new data3, severely limiting the success rate of drug discovery4. Inspired by the state-of-the-art AI training methods, we trained a human-centric hybrid augmented intelligence5 (HAI) to learn a foundation model6 that extracts all-encompassing knowledge of human physiology and diseases. To evaluate the quality of HAIs extracted knowledge, we designed the public, prospective prediction of pivotal ongoing clinical trial outcomes at large scale (PROTOCOLS) challenge to benchmark HAIs real-world performance of predicting drug clinical efficacy without access to human data. HAI achieved a 10.5-fold improvement from the baseline with 99% confidence7 in the PROTOCOLS validation, readily increasing the average clinical success rate of investigational new drugs from 7.9%8 to 90% for almost any human diseases9,10. The validated HAI confirms that exponentially extracted knowledge alone is sufficient for accurately predicting drug clinical efficacy, effecting a total reversal of Erooms law4. HAI is also the worlds first clinically validated model of human aging that could substantially speed up the discovery of preventive medicine for all age-related diseases11. Our results demonstrate that disruptive breakthroughs necessitate the smallest team size to attain the largest HAI for optimal knowledge extraction from high-dimensional low-quality data space, thus establishing the first prospective proof of the previous discovery that small teams disrupt12. The global adoption of training HAI provides a well-beaten economic path to mass-produce scientific and technological breakthroughs via exponential knowledge extraction and better designs of data labels for training better-performing AI13. Using Adversarial Images to Assess the Stability of Deep Learning Models Trained on Diagnostic Images in Oncology PurposeDeep learning (DL) models have rapidly become a popular and cost-effective tool for image classification within oncology. A major limitation of DL models is output instability, as small perturbations in input data can dramatically alter model output. The purpose of the study is to investigate the robustness of DL models in the oncologic image domain through the application of adversarial images: manipulated images with small pixel-level perturbations designed to assess the stability of DL models.

Experimental DesignWe examined the impact of adversarial images on the classification accuracies of DL models trained to classify cancerous lesions across three common oncologic imaging modalities (CT, mammogram, and MRI). The CT model was trained to classify malignant lung nodules using the LIDC dataset. The mammogram model was trained to classify malignant breast lesions using the DDSM dataset. The MRI model was trained to classify brain metastases using an institutional dataset. We also explored the utility of an iterative adversarial training approach to improve the stability of DL models to small pixel-level changes.

ResultsOncologic images showed instability with small pixel-level changes. A pixel-level of perturbation of .004 resulted in a majority of oncologic images to be misclassified by their respective DL models (CT 25.64%, mammogram 23.93%, MRI 6.36%). Adversarial training mitigated improved the stability and robustness of DL models trained on oncologic images compared to naive models [(CT 67.72% vs 26.92%), mammogram (63.39% vs 27.68%), MRI (87.20% vs 24.32%)].

ConclusionsDL models naively trained on oncologic images exhibited dramatic instability to small pixel-level changes resulting in substantial decreases in accuracy. Adversarial training techniques improved the stability and robustness of DL models to such pixel-level changes. Prior to clinical implementation, adversarial training should be considered to proposed DL models to improve overall performance and safety. How Informative Were Early SARS-CoV-2 Treatment and Prevention Trials? A longitudinal cohort analysis of trials registered on clinicaltrials.gov BackgroundEarly in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic.

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

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

ConclusionsLess than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic. Variation in colorectal cancer treatment and outcomes in Scotland: real world evidence from national linked administrative data BackgroundColorectal cancer (CRC) is the third most common type of cancer in Scotland and the second leading cause of cancer death. Despite improvements in CRC survival over time, Scotland lags behind its UK and European counterparts. Linked administrative datasets can provide a real-world representation of current care as a basis for evaluation of new interventions or policies and to understand variation in care and outcomes. In this study, we aim to provide up to date, population level evidence on CRC treatment and survival in Scotland for patients treated with curative or palliative intent as a basis for the understanding of variation, and to provide data to underpin the evaluation of new treatments.

MethodsWe conducted a retrospective analysis of adults with an incident CRC registered on the Scottish Cancer Registry (ICD-10 codes C18-20) between January 2006 and December 2018. Data on patients with incident CRC was linked to hospital inpatient records allowing description of their demographic, diagnostic and treatment characteristics. For a curative cohort (n = 26,204) Cox-Proportional Hazards regression models were used to assess the factors affecting overall survival (OS) and CRC specific survival (CRCS).

ResultsOverall, 32,691 (73%) and 12,184 (27%) patients had a diagnosis of colon and rectal cancer respectively. On average, patients with colorectal cancer had two hospital inpatient stays in the five-years pre-diagnosis. Chemotherapy was used in 42% with colon cancer and 30% with colon cancer. Radiotherapy use was 2% and 39% respectively. Five year OS (CRCS) within the curative cohort was 71% (81%) and 75% (82%) for patients with colon and rectal cancer respectively. After accounting for patient and tumour characteristics, survival outcomes demonstrated significant geographical variation.

ConclusionsNational linked administrative datasets have the ability to provide real-world representation of the treatments and outcomes for patients with cancer. In a Scottish population of curative patients with CRC, there was significant variation in survival depending on sex and geography.