title: The micro-hotspots of cholera in Kano State, Nigeria, 2010-2019:analysis of patient characteristics, Spatio-temporal patterns and contextual determinants at the ward level.

abstract:
Cholera is endemic in Nigeria, and Kano State reports outbreaks yearly with a case fatality rate (CFR) of 3.3% from 2010 to 2019. The lack of data at ward level has enabled the disease to evade focused interventions. The goal of this study was to describe the geographic distributions, care-seeking behaviors, Spatio-temporal cluster patterns of the micro-hotspots (hotspots wards) linked with suspected and confirmed cases and deaths of cholera in Kano State.

Suspected and confirmed cholera morbidity and mortality at the ward level from 2010-2019 were acquired from the Nigeria Centre for Disease Control. Population and waterbody data were obtained from the Nigeria Expanded Program on Immunization and online, respectively. Data analysis used SaTScan and methods recommended by the Global Task Force on Cholera Control.

During these ten years, 18,483 suspected and confirmed cases (617 deaths) were reported with 67.7% of the cases and 72% of the deaths from rural wards. The ages of the cases ranged from 1 month to 100 years with a distribution skewed to the older years. CFRs were statistically higher in the <5-year olds compared to those >14 years (p-value = 0.0005). For 2010-2019, gender was statistically associated with cholera outcome (survived/died) (p-value = 0.0006), and women in the rural setting disproportionately died from cholera than women in the urban area (p-value = 0.003). Cholera severity, as measured by hospitalization and death, was higher in the urban (77.4%) compared with the rural (53.4%) setting with the highest severity (84.7%) registered among those >14 years. Rapid Diagnostic Tests (RDT) were performed in 1.3% (249) samples of all suspected cases and ranged from 0.7% among the 5-14 year-olds in the rural to 3.5 % among the < 5-year-olds in the urban areas. Of the stool samples collected, 62.7% tested positive for V. cholerae using RDT. The positivity rate was least in the urban setting amongst the <5 years (41.2%) while care-seeking-behavior ranged from 52.1% in the urban to 82.7% in the rural settings. Seasonal patterns of disease often differed between urban and rural settings with outbreaks occurring in both the dry and rainy seasons, but with more intense transmission occurring during the rainy season from week 22 (early June) to week 40 (late September). A Spatio-temporal clustering analysis detected 168 micro-hotspots out of 404 wards, with a population of 4,876,254, having a significantly higher risk (relative risk 1.01-18.73) compared to the State as a whole. While 79 micro-hotspots with a population of 2,119,974 had a RR [≥] 2. The micro-hotspots tended to cluster around waterbodies. SaTScan and GTFCC methods generally agreed in micro-hotspots detection.

This study shows the epidemiology of cholera in Kano State differs between urban and rural settings and that hotspot maps at the ward level, not hotpots maps at the Local Government Area level, are best suited for targeting interventions including vaccines. Appropriate studies are needed to further delineate the urban and rural divide of outbreaks but targeting interventions to the identified high-priority micro-hotspots will facilitate cholera elimination from the state.

Author summaryCholera is endemic in Nigeria since 1970, and Kano State reports outbreaks almost every year. From 2010-2019, Kano State reported 18,483 cases and 617 deaths, for a case fatality rate of 3.3%. Focusing interventions at the Local Government Area instead of the ward (local) level contributed to the continuous threat from cholera in Kano State. When we divided the state into its two geographic areas (urban and rural), there were very different epidemiology as well as Spatio-temporal patterns of clustering of wards with elevated relative risk (micro-hotspots). Nearly two-thirds of the cases and deaths were reported from rural wards. The ages of the cases ranged from 1 month to 100 years with case fatality ratios higher in the <5-years olds compared to those >14 years (p-value = 0.0005). Women in the rural area not only had more cases but also were more likely to die from cholera than women in the urban area (p-value = 0.003). The hospitalization rate was higher in the urban than rural setting whereas care-seeking behavior was higher in rural than urban areas. Rapid Diagnostic Tests to confirm cholera was very low overall. Seasonal patterns of disease differed between urban and rural areas with outbreaks occurring in both the dry and rainy seasons, but with more cases from June to September, during the rainy season. A population of 4,876,254 live in the 168 micro-hotspots in which cholera risks were 1.01 to 18.73 times higher compared to the State as a whole. Following the Global Task Force on Cholera Control recommendations, interventions should focus on these identified micro-hotspots for cholera elimination from Kano State.


title: Categories of intimate partner violence and abuse (IPVA) among young women and men: Latent Class Analysis of psychological, physical, and sexual victimisation and perpetration in a UK birth cohort

abstract:
BackgroundIn the UK, around one-third of young people are exposed to IPVA by 21 years old. However, types of IPVA victimisation in this population (psychological, physical, sexual), and their relationship with impact and perpetration are poorly understood.

MethodsParticipants in a UK birth cohort reported IPVA victimisation and perpetration by age 21. We carried out a latent class analysis, where we categorised IPVA by types/frequency of victimisation, and then assigned individuals to their most probable class. Within these classes, we then estimated risks of reported: 1) types of negative impacts (sad, upset/unhappy, anxious, depressed, affected work/studies, angry/annoyed, drank/took drugs more); 2) types/frequency of perpetration.

ResultsAmong 2,130 women and 1,149 men, 32% and 24% reported IPVA victimisation (of which 89% and 73% reported negative impact); 21% and 16% perpetration. Victimisation responses were well represented by five classes, including three apparent in both sexes: No-low victimisation (characterised by low probabilities of all types of victimisation; average probabilities of women and men belonging to this class were 82% and 70%); Mainly psychological (15% and 12%); Psychological & physical victimisation (4% and 7%), and two classes that were specific to women: Psychological & sexual (7%); Multi-victimisation (frequent victimisation for all three types; 4%). In women, all types of negative impact were most common in the Psychological & sexual and Multi-victimisation classes; for men, the Psychological & physical class. In women, all types of perpetration were most common for the Mainly psychological, Psychological & physical, and Multi-victimisation classes; in men, the Mainly psychological and Psychological & physical classes.

DiscussionIn this study of young people, we found categories of co-occurrence of types and frequency of IPVA victimisation associated with differential risks of negative impact and perpetrating IPVA. This is consistent with emerging evidence of IPVA differentiation and its variable impact in other populations.

category: epidemiology


title: Long-term effects of increased adoption of artemisinin combination therapies in Burkina Faso

abstract: Artemisinin combination therapies (ACTs) are the WHO-recommended first-line therapies for uncomplicated Plasmodium falciparum malaria. The emergence and spread of artemisinin-resistant genotypes is a major global public health concern due to the increased rate of treatment failures that result. This is particularly germane for WHO designated  high burden to high impact (HBHI) countries, such as Burkina Faso, where there is increased emphasis on improving guidance, strategy, and coordination of local malaria response in an effort to reduce the prevalence of P. falciparum malaria. To explore how the increased adoption of ACTs may affect the HBHI malaria setting of Burkina Faso, we added spatial structure to a validated individual-based stochastic model of P. falciparum transmission and evaluated the long-term effects of increased ACT use. We explored how de novo emergence of artemisinin-resistant genotypes, such as pfkelch13 580Y, may occur under scenarios in which private-market drugs are eliminated or multiple first-line therapies (MFT) are deployed. We found that elimination of private market drugs would result in lower treatment failures rates (between 11.98% and 12.90%) when compared to the status quo (13.11%). However, scenarios incorporating MFT with equal deployment of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PPQ) may accelerate near-term drug resistance (580Y frequency ranging between 0.62 to 0.84 in model year 2038) and treatment failure rates (26.69% to 34.00% in 2038), due to early failure and substantially reduced treatment efficacy resulting from piperaquine-resistant genotypes. A rebalanced MFT approach (90% AL, 10% DHA-PPQ) results in approximately equal long-term outcomes to using AL alone but may be difficult to implement in practice.


title: Pediatric critical COVID-19 and mortality in a multinational cohort

abstract:
ObjectivesTo understand the international epidemiology of critical pediatric COVID-19 and compare presentation, treatments, and outcomes of younger (<2 years) and older (>2 years) children.

DesignProspective, observational study from April 1 to December 31, 2020

SettingInternational multicenter study from 55 sites from North America, Latin America, and Europe.

ParticipantsPatients <19 years old hospitalized with critical COVID-19

Interventionsnone

Main outcomes measuredClinical course, treatments, and outcomes were compared between younger and older children. Multivariable logistic regression was used to calculate adjusted odds ratios (aOR) for hospital mortality.

Results557 subjects (median age, 8 years; 24% <2 years) were enrolled from 55 sites (63% Latin American). Half had comorbidities. Younger children had more respiratory findings (56% vs 44%), viral pneumonia (45% vs 29%), and treatment with invasive ventilation (50% vs 37). Gastrointestinal (28% vs 69%) or mucocutaneous (16% vs 44%) findings, vasopressor requirement (44% vs 60%), and MIS-C (15% vs 40%) were less common in younger children. Hospital mortality was 10% overall but 15% in younger children (odds ratio 1.89 [95%CI 1.05-3.39]). When adjusted for age, sex, region, and illness severity, mortality-associated factors included cardiac (aOR 2.6; 95%CI 1.07-6.31) or pulmonary comorbidities (aOR 4.4; 95%CI 1.68-11.5), admission hypoxemia (aOR 2.33; 95%CI 1.24-4.37), and lower respiratory symptoms (aOR 2.83; 95%CI 1.49-5.39). Gastrointestinal (aOR 0.49; 95%CI 0.26-0.92) or mucocutaneous symptoms (aOR 0.31; 95%CI 0.15-0.64), treatment with intravenous immune globulin (aOR 0.33; 95%CI 0.17-0.65), and MIS-C (aOR 0.26; 95%CI 0.11-0.64) were associated with lower mortality.

ConclusionsWe identified age-related differences in presentation and mortality for critical pediatric COVID-19 that should prompt more attention to improving management in younger children, especially in developing countries.

Table of Contents SummaryThis is a multinational study describing critical pediatric COVID-19 clinical spectrum and related mortality in high and low-middle income countries during 2020.

Whats known on this subjectPediatric critical illness due to COVID-19 is uncommon and have lower mortality compared to adults when hospitalized. While larger cohorts are from high-income countries (HICs), studies including data from low-middle-income countries (LMICs) remain scarce.

What this study addsIn our multinational cohort of critical pediatric COVID-19, we identified higher mortality than previously reported and age-related disease patterns. Children <2 years old had more respiratory disease and higher mortality, and older children had more non-pulmonary disease and better outcomes.

category: pediatrics


title: The impact on the mental health and well-being of unpaid carers affected by social distancing, self-isolation and shielding during the COVID 19 pandemic in England - a systematic review

abstract:
ObjectiveThis study explores the impact of the COVID 19 lockdown measures on the mental health and well-being of unpaid carers, who make up the largest number of the carer population in England.

Study designA systematic review research protocol was designed and used to conduct the review along with the Enhancing Transparency in Reporting the synthesis of Qualitative Research - ENTREQ statement [43]. Pre-determined inclusion and exclusion criteria were used. EndNote X9 reference management was used and the search process was represented using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram [76]. Appraisal of the included research was carried out using the Critical Appraisal Skills Programme (CASP) [57]. Line by line coding was done using inductive thematic synthesis and EPPI Reviewer 4 software [60].

ResultsFour themes emerged; immediate worries or fears, adapting to change, post pandemic fears and use of technology.

ConclusionThe measures put in place during the first lockdown period have had detrimental impacts on unpaid carers, putting them at greater risk of burnout. However, use of digital platforms could have a positive impact on well-being. Recommendations for further research are provided.

What is new?O_ST_ABSKey findings?C_ST_ABSO_LIDiscontinued or reduced access to activities and services during the first lockdown during the pandemic has had a negative impact on both people who require care and their carers.
C_LIO_LICarers prioritise the mental health and wellbeing needs of the people they care for over their own.
C_LIO_LIFurther qualitative research from different groups of carers would be useful to gain a deeper understanding of the impact of the COVID 19 pandemic measures on unpaid carers.
C_LIO_LIUse of digital technology and digital platforms may be useful tools for carers both during the pandemic and after.
C_LI

What this adds to what is known?O_LIThere have been very few qualitative studies on the impact of the COVID 19 pandemic on the mental health and wellbeing of unpaid carers, this review has synthesised their findings and will contribute to future research.
C_LIO_LIUnpaid carers are known to be at risk of poor mental health and wellbeing outcomes, this review demonstrates that they are even more at risk due to the increased reliance on them during the pandemic.
C_LI

What is this implication and what should change?O_LIThere is limited qualitative data available from a range of different groups of carers for example, spouse carers, parent carers, carers of people who have specific needs or conditions. Therefore, purposeful sample research to determine the needs of groups of carers during the COVID 19 pandemic could be valuable.
C_LIO_LIUnpaid carers who do not have appropriate support are more at risk of poor mental health and wellbeing outcomes. During the pandemic services have had to adapt to the various rules implemented. Digital adaptations to the provision of support to both carers and the people they care for could be beneficial both during and after the pandemic.
C_LI

category: public and global health


title: TP53-mediated clonal hematopoiesis confers increased risk for incident peripheral artery disease

abstract:
BackgroundSomatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP), particularly in DNMT3A, TET2, and JAK2, are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. However, whether CHIP is associated with increased risk of peripheral artery disease (PAD) remains unknown. In addition, chemotherapy frequently causes mutations in DNA Damage Repair (DDR) genes TP53 and PPM1D, and whether CHIP caused by somatic mutations in DDR genes results in increased risk of atherosclerosis is unclear. We sought to test whether CHIP, and CHIP caused by DDR genes, associates with incident peripheral artery disease (PAD) and atherosclerosis.

MethodsWe identified CHIP among 50,122 exome sequences in individuals from UK and Mass General Brigham Biobanks and tested CHIP status (N=2,851) with incident PAD and atherosclerosis across multiple arterial beds. To mimic the human scenario of clonal hematopoiesis and test whether the expansion of p53-deficient hematopoietic cells contributes to atherosclerosis, a competitive bone marrow transplantation (BMT) strategy was used to generate atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% Trp53-/- hematopoietic cells (20% KO-BMT mice). We then evaluated aortic plaque burden and plaque macrophage accumulation 12 weeks after grafting.

ResultsCHIP associated with incident PAD (HR 1.7; P=2.2x10-5) and atherosclerosis in multiple beds (HR 1.3; P=9.7x10-5), with increased risk among individuals with DDR CHIP (HR 2.0; P=0.0084). Among atherosclerosis-prone Ldlr null mice, the p53 -/- 20% KO-BMT mice demonstrated increased aortic plaque size (p=0.013) and accumulation of p53-/- plaque macrophages (P<0.001), driven by an abundance of p53-deficient plaque macrophages. The expansion of p53-deficient cells did not affect the expression of the pro-inflammatory cytokines IL-6 and IL-1{beta} in the atherosclerotic aortic wall.

ConclusionsOur findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system, with evidence of increased plaque among p53 -/- 20% KO-BMT mice via expansion of plaque macrophages. These observations provide new insight into the link between CHIP and cardiovascular disease, and lend human genetic support to the concept that post-cytotoxic chemotherapy patients may benefit from surveillance for atherosclerotic conditions in addition to therapy-related myeloid neoplasms.

category: genetic and genomic medicine


title: Model-based assessment of SARS-CoV-2 Delta variant transmission dynamics within partially vaccinated K-12 school populations

abstract:
BackgroundWe examined school reopening policies amidst rising transmission of the highly transmissible Delta variant, accounting for vaccination among individuals aged 12 years and older, with the goal of characterizing risk to students and teachers under various within-school non-pharmaceutical interventions (NPIs) combined with specific vaccination coverage levels.

MethodsWe developed an individual-based transmission model to simulate transmission of the Delta variant of SARS-CoV-2 among a synthetic population, representative of Bay Area cities. We parameterized the model using community contact rates from vaccinated households ascertained from a household survey of Bay Area families with children conducted between February - April, 2021.

Interventions and outcomesWe evaluated the additional infections in students and teachers/staff resulting over a 128-day semester from in-school instruction compared to remote instruction when various NPIs (mask use, cohorts, and weekly testing of students/teachers) were implemented in schools, across various community-wide vaccination coverages (50%, 60%, 70%), and student ([≥]12 years) and teacher/staff vaccination coverages (50% - 95%). We quantified the added benefit of universal masking over masking among unvaccinated students and teachers, across varying levels of vaccine effectiveness (45%, 65%, 85%), and compared results between Delta and Alpha variant circulation.

ResultsThe Delta variant sharply increases the risk of within-school COVID-transmission when compared to the Alpha variant. In our highest risk scenario (50% community and within-school vaccine coverage, no within-school NPIs, and predominant circulation of the Delta variant), we estimated that an elementary school could see 33-65 additional symptomatic cases of COVID-19 over a four-month semester (depending on the relative susceptibility of children <10 years). In contrast, under the Bay Area reopening plan (universal mask use, community and school vaccination coverage of 70%), we estimated excess symptomatic infection attributable to school reopening among 2.0-9.7% of elementary students (8-36 excess symptomatic cases per school over the semester), 3.0% of middle school students (13 cases per school) and 0.4% of high school students (3 cases per school). Excess rates among teachers attributable to reopening were similar. Achievement of lower risk tolerances, such as <5 excess infections per 1,000 students or teachers, required a cohort approach in elementary and middle school populations. In the absence of NPIs, increasing the vaccination coverage of community members from 50% to 70% or elementary teachers from 70% to 95% reduced the estimated excess rate of infection among elementary school students attributable to school transmission by 24% and 41%, respectively. We estimated that with 70% coverage of the eligible community and school population with a vaccine that is [≤]65% effective, universal masking can avert more cases than masking of unvaccinated persons alone.

ConclusionsAmidst circulation of the Delta variant, our findings demonstrated that schools are not inherently low risk, yet can be made so with high community vaccination coverages and universal masking. Vaccination of adult community members and teachers protects unvaccinated elementary and middle school children. Elementary and middle schools that can support additional interventions, such as cohorts and testing, should consider doing so, particularly if additional studies find that younger children are equally as susceptible as adults to the Delta variant of SARS-CoV-2.

LimitationsWe did not consider the effect of social distancing in classrooms, or variation in testing frequency, and considerable uncertainty remains in key transmission parameters.


title: Primate-specific ZNF808 is essential for pancreatic development in humans

abstract: Identifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. Here we report the identification of homozygous loss of function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of many transposable elements it normally represses during early pancreas development. This results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. We show that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.


title: Early Precursors of Literacy Development in Simultaneous Bilinguals: A Systematic Review and Meta-Analysis

abstract:
Several literacy precursors have been identified in monolingual English-speaking children; however, it is unclear whether the same precursors are also associated with literacy development in bilingual children.

PurposeWe examine whether in simultaneous bilingual children: (i) code-related, oral-language, and domain-general cognitive literacy precursors have been utilized -- similar to monolingual children; (ii) other types of precursors have been identified; (iii) code-related, oral-language, domain-general cognitive, or other types of literacy precursors are associated with word/non-word and/or text-level reading skills; in (a) one or (b) both spoken languages; (iv) the type of literacy outcome measure, and (v) language background measure influence performance on emergent literacy skills.

MethodWe examined reported statistical associations, between a given literacy precursor and outcome measure, and conducted a meta-analysis examining specific code-related and oral-language precursors in relation to word/non-word reading and/or text reading comprehension.

ResultsApart from semantic awareness, all code-related, oral-language, domain-general cognitive and eight additional identified precursors were significantly associated with reading in simultaneous bilinguals. However, these precursors were predominantly assessed only in English, or English in addition to a heritage language. Phonological awareness and vocabulary emerged as commonly-assessed precursors consistently associated with reading.

ConclusionsParticularly, these code-related and oral-language skills may be used as precursor screening tools in simultaneous bilinguals, across heritage and societal languages. Future research should develop language-specific precursor screening tools and investigate the reliability of non-linguistic precursors, to address the evident English assessment bias and support biliteracy development across spoken languages.

category: rehabilitation medicine and physical therapy


title: Anxiety disorders and age-related changes in physiology

abstract:
BackgroundAnxiety disorders are leading contributors to the global disease burden, highly prevalent across the lifespan, and associated with substantially increased morbidity and early mortality.

AimsThe aim of this study was to examine age-related changes across a wide range of physiological measures in middle-aged and older adults with a lifetime history of anxiety disorders compared to healthy controls.

MethodThe UK Biobank study recruited >500,000 adults, aged 37-73, between 2006-2010. We used generalised additive models to estimate non-linear associations between age and hand-grip strength, cardiovascular function, body composition, lung function and heel bone mineral density in cases and in controls.

ResultsThe main dataset included 332,078 adults (mean age = 56.37 years; 52.65% females). In both sexes, individuals with anxiety disorders had a lower hand-grip strength and blood pressure, while their pulse rate and body composition measures were higher than in healthy controls. Case-control differences were larger when considering individuals with chronic and/or severe anxiety disorders, and differences in body composition were modulated by depression comorbidity status. Differences in age-related physiological changes between female anxiety disorder cases and healthy controls were most evident for blood pressure, pulse rate and body composition, while in males for hand-grip strength, blood pressure and body composition. Most differences in physiological measures between cases and controls decreased with increasing age.

ConclusionsIndividuals with a lifetime history of anxiety disorders differed from healthy controls across multiple physiological measures, with some evidence of case-control differences by age. The differences observed varied by chronicity/severity and depression comorbidity.

category: psychiatry and clinical psychology


title: Effect of kettlebell training on bone mineral density in two older adults with osteoporosis: a multiple-case study from the BELL trial

abstract: The purpose of this explanatory retrospective case study was to report clinically significant increases in bone mineral density in a female and a male over 70 years of age with osteoporosis, following 16 weeks of hardstyle kettlebell training. Both case subjects were insufficiently active prior to participating in the BELL trial. Subjects trained five days a week accruing a large training load volume (calculated as kettlebell mass multiplied by repetitions performed) during structured group-based classes (74,872 kg and 110,132 kg, respectively). Regional dual-energy X-ray absorptiometry was used to assess BMD at the hip and lumbar spine. Increases in BMD of 12.7% and 5.9% at the femoral neck and lumbar spine (L2-L4) respectively were observed for the female, and 2.5% and 6.0% respectively for the male. Magnitude of change in BMD (g/cm2) at the lumbar spine was 2.0 and 1.9 times larger than the least significant change for the female and male respectively, and sufficient to advance the female subjects status from osteoporosis to osteopenia. Although these results do not show a definitive causal relationship between kettlebell training and increased BMD, further investigation of the effects of kettlebell training on BMD in older adults with osteoporosis and osteopenia is warranted.


title: Association of post-traumatic stress disorder, traumatic brain injury, and related synergistic factors with prodromal Parkinson's Disease: A case-control study of 1.5 million Veterans

abstract:
ObjectiveTo measure the association of pre-existing post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) on subsequent diagnosis of Parkinsons disease, and to identify common co-occurring sleep, mood, cognitive, and pain disorders that may amplify the association with Parkinsons disease.

MethodsPopulation-based case-control of 1.5 million Veterans within the Veterans Health Administration. Cases of coded Parkinsons disease were matched 4:1 to controls by gender, birth year, age, race, ethnicity, and smoking. For each disorder, the onset, first increase, and synergy index combined with post-traumatic stress disorder and traumatic brain injury were measured.

ResultsOnset times for post-traumatic stress disorder and traumatic brain injury were -22.5 and -10.1 years before diagnosis of Parkinsons disease. For post-traumatic stress disorder, synergy was greatest with chronic pain, mild cognitive impairment, Rapid eye movement behavior sleep disorder, and periodic limb movement disorder and started at -11, -9, -6, -7 years. For traumatic brain injury, synergy was greatest with migraine, anxiety, sleep apnea, hypersomnia, insomnia, and depression and started at -8, -8, -12, -6, -4, and -5 years.

InterpretationThere is a long timeline of association of post-traumatic stress disorder and traumatic brain with prodromal Parkinsons disease and greater-than-additive interactions with other non-motor neurobehavioral disorders. These data provide a more detailed timecourse for post-traumatic stress disorder and traumatic brain injury and identify early synergies potentially worth targeting in clinical trials.

category: neurology


title: Tau spreading is driven by neuronal connectivity in primary tauopathies - evidence from tau-PET and histopathology

abstract: Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2nd generation 18F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.


title: Communicating risk to patients: developing an Efficiency Index for diagnostic and screening tests

abstract: Diagnostic and screening tests may have risks such as misdiagnosis, as well as the potential benefits of correct diagnosis. Effective communication of this risk to both clinicians and patients can be problematic. The purpose of this study was to develop a metric called the "efficiency index" (EI), defined as the ratio of test accuracy and inaccuracy, or the number needed to misdiagnose divided by number needed to diagnose. This was compared with a previously described "likelihood to be diagnosed or misdiagnosed" (LDM), also based on "numbers needed" metrics. Datasets from prospective pragmatic test accuracy studies examining four brief cognitive screening instruments (Mini-Mental State Examination; Montreal Cognitive Assessment; Mini-Addenbrookes Cognitive Examination, MACE; and Free-Cog) were analysed to calculate values for EI and LDM, and to examine their variation with test cut-off for MACE. EI values were also calculated using a modification of McGees heuristic for the simplification of likelihood ratios to estimate percentage change in diagnostic probability. The findings indicate that EI is easier to calculate than LDM and, unlike LDM, may be classified either qualitatively or quantitatively in a manner similar to likelihood ratios. EI shows the utility or inutility of diagnostic and screening tests, illustrating the inevitable trade-off between diagnosis and misdiagnosis. It may be a useful metric to communicate risk in a way that is easily intelligible for both clinicians and patients.


title: Radiosensitivity Index (RSI) is not fit to be used for dose-adjustments: a pan-cancer analysis

abstract:
PurposeRe-analyze both the original preclinical and latest clinical pan-cancer open-source data-set to assess if the "Radiosensitivity Index", "RSI" for short, explains enough of the outcome variance either preclinically or clinically to elucidate a dose-response empirically.

Methods and MaterialsThe original preclinical test-set data from the publication where "RSI" was derived was collected and re-analyzed by comparing the observed versus predicted survival fraction at 2Gy (SF2). In addition, the predictive capability of "RSI" was also compared to random sampling. Clinical data was collected from a recently published data-set that included "RSI" values, overall survival outcomes, radiotherapy dose and tumor site for 5 cancers, glioma, triple negative breast, endometrial, pancreatic and lung cancer. Cox proportional hazards model were used to assess: 1) is "RSI" better than random chance at ordering overall survival times; 2) does adjusting for "RSI" elucidate a dose-response and 3) does an interaction between "RSI" and dose exist.

ResultsPreclinically "RSI" showed a negative correlation (Spearmans rho = -0.61, p = 0.034) between observed and predicted SF2. Furthermore, 98 percent of random samples showed better correlation to SF2 than "RSI". Clinically, the pooled concordance-index for "RSI" was 0.52 (standard error 0.2) i.e. it was found to be no better than random chance and so replicated the preclinical findings. Furthermore, a dose-response was not seen after adjusting for "RSI" (p=0.584) and no interaction between "RSI" and dose was found (p=0.147).

ConclusionsThese results suggest that like the initial in-vitro analysis 12 years previously "RSI" is not a marker of radiotherapy sensitivity, should not be referred to as such and is also not fit to be used in any dose-adjustment algorithms.

category: oncology


title: Genetic assessments of breast cancer risk that do not account for polygenic background are incomplete and lead to incorrect preventative strategies

abstract: Breast cancer is the most common cancer among women and is a leading cause of cancer mortality worldwide. There is a significant genetic component to breast cancer risk which is the result of both rare pathogenic mutations and common genome-wide variation. However, the penetrance of pathogenic mutations varies widely and their frequency is low, both at a population level and amongst breast cancer cases. Polygenic risk scores, which aggregate the effect of hundreds to millions of common genome-wide variants offer a way to further understand the contribution of genetics to disease risk. Here we analyse genome-wide data from 221,479 women and 90,307 high coverage exomes to understand how rare and common variation affect lifetime breast cancer risk. We show that PRS strongly modulates the penetrance of mutations in 8 breast cancer susceptibility genes. For example, lifetime risk in BRCA1 carriers with low polygenic risk is almost one third that of carriers with high PRS (26% v 69% in the bottom and top PRS deciles, respectively). Adding family history of breast cancer provides additional stratification on the potential outcome of disease in carriers of rare mutations. PRS also identifies a significant fraction of the population at equivalent risk to carriers of moderate impact pathogenic variants and who are an order of magnitude more common at a population level. These results have important implications for breast cancer risk mitigation strategies, indicating that the genetic risk of breast cancer is determined by both monogenic mutation and polygenic background, and that assessments of genetic risk for breast cancer risk that do not consider the polygenic background are imprecise and unreliable.


title: Applying the FAIR principles to data in a hospital: challenges and opportunities in a pandemic

abstract:
BackgroundThe COVID-19 pandemic has challenged healthcare systems and research worldwide. Data is collected all over the world and needs to be integrated and made available to other researchers quickly. However, the various heterogeneous information systems that are used in hospitals can result in fragmentation of health data over multiple data  silos that are not interoperable for analysis. Consequently, clinical observations in hospitalised patients are not prepared to be reused efficiently and timely. There is a need to adapt the research data management in hospitals to make COVID-19 observational patient data machine actionable, i.e. more Findable, Accessible, Interoperable and Reusable (FAIR) for humans and machines. We therefore applied the FAIR principles in the hospital to make patient data more FAIR.

ResultsIn this paper, we present our FAIR approach to transform COVID-19 observational patient data collected in the hospital into machine actionable digital objects to answer medical doctors research questions. With this objective, we conducted a coordinated FAIRification among stakeholders based on ontological models for data and metadata, and a FAIR based architecture that complements the existing data management. We applied FAIR Data Points for metadata exposure, turning investigational parameters into a FAIR dataset. We demonstrated that this dataset is machine actionable by means of three different computational activities: federated query of patient data along open existing knowledge sources across the world through the Semantic Web, implementing Web APIs for data query interoperability, and building applications on top of these FAIR patient data for FAIR data analytics in the hospital.

ConclusionsOur work demonstrates that a FAIR research data management plan based on ontological models for data and metadata, open Science, Semantic Web technologies, and FAIR Data Points is providing data infrastructure in the hospital for machine actionable FAIR digital objects. This FAIR data is prepared to be reused for federated analysis, linkable to other FAIR data such as Linked Open Data, and reusable to develop software applications on top of them for hypothesis generation and knowledge discovery.

category: health informatics


title: DICOM Imaging Router: An Open Deep Learning Framework for Classification of Body Parts from DICOM X-ray Scans

abstract: X-ray imaging in Digital Imaging and Communications in Medicine (DICOM) format is the most commonly used imaging modality in clinical practice, resulting in vast, non-normalized databases. This leads to an obstacle in deploying artificial intelligence (AI) solutions for analyzing medical images, which often requires identifying the right body part before feeding the image into a specified AI model. This challenge raises the need for an automated and efficient approach to classifying body parts from X-ray scans. Unfortunately, to the best of our knowledge, there is no open tool or framework for this task to date. To fill this lack, we introduce a DICOM Imaging Router that deploys deep convolutional neural networks (CNNs) for categorizing unknown DICOM X-ray images into five anatomical groups: abdominal, adult chest, pediatric chest, spine, and others. To this end, a large-scale X-ray dataset consisting of 16,093 images has been collected and manually classified. We then trained a set of state-of-the-art deep CNNs using a training set of 11,263 images. These networks were then evaluated on an independent test set of 2,419 images and showed superior performance in classifying the body parts. Specifically, our best performing model (i.e., MobileNet-V1) achieved a recall of 0.982 (95% CI, 0.977- 0.988), a precision of 0.985 (95% CI, 0.975-0.989) and a F1-score of 0.981 (95% CI, 0.976-0.987), whilst requiring less computation for inference (0.0295 second per image). Our external validity on 1,000 X-ray images shows the robustness of the proposed approach across hospitals. These remarkable performances indicate that deep CNNs can accurately and effectively differentiate human body parts from X-ray scans, thereby providing potential benefits for a wide range of applications in clinical settings. The dataset, codes, and trained deep learning models from this study will be made publicly available on our project website at https://vindr.ai/datasets/bodypartxr.


title: Anti-PF4 levels of patients with VITT do not reduce 4 months following AZD1222 vaccination

abstract:
BackgroundAnti-Platelet Factor 4 (PF4) IgG antibodies that activate platelets via Fc{gamma}RIIa have been shown to be an important part of the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). There is now extensive literature on its presentation and initial management. There is no literature however on what happens to these patients following discharge.

MethodsWe collected clinical data and samples from seven patients presenting with VITT and followed them up for 82-145 days. We also collected clinical samples from them at last follow-up. Testing for anti-PF4/heparin antibodies was done using an anti-PF4/heparin enzymatic immunoassay. Flow Cytometry was used to look at Fc{gamma}RIIa levels on patient platelets. Light Transmission Aggregometry with patient serum and healthy donor / patient platelets was used to analyse platelet responsiveness, in the presence and absence of PF4.

FindingsAll patients were discharged on direct oral anticoagulants. Two patients remain completely symptom free, three have ongoing headaches, two have residual neurological deficits. Two patients developed mild thrombocytopenia and worsening headache (but without cerebral venous sinus thrombosis) and were retreated, one of these with rituximab. All patients, except the one treated with rituximab, had similar anti-PF4 antibody titres at 80-120 days to their levels at diagnosis. Platelets from patients at follow-up had normal levels of Fc{gamma}RIIa and had normal responses to thrombin and collagen-related-peptide. Patient serum from diagnosis strongly activated healthy donor platelets in the presence of PF4. Serum from follow-up was much weaker at stimulating platelets, even in the presence of PF4.

InterpretationThis study shows that despite similar PF4 antibody titres at diagnosis and during follow-up, there are further differences in patient serum, that are not apparent from currently used testing, that result in lower levels of platelet activation during the follow-up period. Further understanding of these factors are important in order to assess duration of anticoagulation for these patients.

FundingThis work was supported by an Accelerator Grant (AA/18/2/34218) from the British Heart Foundation (BHF) and by a National Institute for Health Research (NIHR) grant.

Key pointsO_LIPF4 antibody titres do not reduce up to 4-months post ChAdOx1 nCoV-19 in patients with VITT
C_LIO_LIDespite similar PF4 antibody titres, diagnostic serum is more potent at activating platelets in the presence of PF4 than follow-up serum.
C_LI

category: hematology


title: Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation

abstract: Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK cells, {gamma}{delta} T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of {beta} CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1{beta}, IFN-{gamma}, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

category: infectious diseases


title: Nanopore Metagenomic Sequencing for Detection and Characterization of SARS-CoV-2 in Clinical Samples

abstract: The COVID-19 pandemic has underscored the need for rapid novel diagnostic strategies to detect and characterize pathogens from clinical specimens. The MinION sequencing device allows for rapid, cost-effective, high-throughput sequencing; useful features for translation to clinical laboratory settings. Metagenomic Next-Generation Sequencing (mNGS) approaches provide the opportunity to examine the entire genomic material of a sample; allowing for detection of emerging and clinically relevant pathogens that may be missed in targeted assays. Here we present a pilot study on the performance of Sequence-Independent Single Primer Amplification (SISPA) to amplify RNA randomly for the detection and characterization of SARS-CoV-2. We designed a classifier that corrects for barcode crosstalk between specimens. Our assay yielded 100% specificity overall and 95.2% sensitivity for specimens with a RT-qPCR cycle threshold value less than 30. We assembled 10 complete (>95% coverage at 20x depth), and one near-complete (>80% coverage at 20x depth) genomes from 20 specimens that were classified as positive by mNGS. We characterized these genomes through phylogenetic analysis and found that 10/11 specimens from British Columbia had a closest relative to another British Columbian specimen. Of five samples that we had both assembled genomes, as well as Variant of Concern (VOC) PCR results, we found 100% concordance between these results. Additionally, our assay was able to distinguish between the Alpha and Gamma variants, which was not possible with our VOC PCR technique. This study supports future work examining the broader feasibility of SISPA as a diagnostic strategy for the detection and characterization of viral pathogens.


title: Preimmunization correlates of protection shared across malaria vaccine trials in adults

abstract: Identifying preimmunization biological characteristics that promote an effective vaccine response offers opportunities for illuminating the critical immunological mechanisms that confer vaccine-induced protection, for developing adjuvant strategies, and for tailoring vaccination regimens to individuals or groups. In the context of malaria vaccine research, studying preimmunization correlates of protection can help address the need for a widely-effective malaria vaccine, which remains elusive. In this study, common preimmunization correlates of protection were identified using transcriptomic data from four independent, heterogeneous malaria vaccine trials in adults. Systems-based analyses showed that a moderately elevated inflammatory state prior to immunization was associated with protection against malaria challenge. Functional profiling of protection-associated genes revealed the importance of several inflammatory pathways, including TLR signaling. These findings, which echo previous studies that associated enhanced preimmunization inflammation with protection, illuminate common baseline characteristics that set the stage for an effective vaccine response across diverse malaria vaccine strategies in adults.


title: Multiplex Target-Redundant RT-LAMP for Robust Detection of SARS-CoV-2 Using Fluorescent Universal Displacement Probes

abstract: The increasing prevalence of variant lineages during the COVID-19 pandemic has the potential to disrupt molecular diagnostics due to mismatches between primers and variant templates. Point-of-care molecular diagnostics, which often lack the complete functionality of their high throughput laboratory counterparts, are particularly susceptible to this type of disruption, which can result in false negative results. To address this challenge, we have developed a robust Loop Mediated Isothermal Amplification assay with single tube multiplexed multi-target redundancy and an internal amplification control. A convenient and cost-effective target specific fluorescence detection system allows amplifications to be grouped by signal using adaptable probes for pooled reporting of SARS-COV-2 target amplifications or differentiation of the Internal Amplification Control. Over the course of the pandemic, primer coverage of viral lineages by the three redundant sub-assays has varied from assay to assay as they have diverged from the Wuhan-Hu-1 isolate sequence, but aggregate coverage has remained high for all variant sequences analyzed, with a minimum of 97.4% (Variant of Interest: Eta). In three instances (Delta, Gamma, Eta), a high frequency mismatch with one of the three sub-assays was observed, but overall coverage remained high due to multi-target redundancy. When challenged with extracted human samples the multiplexed assay showed 100% sensitivity for samples containing greater than 30 copies of viral RNA per reaction, and 100% specificity. These results are further evidence that conventional laboratory methodologies can be leveraged at the point-of-care for robust performance and diagnostic stability over time.


title: Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, and thrombocytopenic events: whole population cohort study in 46 million adults in England

abstract:
BackgroundThromboses in unusual locations after the COVID-19 vaccine ChAdOx1-S have been reported. Better understanding of population-level thrombotic risks after COVID-19 vaccination is needed.

MethodsWe analysed linked electronic health records from adults living in England, from 8th December 2020 to 18th March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous and thrombocytopenic outcomes 1-28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and [≥]70 years, and adjusted for age, sex, comorbidities, and social and demographic factors.

ResultsOf 46,162,942 adults, 21,193,814 (46%) had their first vaccination during follow-up. Adjusted HRs 1-28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and [≥]70 respectively, were 0.97 (95% CI: 0.90-1.05) and 0.58 (0.53-0.63) for venous thromboses, and 0.90 (0.86-0.95) and 0.76 (0.73-0.79) for arterial thromboses. Corresponding HRs for BNT162b2 were 0.81 (0.74-0.88) and 0.57 (0.53-0.62) for venous thromboses, and 0.94 (0.90-0.99) and 0.72 (0.70-0.75) for arterial thromboses. HRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines.

Rates of intracranial venous thrombosis (ICVT) and thrombocytopenia in adults aged <70 years were higher 1-28 days after ChAdOx1-S (adjusted HRs 2.27, 95% CI:1.33- 3.88 and 1.71, 1.35-2.16 respectively), but not after BNT162b2 (0.59, 0.24-1.45 and 1.00, 0.75-1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1-28 days after ChAdOx1-S were 0.9-3 per million, varying by age and sex.

ConclusionsIncreases in ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults <40 years are needed. For people aged [≥]70 years, rates of arterial or venous thrombotic, events were generally lower after either vaccine.

category: cardiovascular medicine


title: Gene-environment interaction analysis incorporating sex, cardiometabolic diseases, and multiple deprivation index reveals novel genetic associations with COVID-19 severity

abstract: Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.


title: Comparison of the inhomogeneous SEPIR model and data from the COVID-19 outbreak in South Carolina

abstract: During the COVID-19 pandemic authorities have been striving to obtain reliable predictions for the spreading dynamics of the disease. We recently developed a multi-"sub-populations" (multi-compartments: susceptible, exposed, pre-symptomatic, infectious, recovered) model, that accounts for the spatial in-homogeneous spreading of the infection and shown, for a variety of examples, how the epidemic curves are highly sensitive to location of epicenters, non-uniform population density, and local restrictions. In the present work we test our model against real-life data from South Carolina during the period May 22 to July 22 (2020). During this period, minimal restrictions have been employed, which allowed us to assume that the local basic reproduction number is constant in time. We account for the non-uniform population density in South Carolina using data from NASA, and predict the evolution of infection heat-maps during the studied period. Comparing the predicted heat-maps with those observed, we find high qualitative resemblance. Moreover, the Pearsons correlation coefficient is relatively high thus validating our model against real-world data. We conclude that the model accounts for the major effects controlling spatial in-homogeneous spreading of the disease. Inclusion of additional sub-populations (compartments), in the spirit of several recently developed models for COVID-19, can be easily performed within our mathematical framework.


title: Spatiotemporal spread of COVID-19: Comparison of the inhomogeneous SEPIR model and data from South Carolina


title: Improving the reproduction number calculation by treating for daily variations of SARS-CoV-2 cases

abstract: The Covid-19 pandemic impacted the human life all over the globe, starting in the year of its emergence, 2019, and in the following years. A epidemiological key indicator that gained particular recognition in politics and decision making is the time-dependent reproduction number Rt, which is commonly calculated by institutions responsible for disease control following a method presented by Cori et. al. Here, we propose an improved as well as an alternative method, which make the calculation more stable against oscillations arising from daily variations in testing. Both methods can be used without great statistical knowledge or effort. The methods provides a smoother result without increasing the time-lag, and provides an advantage particular in the timeframe of weeks, which might serve as a better ground for forecasts and the raising of alarms.


title: Vaccine Effectiveness against Referral to Hospital and Severe Lung Injury Associated with COVID-19: A Population-based Case-control Study in St. Petersburg, Russia

abstract:
BackgroundResults of a randomised trial showed the safety and efficacy of Gam-COVID-Vac against COVID-19. However, compared to other vaccines used across the globe, the real-world data on the effectiveness of Gam-COVID-Vac, especially against the disease caused by Delta variant of concern, was not available. We aimed to assess the effectiveness of vaccination mainly conducted with Gam-COVID-Vac in St. Petersburg, Russia.

MethodsWe designed a case-control study to assess the vaccine effectiveness (VE) against lung injury and referral to hospital. Self-reported vaccination status was collected for individuals with confirmed SARS-CoV-2 infection who were referred for initial low-dose computed tomography triage in two outpatient centres in July 3 - August 9, 2021 in St. Petersburg, Russia. We used logistic regression models to estimate the adjusted (for age, sex, and triage centre) VE for complete (>14 days after the second dose) vaccination. We estimated the VE against referral for hospital admission, COVID-19-related lung injury assessed with LDCT, and decline in oxygen saturation.

ResultsIn the final analysis, 13,893 patients were included, 1,291 (9.3%) of patients met our criteria for complete vaccination status, and 495 (3.6%) were referred to hospital. In the primary analysis, the adjusted VE against referral to hospital was 81% (95% CI: 68-88) for complete vaccination. The VE against referral to hospital was more pronounced in women (84%, 95% CI: 66-92) compared to men (76%, 95% CI: 51-88). Vaccine protective effect increased with increasing lung injury categories, from 54% (95% CI: 48-60) against any sign of lung injury to 76% (95% CI: 59-86) against more than 50% lung involvement. A sharp increase was observed in the probability of hospital admission with age for non-vaccinated patients in relation to an almost flat relationship for the completely vaccinated group.

ConclusionsCOVID-19 vaccination was effective against referral to hospital in patients with symptomatic SARS-CoV-2 infection in St. Petersburg, Russia. This protection is probably mediated through VE against lung injury associated with COVID-19.


title: Vaccine Effectiveness against Referral to Hospital and Severe Lung Injury Associated with COVID-19: A Population-Based Case-Control Study in St. Petersburg, Russia


title: Vaccine Effectiveness against Referral to Hospital and Severe Lung Injury Associated with COVID-19: A Case-Control Study in St. Petersburg, Russia


title: Changing incidence of invasive pneumococcal disease in infants less than 90 days of age before and after introduction of the 13-valent Pneumococcal Conjugate Vaccine in Blantyre, Malawi: a 14-year hospital based surveillance study

abstract:
BackgroundInvasive pneumococcal disease (IPD) in young infants is uncommon but associated with high morbidity and mortality. Accurate data on the burden of IPD in young infants in low-income countries are lacking. We examined the burden of IPD in infants aged <90 days in Blantyre, Malawi over a 14 year period and evaluated the impact of the 12 November 2011 introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) on vaccine-serotype IPD (VT-IPD) in this population.

MethodsWe conducted laboratory-based prospective IPD surveillance in infants aged <90 days admitted to Queen Elizabeth Central Hospital (QECH) in Blantyre between 2005 and 2018, including 7 years pre- and 7 years post-PCV13 introduction. IPD was defined as Streptococcus pneumoniae identified by culture from blood or cerebrospinal fluid. Serotypes were determined by multiplex PCR and latex agglutination testing.

ResultsWe identified 130 cases of culture-confirmed IPD in infants <90 days old between 2005-2018. Total IPD incidence was declining prior to PCV13 introduction. The mean incidence of IPD was significantly lower in the post-PCV era. Serotypes 5 (27.8%) and 1(15.6%), were most prevalent. Even after PCV13 introduction, VT-IPD remained dominant with serotype 5 accounting for 17.4% and serotype 1 for 13% of cases in young infants.

ConclusionVaccine serotypes were the main cause of IPD in neonates and young infants, both before and after PCV13 introduction. Further strategies need to be considered to protect this vulnerable population, including maternal or neonatal immunization and implementation of an alternative PCV schedule with a booster dose.

SummaryThe incidence of invasive pneumococcal disease in infants in Blantyre, Malawi has declined over the past decade and more significantly after introduction of the pneumococcal conjugate vaccine. Vaccine serotypes have remained the main cause of disease in this population.


title: First-in-human autologous oral mucosal epithelial sheet transplantation to prevent anastomotic re-stenosis in congenital esophageal atresia

abstract:
BackgroundCongenital esophageal atresia postoperative anastomotic stricture occurs in 30-50% of cases. Patients with severe dysphagia are treated with endoscopic balloon dilatation (EBD) and/or local injection of steroids, but many patients continue to experience frequent stricture. In this study, we investigated the transplantation of autologous oral mucosa-derived cell sheets (epithelial cell sheets) as a prophylactic treatment for congenital esophageal atresia postoperative anastomotic stricture.

MethodsEpithelial cell sheets were fabricated from a patients oral epithelial tissue, and their safety was confirmed by quality control tests. The epithelial cell sheets were transported under controlled conditions from the fabrication facility to the transplantation facility and successfully transplanted onto the lacerations caused by EBD using a newly developed transplantation device for pediatric patients. The safety of the transplantation was confirmed by follow-up examinations over 48 weeks.

ResultsThe number of EBDs required after transplantation and the number of days between EDBs were recorded. Before transplantation, EBDs were performed approximately every two weeks, whereas after transplantation, the interval was extended to a maximum of four weeks. The patient was also aware of a reduction in dysphagia.

ConclusionsThis study suggests that cell sheet transplantation might be effective in preventing anastomotic stricture after surgery for congenital esophageal atresia. We chose this very severe case for the first clinical study in humans. Future studies are needed to identify cases in which cell sheet transplantation is most effective and to determine the appropriate timeframes for transplantation.


title: Population birth outcomes in 2020 and experiences of expectant mothers during the COVID-19 pandemic: a Born in Wales mixed methods study using routine data

abstract:
BackgroundPregnancy can be a stressful time and the COVID-19 pandemic has affected all aspects of life. This study aims to investigate the impact of the pandemic on population birth outcomes in Wales, rates of primary immunisations and examine expectant mothers experiences of pregnancy including self-reported levels of stress and anxiety.

MethodsPopulation-level birth outcomes in Wales: Stillbirths, prematurity, birth weight and Caesarean section births before (2016-2019) and during (2020) the pandemic were compared using national-level routine anonymised data held in the Secure Anonymised Information Linkage (SAIL) Databank. The first three scheduled primary immunisations were compared between 2019 and 2020. Self-reported pregnancy experience: 215 expectant mothers (aged 16+) in Wales completed an online survey about their experiences of pregnancy during the pandemic. The qualitative survey data was analysed using codebook thematic analysis.

FindingsThere was no significant difference between annual outcomes including gestation and birth weight, stillbirths, and Caesarean sections for infants born in 2020 compared to 2016-2019. There was an increase in late term births ([≥]42 weeks gestation) during the first lockdown (OR: 1.28, p=0.019) and a decrease in moderate to late preterm births (32-36 weeks gestation) during the second lockdown (OR: 0.74, p=0.001). Fewer babies were born in 2020 (N=29,031) compared to 2016-2019 (average N=32,582). All babies received their immunisations in 2020, but there were minor delays in the timings of vaccines. Those due at 8-weeks were 8% less likely to be on time (within 28-days) and at 16-weeks, they were 19% less likely to be on time. The pandemic had a negative impact on the mental health of 71% of survey respondents, who reported anxiety, stress and loneliness; this was associated with attending scans without their partner, giving birth alone, and minimal contact with midwives.

InterpretationThe pandemic had a negative impact on mothers experiences of pregnancy; however, population-level data suggests that this did not translate to adverse birth outcomes for babies born during the pandemic.


title: Preliminary High-Level Modelling Estimates of Impacts of Denicotinisation on Smoking Prevalence in Aotearoa New Zealand

abstract:
AimTo provide preliminary high-level modelling estimates of the impact of denicotinisation of tobacco on changes in smoking prevalence in Aotearoa New Zealand (NZ).

MethodsAn Excel spreadsheet was populated with smoking/vaping prevalence data from the NZ Health Survey and business-as-usual trends projected. Using various parameters from the literature (NZ trial data, NZ EASE-ITC Study results), we modelled the impact of denicotinisation of tobacco (with no other tobacco permitted for sale) out to 2025, the year of this countrys Smokefree Goal. Scenario 1 used estimates from a published expert knowledge elicitation process, and Scenario 2 considered the addition of extra mass media campaign and quitline support to the base case.

ResultsWith the denicotinisation intervention, adult daily smoking prevalences were all estimated to decline to under 5% in 2025 for non-M[a]ori and in one scenario for M[a]ori (Indigenous population) (2.5% in Scenario 1). However, prevalence did not fall below five percent in the base case for M[a]ori (7.7%) or with Scenario 2 (5.2%). In the base case, vaping was estimated to increase to 7.9% in the adult population in 2025, and up to 10.7% in one scenario (Scenario 1).

ConclusionsThis preliminary, high-level modelling suggests a mandated denicotinisation policy for could provide a realistic chance of achieving the NZ Governments Smokefree 2025 Goal. The probability of success would further increase if supplemented with other interventions such as mass media campaigns with Quitline support (especially if targeted for a predominantly M[a]ori audience). Nevertheless, there is much uncertainty with these preliminary high-level results and more sophisticated modelling is highly desirable.


title: Polyautoimmunity Clusters as a New Taxonomy of Autoimmune Diseases

abstract:
Polyautoimmunity (PolyA) is an emerging concept that may help to develop a better classification of autoimmune diseases (ADs). Thus, we aimed to develop new taxonomy based on PolyA. Two-hundred and fifty-four consecutive patients were included with rheumatoid arthritis (RA, n:146), systemic lupus erythematosus (SLE, n:45), Sjogrens syndrome (SS, n:29), autoimmune thyroid disease (AITD, n:17) and systemic sclerosis (SSc, n:17). Clinical features, autoantigen array chip, lymphocytes immunophenotype and cytokine profile were assessed simultaneously. The coexistence of two or more ADs with classification criteria was termed "Overt PolyA", whereas the presence of autoantibodies unrelated to the index AD, without criteria fulfillment, was named "Latent PolyA". Combination of IgG autoantibodies yielded high accuracy for classification of ADs. In SLE, Histone H2A, Sm/RNP, ssDNA, and dsDNA IgG autoantibodies were the most predictive autoantibodies for this condition. Laminin, Ro/SSA (52 kDa), and U1-snRNP B/B for SS; Thyroglobulin for AITD; Ribo Phosphoprotein P1, and CENP-A for SSc. Interestingly, Thyroglobulin and U1-snRNP B/B were mutual diagnostic biomarkers in SS and SSc. Latent PolyA showed in nearly 70% of patients, whereas overt PolyA was most common in AITD (82.4%) and SLE (40%). Cluster analysis based on autoantibodies yielded three clusters of which clusters 2 and 3 exhibited high frequency of latent and overt PolyA with distinctive clinical and immunological phenotypes. Combination of autoantibodies demonstrated high performance for classification of ADs. Patients with both latent and overt PolyA cluster together and exhibit differential clinical and immunological features. High prevalence of latent and overt PolyA advocates for routinary surveillance in clinical settings.

One Sentence SummaryThis is a proof-of-concept study which allowed a new classification of autoimmune diseases. The results highlight that most patients with both latent and overt polyautoimmunity cluster together, with differential clinical and immunological characteristics.

category: rheumatology


title: EFFECT OF EARLY TREATMENT WITH FLUVOXAMINE ON RISK OF EMERGENCY CARE AND HOSPITALIZATION AMONG PATIENTS WITH COVID-19: THE TOGETHER RANDOMIZED PLATFORM CLINICAL TRIAL

abstract:
BackgroundRecent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER randomized platform clinical trial for acutely symptomatic patients with COVID-19, we assessed the efficacy of fluvoxamine vs. placebo in preventing either extended emergency room observation or hospitalization due to COVID-19. Herein, we report the preliminary findings.

MethodsThis placebo-controlled, randomized, adaptive, platform trial conducted among symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients with a known risk factor for progression to severe disease. Patients were randomly assigned to either fluvoxamine (100 mg twice daily for 10 days) or placebo. The primary endpoint was a composite outcome of emergency room observation for >6 hours or hospitalization from COVID-19 up to 28 days post randomization using intention to treat. Modified intention to treat (mITT) explored patients receiving at least 24 hours of treatment before a primary outcome event. Secondary outcomes included viral clearance at day 7, time to hospitalization, mortality, and adverse drug reactions. We used a Bayesian analytic framework to determine effects along with probability of success of intervention compared to placebo. The trial is registered at clinicaltrials.gov (NCT04727424) and is ongoing.

FindingsThe study team screened 9020 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomization from January 15, 2021 to August 6th 2021, when the trial arms were stopped for superiority. A total of 3238 patients were allocated to fluvoxamine (n=739), placebo (n=733) and other treatments (n=1766). Herein, we report the effectiveness of fluvoxamine vs. a concurrent placebo control. The average age of participants was 50 years (range 18-102 years); 57% were female. The proportion of patients observed in an emergency room for >6 hours or admitted to hospital due to COVID-19 was lower for the fluvoxamine group compared to placebo (77/739 vs 108/733; Relative Risk [RR]: 0.71; 95% Bayesian Credible Interval [95% BCI]: 0.54 - 0.93), with a probability of superiority of 99.4% surpassing the prespecified superiority threshold of 97.6% (risk difference 4.3%). Of the composite primary outcome events, 88% were hospitalizations. Findings were similar for the mITT analysis (RR0.68, 95% BCI : 0.50- 0.91). We found no significant relative effects between the fluvoxamine and placebo groups on viral clearance at day 7 (Odds ratio [OR]: 0.75; 95% Confidence Intervals [95% CI]: 0.53 - 1.07), mortality (OR: 0.70; 95% CI: 0.36 - 1.30), time to death (Hazard ratio [HR]: 0.79; 95% CI: 0.58 - 1.08), days hospitalized (Mean Difference (MD) 1.22 days; 95% CI: 0.98 - 1.53), number of days ventilated (MD 1.10; 95% CI: 0.70 - 1.73) or other secondary outcomes. Data capturing all 28 days of follow-up will be reported after August 26th, 2021.

InterpretationTreatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalization.

FundingThe trial was supported by FastGrants and The Rainwater Foundation.


title: Classifying Refugee Status Using Common Features in EMR

abstract:
ObjectiveAutomated and accurate identification of refugees in healthcare databases is a critical first step to investigate healthcare needs of this vulnerable population and improve health disparities. This study developed a machine-learning method, named refugee identification system (RIS) that uses features commonly collected in healthcare databases to classify refugees and non-refugees.

Materials and MethodsWe compiled a curated data set consisting of 103 refugees and 930 non-refugees in Arizona. For each person in the curated data set, we collected age, primary language, and home address. We supplemented individual-level data with state-level refugee resettlement statistics and world language statistics, then performed feature engineering to convert primary language and home address into quantitative features. Finally, we built a random forest model to classify refugee status.

ResultsEvaluated on holdout testing data, RIS achieved a high classification accuracy of 0.97, specificity of 0.98, sensitivity of 0.88, positive predictive value of 0.83, and negative predictive value of 0.99. The receiver operating characteristic curve had an area under the curve value of 0.96.

Discussion and ConclusionRIS is an automated, accurate, generalizable, and scalable method that can be used to identify refugees in healthcare databases. It enables large-scale investigation of refugee healthcare needs and improvement of health disparities.


title: Long-Term Effectiveness of a Digital Therapeutic Intervention for Smoking Cessation: A Randomized Controlled Trial

abstract:
IntroductionThe present study evaluated the long-term effectiveness of Quit Genius (QG), an extended digital smoking cessation intervention.

MethodsParticipants were adult smokers (N=556) recruited between January and November of 2019 via social media and referrals from primary care practices who were given nicotine replacement therapy and randomly assigned to Quit Genius (QG) (n=277), a cognitive behavioral therapy (CBT) based digital intervention or Very Brief Advice (VBA) (n=279), a face-to-face control intervention. Primary analyses (N=530), by intention-to-treat, compared QG and VBA on biochemically verified continuous 7-day abstinence at 4, 26, and 52 weeks post-quit date. Secondary outcomes included sustained abstinence, quit attempts, self-efficacy and mental well-being.

ResultsSeven-day point prevalence abstinence from weeks 4 through 52 ranged from 27% to nearly 45% among those who received QG, and from 13% to 29% for those in VBA. Continuous 7-day abstinence at 26 and 52 weeks occurred in 27.2% and 22.6% of QG participants, respectively, relative to 16.6% and 13.2% of VBA participants; QG participants were more likely to remain abstinent than those in VBA (Relative Risk [RR]= 1.71, 95% CI 1.17-2.50; p=0.005).

ConclusionsThis study provides evidence for the long-term effectiveness of an extended digital therapeutic intervention.

ImplicationsThe long-term effectiveness of digital smoking cessation interventions has not been well-studied. This study established the long-term effectiveness of an extended CBT-based intervention; results may inform implementation of scalable, cost-effective approaches to smoking cessation in the health system.

category: addiction medicine


title: COVID-19 mitigation measures in primary schools and association with infection and school staff wellbeing: an observational survey linked with routine data in Wales, UK

abstract:
IntroductionSchool-based COVID-19 mitigation strategies have greatly impacted the primary school day (children aged 3-11) including: wearing face coverings, 2-metre distancing, no mixing of children, and no breakfast clubs or extra-curricular activities. This study examines these mitigation methods and association with COVID-19 infection, respiratory infection, and school staff wellbeing between October to December 2020 in Wales, UK.

MethodsA school staff survey captured self-reported COVID-19 mitigation measures in the school, participant anxiety and depression, and open-text responses regarding experiences of teaching and implementing measures. These survey responses were linked to national-scale COVID-19 test results data to examine association of measures in the school and the likelihood of a positive (staff or pupil) COVID-19 case in the school (clustered by school, adjusted for school size and free school meals using logistic regression). Linkage was conducted through the SAIL (Secure Anonymised Information Linkage) Databank.

ResultsResponses were obtained from 353 participants from 59 primary schools within 15 of 22 local authorities. Having more direct non-household contacts was associated with a higher likelihood of COVID-19 positive case in the school (1-5 contacts compared to none, OR 2.89 (1.01, 8.31)) and a trend to more self-reported cold symptoms. Staff face covering was not associated with a lower odds of school COVID-19 cases (mask vs. no covering OR 2.82 (1.11, 7.14)) and was associated with higher self-reported cold symptoms. School staff reported the impacts of wearing face coverings on teaching, including having to stand closer to pupils and raise their voices to be heard. 67.1% were not able to implement 2-metre social distancing from pupils. We did not find evidence that maintaining a 2-metre distance was associated with lower rates of COVID-19 in the school.

ConclusionsImplementing, adhering to and evaluating COVID-19 mitigation guidelines is challenging in primary school settings. Our findings suggest that reducing non-household direct contacts lowers infection rates. There was no evidence that face coverings, 2-metre social distancing or stopping children mixing was associated with lower odds of COVID-19 or cold infection rates in the school. Primary school staff found teaching challenging during COVID-19 restrictions, especially for younger learners and those with additional learning needs.


title: Measuring the digital divide among people with Severe Mental Ill Health using the Essential Digital Skills framework.

abstract:
AimsAmidst the vast digitalisation of health and other services during the pandemic, people with no digital skills are at risk for digital exclusion. This risk might not abide by the end of the pandemic. This paper seeks to understand whether people with severe mental ill health (SMI) have the necessary digital skills to adapt to these changes and avoid digital exclusion.

Methods249 adults with SMI across England completed a survey online or offline. They provided information on their digital skills based on the Essential Digital Skills (EDS) framework, sociodemographic information, and digital access. This is the first time the EDS is benchmarked in people with SMI.

Results42.2% had no Foundation Skills and 46.2% lacked skills for daily life (lacking Foundation or Life Skills). 23.0% of those working lacked skills for professional life (lacking Foundation or Work Skills). The most commonly missing skills were handling passwords and using the device settings (Foundation Skills) and online problem solving (Skills for Life). People were interested in learning more about approximately half of the skills they did not have. People were more likely to lack Foundation Skills if they were older, not in employment, had a psychosis-spectrum disorder, or had no Internet access at home.

ConclusionA significant portion of people with SMI lacked Foundation Skills in this objective and benchmarked survey. This points to a high risk for digital exclusion and the need for focused policy and tailored health sector support, to ensure people retain access to key services and develop digital skills and confidence. To our knowledge this is the first time this has been described using the Essential Digital Skills (EDS) framework. Services, including the NHS, need to be aware and mitigate the risks.


title: Fall 2021 Resurgence and COVID-19 Seroprevalence in Canada: Modelling waning and boosting COVID-19 immunity in Canada, A Canadian Immunization Research Network Study

abstract: There is a threat of COVID-19 resurgence in Fall 2021 in Canada. To understand the probability and severity of this threat, quantification of the level of immunity/protection of the population is required. We use an age-structured model including infection, vaccination and waning immunity to estimate the distribution of immunity to COVID-19 in the Canadian population. By late Summer 2021, coinciding with the end of the vaccination program, we estimate that 60 - 80% of the Canadian population will have some immunity to COVID-19. Model results show that this level of immunity is not sufficient to stave off a Fall 2021 resurgence. The timing and severity of a resurgence, however, varies in magnitude given multiple factors: relaxation of non-pharmaceutical interventions such as social distancing, the rate of waning immunity, the transmissibility of variants of concern, and the protective characteristics of the vaccines against infection and severe disease. To prevent large-scale resurgence, booster vaccination and/or re-introduction of public health mitigation may be needed.


title: Telehealth in Rheumatology: The 2021 Arab League of Rheumatology Best Practice Guidelines

abstract:
BackgroundTelehealth use is increasing and will undeniably continue to play a role beyond the COVID-19 era. Best practice guidelines (BPG) for telehealth add credibility, standardize approaches, facilitate reimbursement, and decrease liability.

ObjectivesTo develop BPG for the use of Telehealth In Rheumatology in the Arab region, to identify the top barriers and facilitators of telehealth in the Arab region, and to provide rheumatologists with a practical toolkit for the implementation of telehealth.

MethodsGuidelines were drafted by a core steering committee from the Arab League of Associations for Rheumatology (ArLAR) after performing a literature search. A multidisciplinary task force (TF), including 18 rheumatologists, 2 patients, and 2 regulators from 15 Arab countries, assessed the BPG using 3 rounds of anonymous online voting by modified Delphi process. The voting on barriers and facilitators was performed through one voting round. The toolkit was developed based on available literature and discussions during the Delphi rounds.

ResultsFour General Principles and twelve Statements were formulated. All statements reached >80% consensus. A teleconsultation was specifically defined for the purpose of these guidelines. The concept of choice in telehealth was highlighted, emphasizing patient confidentiality, medical information security, rheumatologists clinical judgment, and local jurisdictional regulations. The top barrier for telehealth was the concern about the quality of care. The toolkit emphasized technical aspects of teleconsultation and proposed a triage system.

ConclusionsThe ArLAR BPG provides rheumatologists with a series of strategies about the most reliable, productive, and rational approaches to apply telehealth.

Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIBest practice guidelines (BPG) the use of Telehealth In Rheumatology in the Arab region were developed herein under the umbrella of the Arab League of Associations for Rheumatology (ArLAR)
C_LIO_LIA teleconsultation was specifically defined for the purpose of these guidelines
C_LIO_LIThe concept of choice in telehealth was highlighted, emphasizing patient confidentiality, medical information security, rheumatologists clinical judgment, and local jurisdictional regulations
C_LIO_LIThe top barrier for telehealth was the concern about the quality of care
C_LIO_LIThe ArLAR BPG provides rheumatologists with a series of strategies about the most reliable, productive, and rational approaches to apply telehealth in the rheumatology clinic
C_LI


title: Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer's disease

abstract:
PurposeEarly-onset Alzheimers disease (EOAD) and late-onset Alzheimers disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD.

MethodsSeventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n=35, age-at-PET=59{+/-}5, MMSE=23{+/-}4; LOAD: n=44, age-at-PET=71{+/-}5, MMSE=23{+/-}4) underwent a 130 minutes dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition.

ResultsBoth region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipito-parietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND -0.76[≤]st{beta}[≤]-0.48 vs LOAD -0.18[≤]st{beta}[≤]-0.02; EOAD R1 0.37[≤]st{beta}[≤]0.84 vs LOAD -0.25[≤]st{beta}[≤]0.16).

ConclusionsCompared to LOAD, the degree of lateral temporal and occipito-parietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.


title: Detecting orientation of Brain MR scans using deep learning

abstract: AO_SCPLOWBSTRACTC_SCPLOWThere has been a steady escalation in the impact of Artificial Intelligence (AI) on Healthcare along with an increasing amount of progress being made in this field. While many entities are working on the development of significant deep learning models for the diagnosis of brain-related diseases, identifying precise images needed for model training and inference tasks is limited due to variation in DICOM fields which use free text to define things like series description, sequence and orientation [1]. Detecting the orientation of brain MR scans (Axial/Sagittal/Coronal) remains a challenge due to these variations caused by linguistic barriers, human errors and de-identification - essentially rendering the tags unreliable [2, 3, 4]. In this work, we propose a deep learning model that identifies the orientation of brain MR scans with near perfect accuracy.


category: radiology and imaging


title: Diagnostic evaluation of the presence of residues of glyphosate-AMPA and 2.4D pesticides in urine samples from people living in a rural Brazilian community.

abstract: Pesticide contamination in rural communities is a known problem worldwide. In this study, we investigated the levels of pesticide residues in urine samples from residents of a rural community located in the municipality of Francisco Beltrao-Parana, Brazil. According to the residents report obtained through a structured interview, the main form of exposure has been due to the drift of pesticides resulting from the spraying carried out on crops neighboring the community, with one crop existing on the left edge and another on the right edge of the site. The investigation was based on a demand from residents concerned about the frequent occurrence of symptoms after spraying on neighboring crops, such as nausea, headaches, and dizziness. Thus, samples were collected immediately after the occurrence of spraying in the crop surrounding the site. In the collected samples (n=35, 1 sample per family) laboratory analyzes were performed to identify possible pesticide residues. To identify possible contaminating pesticides in the samples, multi-residue analysis was performed by gas chromatography coupled with mass spectrometry (GC-MS/MS). To identify 2.4D residues, an active widely used in the region and not detectable by the technique used for other pesticides, the analyzes were performed using the enzyme immunoassay technique. The results indicate that all urine samples collected showed the presence of 2.4D residues and that 90% of them presented the presence of glyphosate-AMPA residues, without the detection of the other investigated residues. The analysis of data obtained from interviews with residents shows an association between living in the place for longer and having cases of abortion (p<0.05, R=0.43) or feeling unwell after the application of the poison by the neighboring crop (p<0.05, R=0.47). In addition, residents who reported being poisoned with poison also reported having cancer (p<0.05, R=0.42). Assuming that it is unacceptable that urine samples have pesticide residues, it is concluded that the residents of this community are widely contaminated by pesticides potentially coming from the spraying of the neighboring crop, especially by pesticides that have the active ingredients in their formulas. 2,4D and glyphosate-AMPA and that may be impacting the health of these people in the long term.

category: occupational and environmental health


title: Health status and cancer related mortality among nuclear plant workers exposed to ionizing radiation

abstract:
BackgroundThe investigation of potential adverse health effects of occupational exposures to ionizing radiation, on nuclear plant workers, is an important area of research. In this study, we aimed to calculate the incidence and risk of cancer development and mortality during last five years (2015-2019).

Material and Methods456 nuclear industry workers were included into this study (39 cancer patients and 417 healthy. For this cohort, the cancer mortality has been assessed by data obtained from national health registry excluded for the probability of known causes of death. The associations between cumulative occupational radiation exposures (radon, gamma radiation and long-lived radionuclides) and cancer mortality were calculated.

ResultsRadon and Gamma exposure was significantly higher among workers who developed cancer [8.4 (0; 3,224.5) vs 19.7 (0; 128.4), p=0.03] and [12.0 (2.1; 110.0) vs 24.5 (0; 470.1), p=0.02]. However, no significant association was found between long-lived radionuclides and risk of cancer (p=0.07).

ConclusionIn conclusion, significant association has been observed between the risk of cancer development and radon and gamma exposure among nuclear industry workers, but no association was found between cancer and long-live nucleoids exposure.


title: Vascular complexity and severity of diabetic retinopathy by using swept-source optical coherence tomographic angiography

abstract:
PurposeTo evaluate the associations of retinal vascular complexity features, including fractal dimension (FD) and blood vessel tortuosity (BVT), with the severity of diabetic retinopathy (DR) by using noninvasive optical coherence tomographic angiography (OCTA).

MethodsThis prospective cross-sectional study recruited ocular-treatment-naive patients with type 2 diabetes mellitus (DM) registered in the community of Guangzhou, China. OCTA was used to obtain the measurements of FD and BVT in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Univariate and multivariate linear regression was used to analyse the correlation of FD and BVT in different layers with DR severity.

ResultsA total of 1282 patients with DM (1282 eyes), with a mean age of 64.2{+/-}7.8 years, were included. FD in the DCP decreased and BVT in the DCP increased in DR patients compared to non-DR patients, even after adjusting for confounding factors (P< 0.05). Trend analysis showed a significant decrease in the FD values as the DR progressed, while the BVT progressively increased with worsening DR severity (P< 0.01). The FD in DCP had a statistically significant positive correlation with FD in SCP and a negative correlation with BVT in SCP and BVT in DCP in all of the participants, including the non-DR group, moderate DR group and severe DR group (P< 0.01).

ConclusionFD and BVT determined using OCTA might be useful parameters for objectively distinguishing DR from non-DR and indicating DR progression.

category: ophthalmology


title: Macular vascular complexity analysis of diabetes mellitus by swept-source optical coherence tomographic angiography


title: Premature infants display discriminable behavioural, physiological and brain responses to noxious and non-noxious stimuli

abstract: Pain assessment in preterm infants is challenging, as behavioural, autonomic and neurophysiological measures of pain are reported to be less sensitive and specific than in term infants. Understanding the pattern of preterm infants noxious-evoked responses is vital to improve pain assessment in this group. This study investigated the discriminability and development of multi-modal noxious-evoked responses in infants aged 28-40 weeks postmenstrual age. A classifier was trained to discriminate responses to a noxious heel lance from a non-noxious control in 47 infants, using measures of facial expression, brain activity, heart rate and limb withdrawal, and tested in two independent cohorts with a total of 98 infants. The model discriminates responses to the noxious from the non-noxious procedure from 28 weeks onwards with an overall accuracy of 0.77-0.83 and an accuracy of 0.78-0.79 in the 28-31 week group. Noxious-evoked responses have distinct developmental patterns. Heart rate responses increase in magnitude with age, while noxious-evoked brain activity undergoes three distinct developmental stages, including a previously unreported transitory stage consisting of a negative event-related potential between 30-33 weeks postmenstrual age. These findings demonstrate that while noxious-evoked responses change across early development, infant responses to noxious and non-noxious stimuli are discriminable from 28 weeks onwards.

category: pain medicine


title: Distributed genetic architecture across the hippocampal formation implies common neuropathology across major brain disorders

abstract: Despite its major role in complex human behaviours across the lifespan, including memory formation and decline, navigation and emotions, much of the genetic architecture of the hippocampal formation is currently unexplored. Here, through multivariate genome-wide association analysis in volumetric data from 35,411 individuals, we revealed 173 unique genetic loci with distributed associations across the hippocampal formation. We identified profound genetic overlap with eight major developmental and degenerative brain disorders, where common genes suggest partly age- and disorder-independent mechanisms underlying hippocampal pathology.