title: Heterogeneous Mental Health Development During the COVID-19 Pandemic in the United Kingdom

abstract: The COVID-19 pandemic and the mitigation measures by governments have upended the economic and social lives of many, leading to widespread psychological distress. We explore heterogeneity in trajectories of psychological distress during the pandemic in the United Kingdom and relate this heterogeneity to socio-demographic and health factors. We analyze nine waves of longitudinal, nationally representative survey data from the UK Household Longitudinal Study (N =15,914), covering the period from early 2020 to mid-2021. First, latent class mixture modelling (LCCM) is used to identify trajectories of psychological distress. Second, associations of the trajectories with covariates are tested with multinomial logistic regressions. We find four different trajectories of distress: continuously low, temporarily elevated, repeatedly elevated, and continuously elevated distress. Nearly two fifths of the population experienced severely elevated risks of distress during the pandemic. Long-term distress was highest among younger people, women, people living without a partner, those who had no work or lost income, and those with previous health conditions or COVID-19 symptoms. Given the threat of persistent stress on health, policy measures should be sensitized to the unintended yet far-reaching consequences of non-pharmaceutical interventions.


title: MRI Intensity Standardization Evaluation Design for Head and Neck Quantitative Imaging Applications

abstract:
BackgroundConventional MRI poses unique challenges in quantitative analysis due to a lack of specific physical meaning for voxel intensity values. In recent years, intensity standardization methods to optimize MRI signal consistency have been developed to address this problem. However, the effects of standardization methods on the head and neck region have not been previously investigated.

PurposeThis study proposes a workflow based on healthy tissue region of interest (ROI) analysis to determine intensity consistency within a patient cohort. Through this workflow, we systematically evaluate different intensity standardization methods for T2-weighted MRI of the head and neck region.

MethodsTwo image cohorts of five head and neck cancer patients, one with heterogeneous acquisition parameters (median age 59 years [range, 53-61]), and another with homogeneous acquisition parameters from a clinical trial (NCT04265430) (median age 61 years [range, 54-77]) were retrospectively analyzed. The standard deviation of cohort-level normalized mean intensity (SD NMIc), a metric of intensity consistency, was calculated across ROIs to determine the effect of five intensity standardization methods on T2-weighted images. For each cohort, the Friedman test with a subsequent post-hoc Bonferroni-corrected Wilcoxon signed-rank test was conducted to compare SD NMIc among methods.

ResultsConsistency (SD NMIc across ROIs) between T2-weighted images is substantially more impaired in the cohort with heterogeneous acquisition parameters (0.28 {+/-} 0.04) than in the cohort with homogeneous acquisition parameters (0.15 {+/-} 0.05). Consequently, intensity standardization methods more significantly improve consistency in the cohort with heterogeneous acquisition parameters (corrected p < 0.005 for all methods compared to no standardization) than in the cohort with homogeneous acquisition parameters (corrected p > 0.5 for all methods compared to no standardization).

ConclusionsOur findings stress the importance of image acquisition parameter standardization, together with the need for testing intensity consistency before performing quantitative analysis of MRI.

category: radiology and imaging


title: The monocyte-to-lymphocyte: defining a normal range, sex-specific differences in the tuberculosis disease spectrum and diagnostic indices.

abstract:
BackgroundThe monocyte-to-lymphocyte ratio has been advocated as a biomarker in tuberculosis. Our objective was to evaluate its clinical role in diagnosis, prognosis and treatment outcome.

MethodsComplete blood counts from an unselected population aged 16 to 65 years defined normal values of the ratio and associations with other indices. Blood counts, inflammatory markers and clinical parameters were measured in patients with and those screened for tuberculosis. We examined the ratio for its associations with these variables and for diagnosis, screening, prediction of poor prognosis and response to treatment. Results. In the unselected population, monocyte-to-lymphocyte ratios were higher in males than females and correlated with neutrophil counts (Spearmans rho=0.48, P<0.00001, n=14,573). In 356 patients notified with tuberculosis, ratios were higher in males (high monocyte counts), especially in smear-positive pulmonary tuberculosis (S+PTB), lung cavitation and raised inflammatory markers. The sensitivities for confirmed tuberculosis were 42% (males) and 32% (females), with specificities of 70% and 71% respectively. Using sex-specific cut-offs in 629 adults screened for tuberculosis and with a positive tuberculin skin test or interferon-gamma release assay, diagnostic sensitivities for active tuberculosis were better in males (25%; all and contacts of a S+PTB index, respectively) than females (14-17%) with specificities of 89-96%. Positive likelihood ratios were better with upper limits alone but were still poor (6.64 when screening for tuberculosis, with an area under the curve of 0.688). Ratios did not predict death or response to treatment. Ratios were especially higher in males than female ratios in the 16-45 years age group.

ConclusionsSevere tuberculosis and male sex associated with high monocyte-to-lymphocyte ratios. The ratio performed poorly as a clinical aid. (269 words)

category: respiratory medicine


title: COVIDReady2 Study Protocol: Cross-sectional Survey of Medical Student Volunteering and Education During the COVID-19 Pandemic in the United Kingdom

abstract:
Background and objectivesCovid-19 has led to global disruption of healthcare. Many students volunteered to provide clinical support. Volunteering to work in a clinical capacity was a unique medical education opportunity; however, it is unknown whether this was a positive learning experience or which volunteering roles were of most benefit to students.

Methods and DesignThe COVIDReady2 study is a national cross-sectional study of all medical students at UK medical schools. The primary outcome is to explore the experiences of medical students who volunteered during the pandemic in comparison to those who did not. We will compare responses to determine the educational benefit and issues they faced. In addition to quantitative analysis, thematic analysis will be used to identify themes in qualitative responses.

DiscussionThere is a growing body of evidence to suggest that service roles have potential to enhance medical education; yet, there is a shortage of studies able to offer practical advice for how these roles may be incorporated in future medical education. We anticipate that this study will help to identify volunteer structures that have been beneficial for students, so that similar infrastructures can be used in the future, and help inform medical education in a non-pandemic setting.

category: medical education


title: Music therapy as a migraine treatment: protocol for a systematic review and meta-analysis

abstract:
IntroductionHeadache disorders are one of the most common health problems worldwide, they can be classified into primary and secondary disorders. In the primary group, migraine - the second most common type of headache - is the most disabling one and one of the most important reasons why its treatment is mandatory. Migraine treatment involves different steps and kinds of medical therapy and patient education, and in these past years studies have been exploring the effect music therapy can have in reducing the severity and duration of an acute migraine attack. It has been reported that adding music to the pharmacological treatment can help decrease the pain severity, thus, reducing the disability migraine can cause.

ObjectiveEvaluate the effectiveness of music therapy as a treatment or coadjuvant of migraine attacks in people who suffer this condition.

Methods and analysisThis protocol is consistent with the methodology recommended by the PRISMA-P and the Cochrane handbook for systematic reviews of interventions. This study will be carried out as a systematic review and meta-analysis. In order to do so, electronic searches will be performed in PubMed, Medline and Cochrane (through Ovid) and Embase. The data range parameters used in searching all databases are from the last 20 years. Randomized controlled trials (RCTs) published in English, Spanish, French and Portuguese; with the primary outcomes being reduction of headache intensity, resolution of the migraine and decreased frequency of migraine attacks. Three investigators will screen all retrieved studies titles and abstracts, making a first preliminary list. A second screen will be done by the same three investigators similarly to the first one, but reviewing the full texts and building the final list. Then, the evaluation of the risk of bias and extraction of all data will be performed. The risk of bias of the included RCTs will be evaluated by the Cochrane Collaborations tool. A qualitative synthesis will be provided in text and tables, to summarize the main results of the selected publications. The heterogeneity between studies will be assessed through the I2 statistic. If there is sufficient homogeneity across outcomes, a meta-analysis will be conducted.

ConclusionsThis systematic review will provide evidence regarding the effectiveness of music therapy as a single or coadjuvant treatment in patients with migraine attacks. Based on this analysis, it will be feasible to know whether this intervention is effective in the reduction of the intensity of the migraine attack, if it can help resolve the migraine attack, or reduce the frequency of migraine attacks.

category: neurology


title: Sensing and decoding the neural drive to paralyzed muscles during attempted movements of a person with tetraplegia using a sleeve array

abstract:
Motor neurons in the brain and spinal cord convey information about motor intent that can be extracted and interpreted to control assistive devices, such as computers, wheelchairs, and robotic manipulators. However, most methods for measuring the firing activity of single neurons rely on implanted microelectrodes. Although intracortical brain-computer interfaces (BCIs) have been shown to be safe and effective, the requirement for surgery poses a barrier to widespread use. Here, we demonstrate that a wearable sensor array can detect residual motor unit activity in paralyzed muscles after severe cervical spinal cord injury (SCI). Despite generating no observable hand movement, volitional recruitment of motor neurons below the level of injury was observed across attempted movements of individual fingers and overt wrist and elbow movements. Subgroups of motor units were coactive during flexion or extension phases of the task. Single digit movement intentions were classified offline from the EMG power (RMS) or motor unit firing rates with median classification accuracies >75% in both cases. Simulated online control of a virtual hand was performed with a binary classifier to test feasibility of real time extraction and decoding of motor units. The online decomposition algorithm extracted motor units in 1.2 ms, and the firing rates predicted the correct digit motion 88 {+/-} 24% of the time. This study provides the first demonstration of a wearable interface for recording and decoding firing rates of motor neurons below the level of injury in a person with tetraplegia after motor complete SCI.

Significance StatementA wearable electrode array and machine learning methods were used to record and decode myoelectric signals and motor unit firing in paralyzed muscles of a person with motor complete tetraplegia. Motor unit action potentials were extracted from myoelectric signals during attempted movements of the fingers and voluntary movements of the wrist and elbow. The patterns of EMG and motor unit firing rates were highly task-specific, even in the absence of visible motion in the limb, enabling accurate classification of attempted movements of single digits. These results demonstrate the potential to create a wearable sensor for determining movement intentions from spared motor neurons, which may enable people with severe tetraplegia to control assistive devices such as computers, wheelchairs, and robotic manipulators.


title: Long COVID neuropsychological deficits after severe, moderate or mild infection

abstract:
BackgroundThere is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can include long-term neuropsychological deficits, even in its mild or moderate respiratory forms.

MethodsStandardized neuropsychological, psychiatric, neurological and olfactory tests were administered to 45 patients (categorized according to the severity of their respiratory symptoms during the acute phase) 236.51 {+/-} 22.54 days post-discharge following SARS-CoV-2 infection.

ResultsDeficits were found in all the domains of cognition and the prevalence of psychiatric symptoms was also high in the three groups. The severe performed more poorly on long-term episodic memory and exhibited greater anosognosia. The moderate had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. The mild were more stressed, anxious and depressed.

ConclusionThe data support the hypothesis that the virus targets the central nervous system (and notably the limbic system), and support the notion of different neuropsychological phenotypes.


title: Calcium-Sensing Receptor Polymorphisms at rs1801725 are Associated with Increased Risk of Secondary Malignancies

abstract:
PurposeDysregulation of systemic calcium homeostasis during malignancy is common in most patients with high grade tumors. However, it remains unclear whether single nucleotide polymorphisms (SNPs) that alter the sensitivity of the calcium-sensing receptor (CaSR) to circulating calcium are associated with primary and/or secondary neoplasms at specific pathological sites in patients of European and African ancestry.

MethodsMultivariable logistic regression models were used to analyze the association of CASR SNPs with circulating calcium, parathyroid hormone, vitamin D, and primary and secondary neoplasms.

ResultsCirculating calcium is associated with an increased risk for breast, prostate, and skin cancers. In patients of European descent, the rs1801725 CASR SNP is associated with bone-related cancer phenotypes, deficiency of humoral immunity, and a higher risk of secondary neoplasms in the lungs and bone. Interestingly, circulating calcium levels are higher in homozygous patients for the inactivating CASR variant at rs1801725 (TT genotype), and this is associated with a higher risk of secondary malignancies.

ConclusionsBreast, prostate, and skin cancer patients with homozygous inactivating variants (TT genotype) at the CASR rs1801725 locus have a higher risk of developing secondary neoplastic lesions in the lungs and bone, due in part, to cancer-induced hypercalcemia and/or tumor immune suppression.

category: oncology


title: An empirical analysis of what people learned about COVID-19 through a web search and the impacts on misinformation and attitude towards public health safety guidelines.

abstract: Several people flocked to the Internet to learn about the SARS-CoV-2 and COVID-19 after the outbreak in Wuhan, China, in December 2019. As the novel coronavirus spread rapidly worldwide and was declared a global pandemic, the public rushed to Internet platforms to learn about the outbreak through Google search, online news outlets, and social media platforms. This paper evaluates the publics web search to learn about the pandemic and the possible impacts on attitude to the public health guidelines. The results highlight four outcomes: First, a significant global population learned about the ongoing pandemic through a web search. Second, there is a direct correlation between learning SARS-CoV-2, COVID-19, and SARS-CoV and searching information on public health measures (wearing a facial mask and social distancing). Third, learning conspiracy theories or misinformation correspond with a lack of interest in gaining knowledge about public health safety guidelines. Also, the initial high interest in learning about Influenza declined as people gained information about SARS-CoV-2 and COVID-19. The results highlight the critical need to promptly sensitize the public about global health concerns using both the Internet platforms and traditional sources, adopt effective health communication strategies, and build trust.

category: health informatics


title: The Trade-off Between Prioritization and Vaccination Speed Depends on Mitigation Measures

abstract: Calls for eliminating prioritization for SARS-CoV-2 vaccines are growing amid concerns that prioritization reduces vaccination speed. We use an SEIR model to study the effects of vaccination distribution on public health, comparing prioritization policy and speed under mitigation measures that are either eased during the vaccine rollout or sustained through the end of the pandemic period. NASEMs recommended prioritization results in fewer deaths than no prioritization, but does not minimize total deaths. If mitigation measures are eased, abandoning NASEM will result in about 134,000 more deaths at 30 million vaccinations per month. Vaccination speed must be at least 53% higher under no prioritization to avoid increasing deaths. With sustained mitigation, discarding NASEM prioritization will result in 42,000 more deaths, requiring only a 26% increase in speed to hold deaths constant. Therefore, abandoning NASEMs prioritization to increase vaccination speed without substantially increasing deaths may require sustained mitigation.

category: health policy


title: Predicting hospitalizations related to ambulatory care sensitive conditions with machine learning for population health planning: derivation and validation cohort study

abstract:
ObjectiveTo predict older adults risk of avoidable hospitalization related to ambulatory care sensitive conditions (ACSC) using machine learning applied to administrative health data of Ontario, Canada.

Design, Setting, and ParticipantsA retrospective cohort study was conducted on a large cohort of all residents covered under a single-payer system in Ontario, Canada over the period of 10 years, between 2008 and 2017. The study included 1.85 million Ontario residents between 65 and 74 years old at any time throughout the study period.

Data sourcesAdministrative health data from Ontario, Canada obtained from the ICES Data Repository.

Main outcome measuresRisk of hospitalizations due to ACSCs one year after the observation period.

ResultsThe study used a total of 1,854,116 patients, split into train, validation, and test sets. The ACSC incidence rates among the data points were 1.1% for all sets. The final XGBoost model achieved an AUC of 80.5% on the held-out test set, and the predictions were well-calibrated. When ranking the predictions made by the model, those at the top 5% of risk as predicted by the model captured 37.4% of those presented with an ACSC-related hospitalization. A variety of features such as the previous number of ambulatory care visits, presence of ACSC-related hospitalizations during the observation window, age, rural residence, and prescription of certain medications were contributors to the prediction. Our model was also able to capture the geospatial heterogeneity of ACSC risk in the province of Ontario, and especially the elevated risk in rural and marginalized regions.

ConclusionsThis study aimed to predict the 1-year risk of hospitalization from a series of ambulatory-care sensitive conditions in seniors aged 65 to 74 years old with a single, large-scale machine learning model. The model shows the potential to inform population health planning and interventions to reduce the burden of ACSC-related hospitalizations.

category: health systems and quality improvement


title: Sex differences in the mortality rate for coronavirus disease 2019 compared to other causes of death

abstract:
Men are more likely than women to die due to coronavirus disease 2019 (COVID-19). This paper sets out to examine whether the magnitude of the sex differences in the COVID-19 mortality rate are unusual when compared to other common causes of death. In doing so, we aim to provide evidence as to whether the causal pathways for the sex differences in the mortality rate of COVID-19 likely differ from those for other causes of death. We found that sex differences in the age-standardized COVID-19 mortality rate were substantially larger than for the age-standardized all-cause mortality rate and most other common causes of death. These differences were especially large in the oldest age groups.

One Sentence SummaryThe sex difference in the mortality rate of coronavirus disease 2019 is substantially larger than for other common causes of death.

category: infectious diseases


title: SARS-CoV-2 Viremia is Associated with Distinct Proteomic Pathways and Predicts COVID-19 Outcomes

abstract:
BackgroundSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) plasma viremia has been associated with severe disease and death in coronavirus disease 2019 (COVID-19) in small-scale cohort studies. The mechanisms behind this association remain elusive.

MethodsWe evaluated the relationship between SARS-CoV-2 viremia, disease outcome, inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using qRT-PCR based platform. Proteomic data were generated with Proximity Extension Assay (PEA) using the Olink platform.

ResultsThree hundred participants with nucleic acid test-confirmed COVID-19 were included in this study. Levels of plasma SARS-CoV-2 viremia at the time of presentation predicted adverse disease outcomes, with an adjusted odds ratio (aOR) of 10.6 (95% confidence interval [CI] 4.4, 25.5, P<0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and aOR of 3.9 (95%CI 1.5, 10.1, P=0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, endothelium/vasculature and alterations in coagulation pathways.

ConclusionsThese results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes.


title: Discovery of SARS-CoV-2 strain of P.1 lineage harboring K417T/ E484K / N501Y by whole genome sequencing in the city, Japan

abstract: On the February 2020, the very first case was an American female from Diamond Princess cruise ship. Since, we have confirmed 136 patients infected with coronavirus disease 2019 (COVID-19) until February 2021. Here, we conducted the whole genome sequencing analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on samples from 70 of 136 patients (51.5%). These patients were infected in Diamond Princess cruise ship (n=1), Africa (n=2), Japan (n=66) and Brazil (n=1). The viral genome sequence of a patient on the Diamond Princess cruise ship in February 2020 was similar to that of original strain found in Wuhan, China (19A clade). Four patients, including two returnees from Africa and two lived in Japan, confirmed at the end of March 2020 had sequences similar to those of lineage with D614G mutation, which was endemic in Europe (20A [n=3] and 20B [n=1] clade). The 64 Japanese patients confirmed from September 2020 to January 2021 had sequences similar to those of the currently prevalent lineage (20B [n=58] and 20C clade [n=6]). Subsequent analysis revealed three mutations (K417T/ E484K / N501Y) in the receptor binding domain of the spike protein in a man in his 40s. The sequence was identical to the P.1 lineage (also known as 20J/501Y.V3) reported in Brazil. This is the first report of SARS-CoV-2 P.1 lineage identified in the city, Japan.


title: Prophylaxis for covid-19: living systematic review and network meta-analysis

abstract:
ObjectiveTo determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19).

DesignLiving systematic review and network meta-analysis.

Data sourcesWHO covid-19 database, a comprehensive multilingual source of global covid-19 literature to 19 January 2021, and six additional Chinese databases to 20 January 2021.

Study selectionRandomized trials in which people at risk of covid-19 were randomized to drug prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

MethodsAfter duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach.

ResultsThe first iteration of this living network meta-analysis includes nine randomized trials - six addressing hydroxychloroquine (6,059 participants), one addressing ivermectin combined with iota-carrageenan (234 participants) and two addressing ivermectin alone (540 participants), all compared to standard care or placebo. Hydroxychloroquine has no important effect on admission to hospital (risk difference (RD) 1 fewer per 1,000, 95% credible interval (CrI) 3 fewer to 4 more, high certainty) or mortality (RD 1 fewer per 1,000, 95% CrI 2 fewer to 3 more, high certainty). Hydroxychloroquine probably has no important effect on laboratory-confirmed infection (RD 2 more per 1,000, 95% CrI 18 fewer to 28 more, moderate certainty), probably increases adverse effects leading to drug discontinuation (RD 19 more per 1,000, 95% CrI 1 fewer to 70 more, moderate certainty) and may have no important effect on suspected, probable or laboratory-confirmed infection (RD 15 fewer per 1,000, 95% CrI 64 fewer to 41 more, low certainty). Due to serious risk of bias and very serious imprecision - and thus very low certainty evidence, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed infection (RD 52 fewer per 1,000, 95% CrI 58 fewer to 37 fewer), and ivermectin alone on laboratory-confirmed infection (RD 50 fewer per 1,000, 95% CrI 59 fewer to 16 fewer) and suspected, probable or laboratory-confirmed infection (RD 159 fewer per 1,000, 95% CrI 165 fewer to 144 fewer) remain uncertain.

ConclusionHydroxychloroquine prophylaxis does not have an important effect on hospital admission and mortality, probably increases adverse effects, and probably does not have an important effect on laboratory-confirmed SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, we are highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.

Systematic review registrationThis review was not registered. The protocol established a priori is included as a supplement.

FundingThis study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

Readers noteThis article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.


title: The role of sociodemographic and psychosocial variables in early childhood development: A secondary data analysis of the 2014 Multiple Indicator Cluster Survey in the Dominican Republic

abstract:
IntroductionThe association between sociodemographic factors, such as poverty, lack of maternal schooling, and being male at birth, and childhood developmental delay and poor educational outcomes has been established in the Dominican Republic. However, moderating factors present or introduced in families to buffer the effects of such factors on childhood development are still unknown.

MethodsWe conducted a secondary analysis of the 2014 Multiple Indicator Cluster Survey for the Dominican Republic, a national household survey focused on maternal and child health and development. The first aim of our study was to determine if a sociodemographic model predicted early childhood development. The second aim was to determine if a psychosocial model (including family childrearing practices, discipline, and early childhood stimulation) predicted early childhood development above and beyond the sociodemographic model.

ResultsWe found that both models predicted childhood development significantly, but that the psychosocial model explained 5% more variance than the sociodemographic model. The most relevant sociodemographic predictors were socioeconomic position and mothers education, which uniquely explained 21% and 17% of the early childhood development variance, respectively. The most salient psychosocial predictors of early childhood development were: 1) attendance to an early childhood education program, which uniquely explained 15.0% of the variance; 2) negative discipline, which uniquely explained 12.4% (negative impact); 3) the number of childrens books at home, which uniquely explained 12.0%; and 4) stimulating activities at home, which uniquely explained 5%.

ConclusionThese results have multiple implications for social programs that aim to improve childrens developmental potential in contexts of poverty. Although the results show a protective effect of psychosocial factors, sustainable and large-scale intervention should not be limited to just buffering effects, but to actually solve the underlying problem which is that poverty prevents children from reaching their developmental potential.

category: public and global health


title: Interaural place-of-stimulation mismatch estimates using CT scans and binaural perception, but not pitch, are consistent in cochlear-implant users

abstract:
ABSTRACT

Bilateral cochlear implants (BI-CIs) or a CI for single-sided deafness (SSD; one normally functioning acoustic ear) can partially restore spatial-hearing abilities including sound localization and speech understanding when there are competing sounds. However for these populations, frequency information is not explicitly aligned across the ears, resulting in interaural place-of-stimulation mismatch. This diminishes spatial-hearing abilities because binaural encoding occurs in interaurally frequency-matched neurons. This study examined whether plasticity - the reorganization of central neural pathways over time - can compensate for peripheral interaural place mismatch. We hypothesized differential plasticity across two systems: none for binaural processing but adaptation toward the frequencies delivered by the specific electrodes for sequential pitch perception. Interaural place mismatch was evaluated in 43 human subjects (20 BI-CI and 23 SSD-CI, both sexes) using interaural-time-difference (ITD) discrimination (simultaneous bilateral stimulation), place-pitch ranking (sequential bilateral stimulation), and physical electrode- location estimates from computed-tomography (CT) scans. On average, CT scans revealed relatively little BI-CI interaural place mismatch (26{degrees} insertion-angle mismatch), but relatively large SSD-CI mismatch, particularly at the apical end of the array (166{degrees} for an electrode tuned to 300 Hz, decreasing to 14{degrees} at 7000 Hz). ITD and CT measurements were in agreement, suggesting little binaural-system plasticity to mismatch. The pitch measurements did not agree with the binaural and CT measurements, suggesting plasticity for pitch encoding or procedural biases. The combined results show that binaural processing may be optimized by using CT-scan information, but not pitch measurements, to program the CI frequency allocation to reduce interaural place mismatch.

SIGNIFICANCE STATEMENTPlacement of electrode arrays in users of cochlear implants (CIs; bionic auditory prostheses that partially restore hearing) does not align the frequency information to acoustic neural encoding across the ears. This interaural place-of-stimulation mismatch diminishes spatial hearing abilities. This study shows that for experienced adult CI users with two CIs or with one CI and one normal-hearing ear, the best possible binaural sensitivity occurs when the same cochlear location is stimulated in both ears. This means that binaural brainstem pathways do not experience "plasticity" to compensate for interaural place mismatch - i.e., they do not reorganize to respond to input from different cochlear places. Therefore, explicit correction of interaural place mismatch by a clinician is necessary to derive maximum spatial-hearing benefits.

category: otolaryngology


title: Risk Factors for Klebsiella infections among hospitalized patients with Pre-Existing Colonization

abstract:
BackgroundKlebsiella commonly colonizes the intestinal tract of hospitalized patients and is a leading cause of healthcare-associated infections. Colonization is associated with subsequent infection, but the factors determining this progression are unclear.

MethodsIntensive care and hematology/oncology patients were screened for Klebsiella colonization by rectal swab culture and monitored for infection for 90 days after a positive swab. Electronic medical records were analyzed for patient factors associated with subsequent infection, and variables of potential significance in bivariable analysis were used to build a final multivariable model. Concordance between colonizing and infecting isolates was assessed by wzi capsular gene sequencing.

ResultsAmong 2087 hospital encounters from 1978 colonized patients, 90 cases of infection (4.3%) were identified. Mean time to infection was 20.6 {+/-}24.69 (range 0-91, median 11.5) days. Of 86 typed cases, 68 unique wzi types were identified and 69 cases (80.2%) were colonized with an isolate of the same type prior to infection. Based on multivariable modeling, overall comorbidities, depression and low albumin level at the time of rectal swab were independently associated with subsequent Klebsiella infection.

ConclusionsDespite the high diversity of colonizing strains of Klebsiella, there is high concordance with subsequent infecting isolates and progression to infection is relatively quick. Readily accessible data from the medical record could be used by clinicians to identify colonized patients at increased risk of subsequent Klebsiella infection.

ImportanceKlebsiella is a leading cause of healthcare-associated infections. Patients who are intestinally colonized with Klebsiella are at significantly increased risk of subsequent infection, but only a subset of colonized patients progress to disease. Colonization offers a potential window of opportunity to intervene and prevent these infections, if the patients at greatest risk could be identified. To identify patient factors associated with infection in colonized patients, we studied 1978 colonized patients. We found that patients with a higher burden of underlying disease in general, depression in particular, and low albumin in a blood test were more likely to be a case of infection. However, these variables did not completely predict infection, suggesting that other host and microbial factors may also be important. The average time to infection was 3 weeks, suggesting that there is time to intervene and prevent Klebsiella infections in hospitalized patients.


title: A statewide analysis of SARS-CoV-2 transmission in New York

abstract: New York State, in particular the New York City metropolitan area, was the early epicenter of the SARS-CoV-2 pandemic in the United States. Similar to initial pandemic dynamics in many metropolitan areas, multiple introductions from various locations appear to have contributed to the swell of positive cases. However, representation and analysis of samples from New York regions outside the greater New York City area were lacking, as were SARS-CoV-2 genomes from the earliest cases associated with the Westchester County outbreak, which represents the first outbreak recorded in New York State. The Wadsworth Center, the public health laboratory of New York State, sought to characterize the transmission dynamics of SARS-CoV-2 across the entire state of New York from March to September with the addition of over 600 genomes from under-sampled and previously unsampled New York counties and to more fully understand the breadth of the initial outbreak in Westchester County. Additional sequencing confirmed the dominance of B.1 and descendant lineages (collectively referred to as B.1.X) in New York State. Community structure, phylogenetic, and phylogeographic analyses suggested that the Westchester outbreak was associated with continued transmission of the virus throughout the state, even after travel restrictions and the on-pause measures of March, contributing to a substantial proportion of the B.1 transmission clusters as of September 30th, 2020.

category: epidemiology


title: Histopathological assessments reveal retinal vascular changes, inflammation, and gliosis in patients with lethal COVID-19

abstract:
PurposeTo assess for histopathological changes within the retina and the choroid and determine the long-term sequelae of the SARS-CoV-2 infection.

DesignComparative analysis of human eyes.

SubjectsEleven donor eyes from COVID-19 positive donors and similar age-matched donor eyes from patients with a negative test for SARS-CoV-2 were assessed.

MethodsGlobes were evaluated ex-vivo with macroscopic, SLO and OCT imaging. Macula and peripheral regions were processed for epon-embedding and immunocytochemistry

Main Outcome MeasuresRetinal thickness and histopathology, detection of SARS-CoV-2 Spike protein, changes in vascular density, gliosis, and degree of inflammation.

ResultsFundus analysis shows hemorrhagic spots and increased vitreous debris in several of the COVID-19 eyes compared to the control. OCT based measurements indicated an increased trend in retinal thickness in the COVID-19 eyes, however the difference was not statistically significant. Histology of the retina showed presence of hemorrhages and central cystoid degeneration in several of the donors. Whole mount analysis of the retina labeled with markers showed changes in retinal microvasculature, increased inflammation, and gliosis in the COVID-19 eyes compared to the controls. The choroidal vasculature displayed localized changes in density and signs of increased inflammation in the COVID-19 samples.

ConclusionsIn situ analysis of the retinal tissue suggested that there are severe subclinical abnormalities that could be detected in the COVID-19 eyes. This study provides a rationale for evaluating the ocular physiology of patients that have recovered from COVID-19 infections to further understand the long-term effects caused by this virus.

category: ophthalmology


title: Racial and ethnic differences in COVID-19 vaccine hesitancy and uptake

abstract:
BackgroundRacial and ethnic minorities have been disproportionately impacted by COVID-19. In the initial phase of population-based vaccination in the United States (U.S.) and United Kingdom (U.K.), vaccine hesitancy and limited access may result in disparities in uptake.

MethodsWe performed a cohort study among U.S. and U.K. participants in the smartphone-based COVID Symptom Study (March 24, 2020-February 16, 2021). We used logistic regression to estimate odds ratios (ORs) of COVID-19 vaccine hesitancy (unsure/not willing) and receipt.

ResultsIn the U.S. (n=87,388), compared to White non-Hispanic participants, the multivariable ORs of vaccine hesitancy were 3.15 (95% CI: 2.86 to 3.47) for Black participants, 1.42 (1.28 to 1.58) for Hispanic participants, 1.34 (1.18 to 1.52) for Asian participants, and 2.02 (1.70 to 2.39) for participants reporting more than one race/other. In the U.K. (n=1,254,294), racial and ethnic minorities had similarly elevated hesitancy: compared to White participants, their corresponding ORs were 2.84 (95% CI: 2.69 to 2.99) for Black participants, 1.66 (1.57 to 1.76) for South Asian participants, 1.84 (1.70 to 1.98) for Middle East/East Asian participants, and 1.48 (1.39 to 1.57) for participants reporting more than one race/other. Among U.S. participants, the OR of vaccine receipt was 0.71 (0.64 to 0.79) for Black participants, a disparity that persisted among individuals who specifically endorsed a willingness to obtain a vaccine. In contrast, disparities in uptake were not observed in the U.K.

ConclusionsCOVID-19 vaccine hesitancy was greater among racial and ethnic minorities, and Black participants living in the U.S. were less likely to receive a vaccine than White participants. Lower uptake among Black participants in the U.S. during the initial vaccine rollout is attributable to both hesitancy and disparities in access.


title: Interpreting vaccine efficacy trial results for infection and transmission

abstract:
Randomized controlled trials (RCTs) have shown high efficacy of multiple vaccines against SARS-CoV-2 disease (COVID-19), and recent studies have shown the vaccines are also effective against infection. Evidence for the effect of each of these vaccines on ability to transmit the virus is also beginning to emerge. We describe an approach to estimate these vaccines effects on viral positivity, a prevalence measure which under the reasonable assumption that vaccinated individuals who become infected are no more infectious than unvaccinated individuals forms a lower bound on efficacy against transmission. Specifically, we recommend separate analysis of positive tests triggered by symptoms (usually the primary outcome) and cross-sectional prevalence of positive tests obtained regardless of symptoms. The odds ratio of carriage for vaccine vs. placebo provides an unbiased estimate of vaccine effectiveness against viral positivity, under certain assumptions, and we show through simulations that likely departures from these assumptions will only modestly bias this estimate. Applying this approach to published data from the RCT of the Moderna vaccine, we estimate that one dose of vaccine reduces the potential for transmission by at least 61%, possibly considerably more. We describe how these approaches can be translated into observational studies of vaccine effectiveness.

HighlightsO_LISARS-CoV-2 vaccine trials did not directly estimate vaccine efficacy against transmission.
C_LIO_LIWe describe an approach to estimate a lower bound of vaccine efficacy against transmission.
C_LIO_LIWe estimate one dose of the Moderna vaccine reduces the potential for transmission by at least 61%.
C_LIO_LIWe recommend separate analysis of tests triggered by symptoms vs. cross-sectional tests.
C_LI


title: Cardiometabolic risk factors associated with brain age and accelerate brain ageing

abstract: The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean and standard deviation = 19.7 {+/-} 0.5 months), including 1062 datasets from 790 healthy individuals (mean (range) age = 46.7 (18-94) years, 54% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modelling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomised controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.


title: The impact of genomic structural variation on the transcriptome, chromatin, and proteome in the human brain

abstract: Structural variants (SVs), defined as any genomic rearrangements of 50 or more bp, are an important source of genetic diversity and have been linked to many diseases. However, their contribution to molecular traits in the brain and impact on neurodegenerative diseases remains unknown. Here, we report 170,996 SVs which were constructed using 1,760 short-read whole genomes from aging and Alzheimers disease subjects. We quantified the impact of cis-acting SVs on several molecular traits including histone modification, gene expression, mRNA splicing, and protein abundance in post-mortem brain tissues. More than 3,800 genes were associated with at least one molecular phenotype, and 712 (18%) with more than one phenotype, with a significant positive correlation in the direction of effect between RNA, histone peaks, and protein levels. SV associations with RNA and protein levels shared the same direction of effect in more than 87% of SV-gene pairs. We found reproducibility of SV-eQTLs across three groups of samples and multiple brain regions ranging from 81 to 98%, including the innate immune system related genes ERAP2 and GBP3. Additionally, associations of SVs with progressive supranuclear palsy, an amyloid-independent primary tauopathy, identified previously known and novel SVs at the 17q.21.31 MAPT locus and several other novel suggestive associations. Our study provides a comprehensive view of the mechanisms linking structural variation to gene regulation and provides a valuable resource for understanding the functional impact of SVs in the aged human brain.

category: genetic and genomic medicine


title: A precise score for the regular monitoring of COVID-19 patients condition validated within the first two waves of the pandemic

abstract:
PurposeThe sudden outbreak of COVID-19 pandemic have shown that medical community needs an accurate and interpretable aggregated score not only for an outcome prediction but also for a daily patients condition assessment. Due to a continuously changing pandemic landscape, a robustness becomes a crucial additional requirement for the score.

Materials and methodsIn this research a real-world data collected within the first two waves of COVID-19 pandemic was used. The first wave data (1349 cases collected from 27.04.2020 to 03.08.2020) was used as a training set for the score development, while the second wave data (1453 cases collected from 01.11.2020 to 19.01.2021) was used as a validating set. For all the available patients features we tested their association with an outcome using a robust linear regression. Statistically significant features were taken to the further analysis for each of which their partial sensitivity, specificity and promptness were estimated. The sensitivity and the specificity were further combined into a feature informativeness index.

ResultsThe developed score was derived as a weighted sum of the following 9 features showed the best trade-off between informativeness and promptness: APTT (> 42 sec, 4 points), CRP (> 146 mg/L, 3 points), D-dimer (> 2149 mkg/L, 4 points), Glucose (> 9 mmol/L, 4 points), Hemoglobin (< 115 g/L, 3 points), Lymphocytes (< 0,7*10^9/L, 3 points), Total protein (< 61 g/L, 6 points), Urea (> 11 mmol/L, 5 points) and WBC (> 13,5*10^9/L, 4 points). Thus, the proposed score ranges between 0 and 36 points. Internal and temporal validation showed that sensitivity and specificity over 90% may be achieved with an expected prediction range >7 days. Moreover, we demonstrated a high robustness of the score to the varying peculiarities of the pandemic. For the additional simplicity of application we split the full range of the score into five grades delimited with 9, 14, 19 and 24 points which determine expected death:discharge odds 1:100, 1:25, 1:5 and 1:1 correspondingly.

ConclusionsAn extensive application of the score within the second wave of COVID-19 pandemic showed its potential for the optimization of patients management as well as improvement of medical staff attentiveness during a high workload stress. The transparent structure of the score as well as tractable cut-off bounds simplified its implementation into a clinical practice.


title: Integrated Transcriptomic and Neuroimaging Brain Model Decodes Biological Mechanisms in Aging and Alzheimer's disease

abstract:
Both healthy aging and Alzheimers disease (AD) are characterized by concurrent alterations in several biological factors. However, generative brain models of aging and AD are limited in incorporating the measures of these biological factors at different spatial resolutions. Here, we propose a personalized bottom-up spatiotemporal brain model which accounts for the direct interplay between hundreds of RNA transcripts and multiple macroscopic neuroimaging modalities (PET, MRI). In normal elderly and AD participants, the model identifies top genes modulating tau and amyloid-{beta} burdens, vascular flow, glucose metabolism, functional activity, and atrophy to drive cognitive decline. The results also revealed that AD and healthy aging share specific biological mechanisms, even though AD is a separate entity with considerably more altered pathways. Overall, this personalized model offers novel insights into the multiscale alterations in the elderly brain, with important implications for identifying effective genetic targets for extending healthy aging and treating AD progression.

Highlights- A multiscale model integrating gene expression and neuroimaging identifies causal genes driving healthy aging and Alzheimers disease progression.

- The specific neuroimaging modalities modulated by the causal genes are revealed.

- Healthy aging and Alzheimers disease share specific biological pathways even though Alzheimers disease has more altered pathways.

category: geriatric medicine


title: Remdesivir as a tool to relieve hospital care systems stressed by COVID-19: A modelling study on bed resources and budget impact.

abstract: Remdesivir and dexamethasone are the only drugs providing reductions in the lengths of hospital stays for COVID-19 patients. We assessed the impacts of remdesivir on hospital-bed resources and budgets affected by the COVID-19 outbreak. A stochastic agent-based model was combined with epidemiological data available on the COVID-19 outbreak in France and data from two randomized control trials. Strategies involving treating with remdesivir only patients with low-flow oxygen and patients with low-flow and high-flow oxygen were examined. Treating all eligible low-flow oxygen patients during the entirety of the second wave would have decreased hospital-bed occupancy in conventional wards by 4% [2%; 7%] and intensive care unit (ICU)-bed occupancy by 9% [6%; 13%]. Extending remdesivir use to high-flow-oxygen patients would have amplified reductions in ICU-bed occupancy by up to 14% [18%; 11%]. A minimum remdesivir uptake of 20% was required to observe decreases in bed occupancy. Dexamethasone had effects of similar amplitude. Depending on the treatment strategy, using remdesivir would, in most cases, generate savings (up to 722{euro}) or at least be cost neutral (an extra cost of 34{euro}). Treating eligible patients could significantly limit the saturation of hospital capacities, particularly in ICUs. The generated savings would exceed the costs of medications.


title: Synthetic protein antigens for COVID-19 diagnostics

abstract: There is an urgent need for inexpensive, rapid and specific antigen-based assays to test for infection with SARS-CoV-2 and distinguish variants arising as the COVID-19 pandemic spreads. We have identified a small, synthetic protein (JS7), representing a region of maximum variability within the receptor binding domain (RBD), which binds antibodies in sera from nine patients with PCR-verified COVID-19 of varying severity. Antibodies binding to either JS7 or the SARS-CoV-2 recombinant RBD, as well as those that disrupt binding between a fragment of the ACE2 receptor and the RBD, are proportional to disease severity and clinical outcome. Binding to JS7 was inhibited by linear peptides from the RBD interface with ACE2. Variants of JS7, such as N501Y, can be quickly synthesized in a pure form in large quantities by automated methods. JS7 and related synthetic antigens can provide a basis for specific diagnostics for SARS-CoV-2 infections.


title: Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke

abstract:
BackgroundThe relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations.

MethodsGenetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. Analyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any of the cardiovascular outcomes for which genetic correlation was identified.

ResultsThere was evidence of genetic correlation between critical Covid-19 and ischemic stroke (rg=0.29, FDR p-value=4.65x10-3), body mass index (rg=0.21, FDR-p-value=6.26x10-6) and C-reactive protein (rg=0.20, FDR-p-value=1.35x10-4), but none of the other considered traits. In Mendelian randomization analysis, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06, p-value=0.03). Similar estimates were obtained when considering ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.

ConclusionsThese data support that liability to critical Covid-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe Covid-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.

category: cardiovascular medicine


title: Prenatal and Childhood Adverse Events and Child Brain Morphology: A Population-Based Study

abstract:
BackgroundPrenatal and childhood adverse events have been shown to be related to childrens cognitive and psychological development. However, the influence of early-life adversities on child brain morphology is not well understood and most studies are based on small samples and often examine only one adversity. Thus, the goal of our study is to examine the relationship between cumulative exposures to prenatal and childhood adversities and brain morphology in a large population-based study.

MethodsParticipants included 2,993 children in whom prenatal adversities were reported by mothers at 20-25 weeks of pregnancy and the childs lifetime exposure to adversities was reported by mothers when the children were 10 years-of-age. The total brain, grey and white matter volumes and the volume of the cerebellum, amygdala and hippocampus were assessed with magnetic resonance imaging when children were 10 years old.

ResultsIn total, 36% of children had mothers who were exposed to at least one adversity during pregnancy and 35% of children were exposed to adversities in childhood. In our study sample, the cumulative number of prenatal adversities was not related to any brain outcome. In contrast, per each additional childhood adverse event, the total brain volume was 0.07 standard deviations smaller (SE = 0.02, p = 0.001), with differences in both grey and white matter volumes. Childhood adversities were not related to the amygdala or hippocampal volumes. Additionally, the link between childhood events and the preadolescent brain was not modified by prenatal events and was not explained by maternal psychopathology.

ConclusionsOur results suggest that childhood adversities, but not prenatal adverse events, are associated with smaller global brain volumes in preadolescence. Notably, this is the first large population-based study to prospectively assess the association between the cumulative number of prenatal adversities and the preadolescent brain morphology. The study findings extend the evidence from high-risk samples, providing support for a link between cumulative childhood adverse events and brain morphology in children from the general population.


title: Graphical Models of Pandemic

abstract:
Both COVID-19 and novel pandemics challenge those of us within the modeling community, specifically in establishing suitable relations between lifecycles, scales, and existing methods. Herein we demonstrate transitions between models in space/time, individual-to-community, county-to-city, along with models for the trace beginning with exposure, then to symptom manifest, then to community transmission. To that end, we leverage publicly available data to compose a chain of Graphical Models (GMs) for predicting infection rates across communities, space, and time. Well anchor our GMs against the more expensive yet state-of-the-art Agent-Based Models (ABMs). Insight obtained from designing novel GMs calibrated to ABMs furnishes reduced, yet reliable surrogates for the end-to-end public health challenge of community contact tracing and transmission. Further, this novel research transcends and synergizes information integration and informatics, leading to an advance in the science of GMs. Cognizance into the data lifecycle using properly coarse-grained modeling will broaden the toolkit available to public health specialists, and hopefully empower governments and health agencies, here and abroad, in addressing the profound challenges in disease and vaccination campaigns confronting us by COVID and future pandemics.

In this proof of principle study, focusing on the GM methodology development, we show, first, how static GM of the Ising model type (characterized by pair-wise interaction between nodes related to traffic and communications between nodes representing communities, or census tracts within a given city, and with local infection bias) emerge from a dynamic GM of the Independent Cascade type, introduced and studied in Computer and Networks sciences mainly in the context of the spread of social influences. Second, we formulate the problem of inference in epidemiology as inference problems in the Ising model setting. Specifically, we pose the challenge of computing Conditional A-posteriori Level of Infection (CALI), which provides a quantitative answer to the questions: What is the probability that a given node in the GM (given census tract within the city) becomes infected in the result of injection of the infection at another node, e.g. due to arrival of a super-spreader agent or occurence of the super-spreader event in the area. To answer the question exactly is not feasible for any realistic size (larger than 30-50 nodes) model. We therefore adopt and develop approximate inference techniques, of the variational and variable elimination types, developed in the GM literature. To demonstrate utility of the methodology, which seems new for the public health application, we build a 123-node model of Seattle, as well as its 10-node and 20-node coarsegrained variants, and then conduct the proof of principles experimental studies. The experiments on the coarse-grained models have helped us to validate the approximate inference by juxtaposing it to the exact inference. The experiments also lead to discovery of interesting and most probably universal phenomena. In particular, we observe (a) a strong sensitivity of CALI to the location of the initial infection, and (b) strong alignment of the resulting infection probability (values of CALI) observed at different nodes in the regimes of moderate interaction between the nodes. We then speculate how these, and other observations drawn from the synthetic experiments, can be extended to a more realistic, data driven setting of actual operation importance. We conclude the manuscript with an extensive discussion of how the methodology should be developed further, both at the level of devising realistic GMs from observational data (and also enhancing it with microscopic ABM modeling and simulations) and also regarding utilization of the GM inference methodology for more complex problems of the pandemic mitigation and control.


title: Characterizing an epidemiological geography of the United States: influenza as a case study

abstract: The prediction, prevention, and management of infectious diseases in the United States is either geographically homogeneous or is coordinated through ad-hoc administrative regions, ignoring the intense spatio-temporal heterogeneity displayed by most outbreaks. Using influenza as a case study, we characterize a regionalization of the United States. Based on influenza time series constructed from fine-scale insurance claims data from 2002-2009, we apply a complex network approach to characterize regions of the U.S. which experience comparable influenza dynamics. Our results identify three to five epidemiologically distinct regions for each flu season, with all locations within each region experiencing synchronous epidemics, and with an average of a two week delay in peak timing between regions. We find that there is significant heterogeneity across seasons in the identity of the regions and the relative timing across regions, making predictability from one season to the next challenging. Within a given season, however, our approach shows the potential to inform on the shaping of regions over time, to improve resources mobilization and targeted communication. Our epidemiologically-driven regionalization approach could allow for disease monitoring and control based on epidemiological risk rather than geopolitical boundaries, and provides a tractable public health approach to account for vast heterogeneity that exists in respiratory disease dynamics.


title: A Multi-Stage Stochastic Programming Approach to Epidemic Resource Allocation with Equity Considerations

abstract: Existing compartmental models in epidemiology are limited in terms of optimizing the resource allocation to control an epidemic outbreak under disease growth uncertainty. In this study, we address this core limitation by presenting a multi-stage stochastic programming compartmental model, which integrates the uncertain disease progression and resource allocation to control an infectious disease outbreak. The proposed multi-stage stochastic program involves various disease growth scenarios and optimizes the distribution of treatment centers and resources while minimizing the total expected number of new infections and funerals. We define two new equity metrics, namely infection and capacity equity, and explicitly consider equity for allocating treatment funds and facilities over multiple time stages. We also study the multistage value of the stochastic solution (VSS), which demonstrates the superiority of the proposed stochastic programming model over its deterministic counterpart. We apply the proposed formulation to control the Ebola Virus Disease (EVD) in Guinea, Sierra Leone, and Liberia of West Africa to determine the optimal and fair resource-allocation strategies. Our model balances the proportion of infections over all regions, even without including the infection equity or prevalence equity constraints. Model results also show that allocating treatment resources proportional to population is sub-optimal, and enforcing such a resource allocation policy might adversely impact the total number of infections and deaths, and thus resulting in a high cost that we have to pay for the fairness. Our multi-stage stochastic epidemic-logistics model is practical and can be adapted to control other infectious diseases in meta-populations and dynamically evolving situations.


title: HYPER: Group testing via hypergraph factorization applied to COVID-19

abstract: Large scale screening is a critical tool in the life sciences, but is often limited by reagents, samples, or cost. An important challenge in screening has recently manifested in the ongoing effort to achieve widespread testing for individuals with SARS-CoV-2 infection in the face of substantial resource constraints. Group testing methods utilize constrained testing resources more efficiently by pooling specimens together, potentially allowing larger populations to be screened with fewer tests. A key challenge in group testing is to design an effective pooling strategy. The global nature of the ongoing pandemic calls for something simple (to aid implementation) and flexible (to tailor for settings with differing needs) that remains efficient. Here we propose HYPER, a new group testing method based on hypergraph factorizations. We provide theoretical characterizations under a general statistical model, and exhaustively evaluate HYPER and proposed alternatives for SARS-CoV-2 screening under realistic simulations of epidemic spread and within-host viral kinetics. We demonstrate that HYPER performs at least as well as other methods in scenarios that are well-suited to each method, while outperforming those methods across a broad range of resource-constrained environments, being more flexible and simple in design, and taking no expertise to implement. An online tool to implement these designs in the lab is available at http://hyper.covid19-analysis.org.


title: Impact of a new SARS-CoV-2 variant on the population: A mathematical modeling approach

abstract: Several SARS-CoV-2 variants have emerged around the world and the appearance of other variants depends on many factors. These new variants might have different characteristics that can affect the transmissibility and death rate. The administration of vaccines against the coronavirus disease 2019 (COVID-19) started in early December of 2020 and in some countries the vaccines will not soon be widely available. In this article, we study the impact of a new more transmissible SARS-CoV-2 strain on prevalence, hospitalizations, and deaths related to the SARS-CoV-2 virus. We study different scenarios regarding the transmissibility in order to provide a scientific support for public health policies and bring awareness of potential future situations related to the COVID-19 pandemic. We construct a compartmental mathematical model based on differential equations to study these different scenarios. In this way, we are able to understand how a new, more infectious strain of the virus can impact the dynamics of the COVID-19 pandemic. We study several metrics related to the possible outcomes of the COVID-19 pandemic in order to assess the impact of a higher transmissibility of a new SARS-CoV-2 strain on these metrics. We found that, even if the new variant has the same death rate, its high transmissibility can increase the number of infected people, those hospitalized, and deaths. The simulation results show that health institutions need to focus on increasing non-pharmaceutical interventions and the pace of vaccine inoculation since a new variant with higher transmissibility as, for example, VOC-202012/01 of lineage B.1.1.7, may cause more devastating outcomes in the population.


title: A novel 5E training model and other methods implemented for rapid readiness at an ad-hoc COVID-19 facility in India

abstract:
BackgroundA ad-hoc dedicated COVID-19 hospital was setup in New Delhi, India over a span of 12 days. At this time, new teaching modalities were employed to train the staff. This study aims to identify and quantify the effectiveness of these teaching models in terms of learning which was evaluated using case scenarios before and after the teaching session.

ObjectivesTo assess education methods and models for training of healthcare workers during rapid deployment at an ad-hoc dedicated COVID-19 hospital.

MethodsThe 5E (Engage, Explore, Explain, Elaborate and Evaluate) teaching modality through peer group teaching methods was utilised in the situation. Statistical analysis was done using Mann Whitney U test.

ResultsA total of 86 participants (43 doctors and 43 nurses) answered the pre and post test questionnaires. The number of correct responses per question in the pre test (Mean + SD;49.0+ 18.53) vs post test (Mean + SD;54.40+ 15.95) with stratification by the domain of learning was analysed. No significant difference was found in the pre and post test responses.

ConclusionFurther studies of this nature will contribute towards assessing efficacy of teaching modalities employed in rapid readiness for future pandemic scenarios.


title: High-intensity exercise is a risk factor for renal medullary carcinoma in individuals with sickle cell trait

abstract: Renal medullary carcinoma (RMC) predominantly occurs in individuals with sickle cell trait (SCT). We found that patients with RMC more frequently participated in high-intensity exercise than matched controls, and renal medullary hypoxia significantly increased predominantly in the right kidney of mice with SCT following high-but not moderate-intensity exercise, consistent with the distinct predilection of RMC toward the right kidney. These results establish high-intensity exercise as a risk factor for RMC in individuals with SCT.


title: Multi-objective Risk-based Resource Allocation for Urban Pandemic Preparedness: The COVID-19 Case in Bogota, Colombia

abstract: Determining how best to allocate resources to be used during a pandemic is a strategic decision that directly affects the success of pandemic response operations. However, government agencies have finite resources, so they cant monitor everything all of the time: they have to decide how best to allocate their scarce resources (i.e., budget for antivirals and preventive vaccinations, Intensive Care Unit (ICU), ventilators, non-intensive Care Unit (non-ICU), doctors) across a broad range of risk exposures (i.e., geographic spread, routes of transmission, overall poverty, medical preconditions). This paper establishes a comprehensive risk-based emergency management framework that could be used by decision-makers to determine how best to manage medical resources, as well as suggest patient allocation among hospitals and alternative healthcare facilities. A set of risk indexes are proposed by modeling the randomness and uncertainty of allocating resources in a pandemic. The city understudy is modeled as a Euclidean complex network, where depending on the neighborhood influence of allocating a resource in a demand point (i.e., informing citizens, limit social contact, allocate a new hospital) different network configurations are proposed. Finally, a multi-objective risk-based resource allocation (MoRRA) framework is proposed to optimize the allocation of resources in pandemics. The applicability of the framework is shown by the identification of high-risk areas where to prioritize the resource allocation during the current COVID-19 pandemic in Bogota, Colombia.


title: Genetics of symptom remission in outpatients with COVID-19

abstract: We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 x 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 x 10-8) in interaction with colchicine (P = 1.19 x 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.


title: Consistency of performance of adverse outcome prediction models for hospitalized COVID-19 patients

abstract:
BackgroundWe previously reported and validated a risk prediction tool based on COVID-19 hospitalizations prior to June 2020. Here, we report performance of that model on subsequent data from 6 hospitals and among individual patient subgroups.

MethodWe included individuals age 18 or older hospitalized at one of 2 academic medical centers and 4 community hospitals from 6/7/2020 through 1/22/2021 with positive PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 5 days of admission. Coefficients from our previously reported least absolute shrinkage and selection operator (Lasso) risk models were applied to estimate probability of a mortality, as well as a composite severe illness outcome, including admission to the ICU, mechanical ventilation or mortality.

ResultsOverall model performance for mortality included AUC of 0.83 (95% CI:0.80-0.87) for mortality, with a PPV 0.55 and NPV of 0.95 when using a cutoff corresponding to the highest 20% of predicted risk derived in the training set. For all adverse outcomes, AUC was 0.79 (95% CI:0.75-0.81) and PPV 0.48 and NPV 0.98 in the top 20% risk group. Model discrimination was generally similar between genders and race/ethnicity groups, but markedly poorer for younger age groups.

ConclusionAlthough the population of individuals hospitalized for COVID-19 has shifted and outcomes have improved overall, prediction models derived earlier in the pandemic may maintain utility.


title: Reanalysis of the Pfizer mRNA BNT162b2 SARS-CoV-2 vaccine data fails to find any increased efficacy following the boost: Implications for vaccination policy and our understanding of the mode of action

abstract:
BackgroundIn clinical trials two vaccinations with mRNA vaccines have shown high efficacy in preventing COVID-19. However, in the context of a pandemic, the time to generation of protective immunity, the need for and timing of a second vaccination are matters of legitimate debate. This manuscript explores the efficacy and timing of the second dose COVID-19 vaccines, including a reanalysis of data from the Pfizer mRNA BNT162b2 mRNA SARS-CoV-2 vaccine phase 3 study.

Methods and findingsA non-weighted three-segment, two knot linear regression was fitted to the published cumulative infection incidence from the Pfizer BNT162b2 vaccine Phase III trial using the lspine routine in R. The optimal knot days were estimated through sensitivity analysis and the confidence limits for efficacy estimates were determined by Monte Carlo Simulations. This analysis showed the vaccine was effective from day 11 post first vaccination. The estimated efficacy over the period 11 to 28 days post first vaccination was 0.94 and there was no detectable increase in efficacy following the second vaccination. The efficacy post first vaccination substantially preceded the development of detectable serum neutralizing antibody.

ConclusionsStrongly protective immunity develops rapidly following a single vaccination and at least in the short period covered by the timetable of the Phase III trial, there was no additional benefit from a second vaccination. This increases options for use of this vaccine, e.g., for ring fence vaccination, for use in travelers and for mass vaccination rollout. It highlights the need for further research into duration of immunity following a single vaccination and for understanding mechanisms of protection.


title: Epidemiological cutoff values for a 96-well broth microdilution plate for high throughput research antibiotic susceptibility testing of M. tuberculosis

abstract:
Drug susceptibility testing of M. tuberculosis is rooted in a binary susceptible/resistant paradigm.

Whilst there are considerable advantages in measuring the minimum inhibitory concentrations (MICs) of a panel of drugs for an isolate it is n ecessary to measure the epidemiological cutoff values (ECOFF/ECVs) to permit comparison with qualitative data. Here we present ECOFF/ECVs for 13 anti-TB compounds, including bedaquiline and delamanid, derived from 20,637 clinical isolates collected by 14 laboratories based in 11 countries on five continents. Each isolate was incubated for 14 days on a dry 96-well broth microdilution plate and then read. Resistance to most of the drugs due to prior exposure is expected and the MIC distributions for many of the compounds are complex and therefore a phenotypically wild-type population could not be defined. Since a majority of samples also underwent genetic sequencing, we defined a genotypically wild-type population and measured the MIC of the 99th percentile by direct measurement and via fitting a Gaussian using interval regression.

The proposed ECOFF/ECV values were then validated by comparing to the MIC distributions of high-confidence genetic variants that confer resistance and to qualitative drug susceptibility tests obtained via Mycobacterial Growth Indicator Tube and the Microscopic-Observation Drug-Susceptibility assay.

These ECOFF/ECV values will inform and encourage the more widespread adoption of broth microdilution - this is a cheap culture-based method that tests the susceptibility of 12-14 antibiotics on a single 96-well plate and so could help personalise the treatment of tuberculosis.


title: Predicting COVID-19 related death using the OpenSAFELY platform

abstract:
ObjectivesTo compare approaches for obtaining relative and absolute estimates of risk of 28-day COVID-19 mortality for adults in the general population of England in the context of changing levels of circulating infection.

DesignThree designs were compared. (A) case-cohort which does not explicitly account for the time-changing prevalence of COVID-19 infection, (B) 28-day landmarking, a series of sequential overlapping sub-studies incorporating time-updating proxy measures of the prevalence of infection, and (C) daily landmarking. Regression models were fitted to predict 28-day COVID-19 mortality.

SettingWorking on behalf of NHS England, we used clinical data from adult patients from all regions of England held in the TPP SystmOne electronic health record system, linked to Office for National Statistics (ONS) mortality data, using the OpenSAFELY platform.

ParticipantsEligible participants were adults aged 18 or over, registered at a general practice using TPP software on 1st March 2020 with recorded sex, postcode and ethnicity. 11,972,947 individuals were included, and 7,999 participants experienced a COVID-19 related death. The study period lasted 100 days, ending 8th June 2020.

PredictorsA range of demographic characteristics and comorbidities were used as potential predictors. Local infection prevalence was estimated with three proxies: modelled based on local prevalence and other key factors; rate of A&E COVID-19 related attendances; and rate of suspected COVID-19 cases in primary care.

Main outcome measuresCOVID-19 related death.

ResultsAll models discriminated well between patients who did and did not experience COVID-19 related death, with C-statistics ranging from 0.92-0.94. Accurate estimates of absolute risk required data on local infection prevalence, with modelled estimates providing the best performance.

ConclusionsReliable estimates of absolute risk need to incorporate changing local prevalence of infection. Simple models can provide very good discrimination and may simplify implementation of risk prediction tools in practice.


title: Characterization of the indoor near-field and far-field aerosol transmission in a model commercial office building

abstract:
To simulate the exposure potential of infectious aerosol such as SARS-CoV-2 in an office building setting, experimental studies for airborne particle transmission have been conducted in a model commercial office building at the Oak Ridge National Laboratory. The synthetic test aerosol particles had diameters similar to that of viral particles, in the nanometer size range of genetic fragments. Thus, the test aerosol provided a realistic representation of SARS-CoV-2 viral particle transmission. The study results, which are still being analyzed carefully at the present, suggest that in a door-closed single room setting, the heating, ventilating, and air-conditioning (HVAC) system can facilitate aerosol transmission, and 10 measuring points in a single room report the normalized concentration ranged from 0.45 - 0.66. Additionally, at a measuring point 6 feet away from the source, the aerosol concentration can reach a plateau normalized concentration of about 0.6 within 30 minutes. When interior doors were closed, aerosol particle transmission into adjacent rooms occurred through the building HVAC system, at a lower rate compared to the open-door scenario. If the interior doors were open, however, then the transmission into adjacent rooms depends on building indoor air movement and distance from the source. The building HVAC system provided an approximately less than 10% aerosol transmission rate, while transmission through a door opening can add up to 40% of transmission into adjacent rooms from the source location.

FootnoteThis manuscript has been authored by UT-Battelle, LLC, under contract DE-AC05-00OR22725 with the US Department of Energy (DOE). The US government retains and the publisher, by accepting the article for publication, acknowledges that the US government retains a nonexclusive, paid-up, irrevocable, worldwide license to publish or reproduce the published form of this manuscript, or allow others to do so, for US government purposes. DOE will provide public access to these results of federally sponsored research in accordance with the DOE Public Access Plan (http://energy.gov/downloads/doe-public-access-plan).


title: What is the effect of lockdown upon hospitalisation due to COVID-19 amongst patients from a heart failure registry?

abstract:
IntroductionCoronavirus disease 2019 (COVID-19) is associated with a high risk of mortality especially in patients with cardiovascular conditions such as heart failure. The UK government announced a national lockdown last year to curb the spread of the virus. We conducted this study primarily to ascertain the impact of lockdown upon the incidence of COVID-19 hospitalisation amongst patients with a known diagnosis of heart failure (HF)

MethodsThis was a retrospective cohort study of 1097 patients from our HF registry who had presented with acute decompensated HF in 2018 and 2019. Incidence and outcomes of hospitalisation due to COVID-19 were analysed in this cohort both during the 1st UK lockdown as well as after the lockdown period. Co-morbidities, frailty index, clinical features, blood results, and heart failure treatments were compared between the 2 groups (COVID versus no-COVID) and between the group of patients who died versus survivors.

Results50 out of 801 surviving (6.2%) HF patients required hospitalisation due to COVID-19 from March to November 2020; 24 patients (3.1%) during the first lockdown and 26 (3.5%) in the post-lockdown period; p=0.7. In comparison to patients not hospitalised with COVID-19 ("no-COVID group), there was a significantly higher prevalence of co-morbidities amongst HF patients who were hospitalised with COVID-19, such as hypertension (p<0.001), diabetes (p=0.005), ischaemic heart disease (p=0.01) and increased body mass index. 30 day mortality amongst HF patients hospitalised due to COVID-19 was 52%. Rockwood Frailty Score [≥]6 (OR 6.530695 % CI:1.8958 to 22.4961; p=0.003) and diabetes (OR 3.82;95% CI 1.13 to 12.95; p=0.03) were independent predictors of 30 day mortality.

ConclusionOur data suggests that the incidence of hospitalisation due to COVID-19 was similar both during as well as post lockdown amongst patients from our HF registry. HF patients with cardiovascular co-morbidities such as obesity, hypertension, diabetes and ischaemic heart disease have a higher risk of hospitalisation due to COVID-19. Diabetes and Rockwood Frailty score are independent predictors of short term mortality. Co-morbidity and frailty scores should be incorporated during initial assessment to help risk-prediction.


title: A qualitative study on cultural determinants for breastfeeding cessation and their association with child diarrhoea in the rural Peruvian Andes

abstract:
BackgroundIn some parts of the world, breast milk is seen as a potential source of child diarrhoea. While this belief has been explored in African and Southeast Asian countries, it remains vastly understudied in Latin American contexts. We investigate cultural factors contributing to breastfeeding cessation in rural high-altitude populations of the Peruvian Andes. The role of cultural factors in the local explanatory model of child diarrhoea, and whether these perceptions are integrated in the local healthcare system were assessed.

MethodsWe carried out semi-structured interviews with mothers (n=40) from 29 communities participating in a large community-randomised controlled trial and health personnel (n=15). We used trials baseline information to describe characteristics of women participants.

ResultsCultural beliefs for breastfeeding cessation included the perception that breast milk turned into "blood" after six months and that breastfeeding caused child diarrhoea. We identified eight local types of child diarrhoea, and women associated six of them with breastfeeding practices. "Infection" was the only diarrhoea mothers linked to hygiene and the germ disease concept and perceived as treatable through drug therapy. Women believed that other types of diarrhoea could not be treated within the formal healthcare sector. Interviews with health personnel revealed no protocol for, or consensus about, the integration of the local explanatory model for child diarrhoea in local healthcare and service provision.

ConclusionThe local explanatory model in rural Andean Peru associated breastfeeding with child diarrhoeas. Cultural beliefs regarding diarrhoea management may increase home treatments, even in cases of severe diarrhoeal episodes. Future breastfeeding interventions should promote peer-counselling approaches to reduce negative attitudes towards breastfeeding and health practitioners. Local explanatory models should be incorporated into provincial and regional strategies for child diarrhoea management to promote equity in health and improve provider-patient relationships.


title: Emergent effects of contact tracing robustly stabilize outbreaks

abstract: Covid-19 neither dissolved nor got out of control over a year. In many instances, the new daily cases exhibit an equilibrium at a meagre percentage of the population. Seemingly impossible due to the precise cancellation of positive and negative effects. Here, I propose models on real-world networks that capture the mysterious dynamics. I investigate the contact-tracing and related effects as possible causes. I differentiate the impact of contact-tracing into three--one direct and two emergent--effects: isolation of the documented patients direct infectees (descendants), isolation of non-descendant infectees, and temporary isolation of susceptible contacts. Contrary to expectation, isolation of descendants cannot stabilize an equilibrium; based on current data, the effect of the latter two are necessary and greater in effect overall. The reliance on emergent effects shows that even if contact-tracing is 100% efficient, its effect on the epidemic dynamics would be dependent. Moreover, This newly characterized dynamic claims that all outbreaks will eventually show such stable dynamics.


title: Seroepidemiology of SARS-CoV-2 infections in an urban Nicaraguan population

abstract: In a Nicaraguan population-based cohort, SARS-CoV-2 seroprevalence was 34%, with higher prevalence in children compared to adults. Having a seropositive household member was associated with a two-fold probability of individual seropositivity, suggesting a role for household transmission. Co-morbidities and preventive behaviors were not associated with SARS-CoV-2 seroprevalence.


title: RT-qPCR assay for detection of British (B.1.1.7) and South Africa (B.1.351) variants of SARS-CoV-2

abstract: Less than a year following the SARS-CoV-2 outbreak, variants of concern have emerged in the form of the British variant B.1.1.7 and the South Africa variant B.1.351. Due to their high infectivity and morbidity, it is crucial to quickly and effectively detect them. Current methods of detection are either time-consuming, expensive or indirect. Here, we report the development of a rapid, cost-effective and direct RT-qPCR method for detection of the two variants of concern. We developed and validate a detection system for the detection of the B.1.1.7 variant and another single detection set for the B.1.351 variant. The developed approach was characterized and tested on wastewater samples and illustrated that all primers and probes were sensitive and specific. The novel system presented here will allow proper response and pandemic containment with regard to these variants. In addition, it may provide a basis for developing tools for the detection of additional variants of concern.


title: Trade-offs between individual and ensemble forecasts of an emerging infectious disease

abstract: When new pathogens emerge, numerous questions arise about their future spread, some of which can be addressed with probabilistic forecasts. The many uncertainties about the epidemiology of emerging pathogens can make it difficult to choose among model structures and assumptions, however. To assess the potential for uncertainties about emerging pathogens to affect forecasts of their spread, we evaluated the performance of a suite of 16 forecasting models in the context of the 2015-2016 Zika epidemic in Colombia. Each model featured a different combination of assumptions about the role of human mobility in driving transmission, spatiotemporal variation in transmission potential, and the number of times the virus was introduced. All models used the same core transmission model and the same iterative data assimilation algorithm to generate forecasts. By assessing forecast performance through time using logarithmic scoring with ensemble weighting, we found that which model assumptions had the most ensemble weight changed through time. In particular, spatially coupled models had higher ensemble weights in the early and late phases of the epidemic, whereas non-spatial models had higher ensemble weights at the peak of the epidemic. We compared forecast performance of the equally weighted ensemble model to each individual model and identified a trade-off whereby certain individual models outperformed the ensemble model early in the epidemic but the ensemble model outperformed all individual models on average. On balance, our results suggest that suites of models that span uncertainty across alternative assumptions are necessary to obtain robust forecasts in the context of emerging infectious diseases.


title: Unwelcome memento mori or best clinical practice? Community end-of-life anticipatory medication prescribing practice: a mixed methods observational study

abstract:
BackgroundAnticipatory medications are injectable drugs prescribed ahead of possible need for administration if distressing symptoms arise in the final days of life. Little is known about how they are prescribed in primary care.

AimTo investigate the frequency, timing and recorded circumstances of anticipatory medications prescribing for patients living at home and in residential care.

DesignRetrospective mixed methods observational study using General Practitioner and community nursing clinical records.

Setting/participants329 deceased adult patients registered with Eleven General Practitioner practices and two associated community nursing services in Hertfordshire and Cambridgeshire, England (30 most recent deaths per practice). Patients died from any cause except trauma, sudden death or suicide, between 4 March 2017 and 25 September 2019.

ResultsAnticipatory medications were prescribed for 167/329 (50.8%) of the deceased patients, between 0 and 1212 days before death (median 17 days). The likelihood of prescribing was significantly higher for patients with a recorded preferred place of death (odds ratio [OR] 34; 95% CI 15-77; p < 0.001) and specialist palliative care involvement (OR 7; 95% CI 3-19; p < 0.001). For 66.5% of patients (111/167) anticipatory medications were recorded as being prescribed as part of a single end of-life planning intervention.

ConclusionThe variability in the timing of prescriptions highlights the challenges in diagnosing the end-of-life phase and the potential risks of prescribing far in advance of possible need. Patient and family preferences for involvement in anticipatory medications prescribing decision-making and their experiences of care warrant urgent investigation.

Summary Box O_TEXTBOXWhat is already known on this topicO_LIThe prescribing of injectable anticipatory medications to provide symptom relief in the last days of life care is recommended and widespread practice in a number of counties.
C_LIO_LIThere is limited research concerning the frequency, timing and context of prescriptions.
C_LI

What this paper addsO_LIHalf (50.8%) of 319 patients whose deaths were potentially predictable deaths were prescribed anticipatory medications, the timing of prescriptions ranging from 0 to 1212 days before death (median 17 days).
C_LIO_LIAnticipatory medications were frequently prescribed as standardised drugs and doses, and often as part of a single end-of-life care planning intervention.
C_LIO_LIThe extent to which patients and family carers were involved in prescribing decisions was unclear.
C_LI

Implications for practice, theory or policyO_LIPatient and family preferences for involvement in anticipatory medications prescribing decision-making and their experiences of care warrant urgent investigation.
C_LIO_LIThe presence of anticipatory medications for long periods of time may compromise patient safety unless robust systems are in place to review their continued appropriateness and safe use.
C_LI

C_TEXTBOX

category: palliative medicine


title: Donor Anti-Spike Immunity is Related to Recipient Recovery and Can Predict the Efficacy of Convalescent Plasma Units.

abstract:
BackgroundThe novel coronavirus, SARS-CoV2 that causes COVID-19 has resulted in the death of more than 2.31 million people within the last year and yet no cure exists. Whereas passive immunization with COVID-19 convalescent plasma (CCP) provides a safe and viable option, selection of optimal units for therapy and lack of clear therapeutic benefit from transfusion remain as barriers to the use of CCP.

Study design and methodsTo identify plasma that is expected to benefit recipients, we measured anti-SARS-CoV2 antibody levels using clinically available serological assays and correlated with the neutralizing activity of CCP from donors. Neutralizing titer of plasma samples was measured by assaying infectivity of SARS-CoV-2 spike protein pseudotyped retrovirus particles in the presence of dilutions of plasma samples. We also used this assay to identify evidence of passive transfusion of neutralizing activity in CCP recipients.

ResultsViral neutralization and anti-spike protein antibodies in 109 samples from 87 plasma donors were highly varied but modestly correlated with each other. Recipients who died of COVID-19 were found to have been transfused with units with lower anti-spike antibody levels and neutralizing activity. Passive transfer of neutralization activity was documented in 62% of antibody naive plasma recipients.

ConclusionsSince viral neutralization is the goal of CCP transfusion, our observations not only support the use of anti-spike SARS-CoV2 serology tests to identify beneficial CCP units, but also support the therapeutic value of convalescent plasma with high titers of anti-spike antibodies.

category: pathology