title: Cross-sector Decision Landscape in Response to COVID-19: A Qualitative Analysis of North Carolina Decision-Makers

abstract:
ContextThe COVID-19 pandemic response has demonstrated the interconnectedness of individuals, organizations, and other entities jointly contributing to the production of community health. This response has involved stakeholders from numerous sectors who have been faced with new decisions, objectives, and constraints.

ObjectiveWe aimed to examine the cross-sector organizational decision landscape that formed in response to the COVID-19 pandemic.

DesignWe applied a systems approach to the qualitative analysis of semi-structured interviews on the cross-sector, organizational response to the COVID-19 pandemic. We analyzed transcribed interviews using conventional content analysis to synthesize key themes.

SettingSemi-structured interviews were conducted via secure, video-conferencing platform between October 2020 and January 2021.

ParticipantsForty-four state and local decision-makers representing organizations from nine sectors in North Carolina participated.

Main Outcome MeasuresWe defined the decision landscape as including decision-maker roles, key decisions, and inter-relationships involved in producing community health.

ResultsDecision-maker roles were characterized by underlying tensions between balancing organizational mission with employee/community health and navigating organizational versus individual responsibility for reducing transmission. Key Decisions fell into several broad categories, including how to translate public health guidance into practice; when to institute, and subsequently loosen, public health restrictions; and how to address downstream social and economic impacts of public health restrictions. Lastly, given limited and changing information, as well as limited resources and expertise, the COVID-19 response required cross-sector collaboration, which was commonly coordinated by local health departments.

ConclusionsBy documenting the local, cross-sector decision landscape that formed in response to COVID-19, we illuminate the impacts different organizations may have on information/misinformation, prevention behaviors, and, ultimately, health. Public health researchers and practitioners must understand, and work within, this complex decision landscape when responding to COVID-19 and future community health challenges.


title: Knowledge, attitudes, and positions of religious leaders towards female genital mutilation: A cross-sectional study from the Kurdistan Region of Iraq

abstract:
BackgroundUnderstanding the perspectives of the key players in the community regarding female genital cutting (FGC) is very important for directing preventive programs. Religious leaders help shape community behaviors, which is highly pertinent in the case of FGC as it is frequently perceived to be a religious requirement. This study assesses religious leaders knowledge, attitudes, and positions towards FGC in the Kurdistan Region of Iraq.

MethodsThis cross-sectional study was conducted in the Kurdistan Region of Iraq. It included a purposive sample of 147 local religious leaders (khateebs) representing the three governorates of Erbil, Sulaimaniyah, and Duhok. A self-administered questionnaire was used to collect data about the religious leaders knowledge, attitude, and position towards FGC.

ResultsThe participants identified reduction of the sexual desire of women as the main benefit (37%) and risk (24%) of FGC. Cultural tradition and religious requirements were the main reasons for practicing FGC. About 59% of the religious leaders stated that people ask for their advice on FGC. Around 14% of the participants supported performing FGC, compared to 39.1% who opposed it. Religious (73.9%) and cultural (26.1%) rationales were the main reasons given for supporting FGC. Being a cultural practice and having harmful effects (53.5%) and lack of clear religious evidence (46.6%) were the main reasons for being against FGC. Around 52% of the participants recommended banning FGC by law, while 43.5% did not support banning it. A statistically significant association (P=0.015) was found between religious leaders residence and their position on performing FGC. More than 46% of those residing in Duhok were against performing FGC, compared to lower proportions in Erbil (38.8%) and Sulaimaniyah (30%).

ConclusionA conclusive decision concerning FGC banning needs to be made by religious authorities to advise people to avoid the practice. Health awareness activities incorporating FGC risks should be carried out to enlighten religious leaders at different levels of religious positions. Further research exploring perspectives of religious authorities concerning religious leaders inconclusive judgments about FGC is deemed necessary.

category: public and global health


title: Interstitial lung damage following COVID-19 hospitalisation: an interim analysis of the UKILD Post-COVID study.

abstract:
IntroductionShared characteristics between COVID-19 and pulmonary fibrosis, including symptoms, genetic architecture, and circulating biomarkers, suggests interstitial lung disease (ILD) development may be associated with SARS-CoV-2 infection.

MethodsThe UKILD Post-COVID study planned interim analysis was designed to stratify risk groups and estimate the prevalence of Post-COVID Interstitial Lung Damage (ILDam) using the Post-HOSPitalisation COVID-19 (PHOSP-COVID) Study. Demographics, radiological patterns and missing data were assessed descriptively. Bayes binomial regression was used to estimate the risk ratio of persistent lung damage >10% involvement in linked, clinically indicated CT scans. Indexing thresholds of percent predicted DLco, chest X-ray findings and severity of admission were used to generate risk strata. Number of cases within strata were used to estimate the amount of suspected Post-COVID ILDam.

ResultsA total 3702 people were included in the UKILD interim cohort, 2406 completed an early follow-up research visit within 240 days of discharge and 1296 had follow-up through routine clinical review. We linked the cohort to 87 clinically indicated CTs with visually scored radiological patterns (median 119 days; interquartile range 83 to 155, max 240), of which 74 people had ILDam. ILDam was associated with abnormal chest X-ray (RR 1.21 95%CrI 1.05; 1.40), percent predicted DLco<80% (RR 1.25 95%CrI 1.00; 1.56) and severe admission (RR 1.27 95%CrI 1.07; 1.55). A risk index based on these features suggested 6.9% of the interim cohort had moderate to very-high risk of Post-COVID ILDam. Comparable radiological patterns were observed in repeat scans >90 days in a subset of participants.

ConclusionThese interim data highlight that ILDam was not uncommon in clinically indicated thoracic CT up to 8 months following SARS-CoV-2 hospitalisation. Whether the ILDam will progress to ILD is currently unknown, however health services should radiologically and physiologically monitor individuals who have Post-COVID ILDam risk factors.

category: respiratory medicine


title: Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation

abstract:
Antibody-mediated rejection (AMR) is the leading cause of graft failure. While donor-specific antibodies (DSA) are associated with a higher risk of AMR, not all patients with DSA develop rejection suggesting that the characteristics of alloantibodies that determine their pathogenicity remain undefined. Using human leukocyte antigen (HLA)-A2-specific antibodies as a model, we applied systems serology tools to investigate qualitative features of immunoglobulin G (IgG) alloantibodies including Fc-glycosylation patterns and Fc{gamma}R binding properties. The levels of afucosylation of anti-A2 antibodies were elevated in all seropositive patients and were significantly higher in AMR patients, suggesting potential cytotoxicity via Fc{gamma}RIII-mediated mechanisms. Afucosylation of both glycoengineered monoclonal and naturally glycovariant polyclonal serum IgG specific to HLA-A2 exhibited potentiated binding to, slower dissociation from, and enhanced signaling through Fc{gamma}RIII, a receptor widely expressed on innate effector cells. Collectively, these results suggest that afucosylated DSA may be a biomarker of AMR and could contribute to its pathogenesis.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=62 SRC="FIGDIR/small/22272152v1_ufig1.gif" ALT="Figure 1">
View larger version (24K):
org.highwire.dtl.DTLVardef@55413dorg.highwire.dtl.DTLVardef@12e1532org.highwire.dtl.DTLVardef@71938eorg.highwire.dtl.DTLVardef@8e8847_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Potential influence of HLA-A2-specific IgG1 afucosylation, Fc{gamma}RIIIa binding and activation on ADCC and graft rejection.Illustration created with https://BioRender.com.

C_FIG

category: transplantation


title: Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

abstract: Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Here, we performed mRNA sequencing of full blood for 27 patients of the OPTIMISTIC cohort before and after the CBT intervention. We identified 608 genes for which their expression was significantly associated with the disease causing CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes significantly associated with both returned to more normal levels in patients who benefited most from CBT. This trend was consistent with the difference observed between DM1 patients and controls in an earlier study of blood mRNA expression levels, singling these genes out as candidate biomarkers for therapy response. Together these results highlight the ability to find disease relevant information in full blood of DM1 patients, opening new avenues to monitor therapy effects.

category: neurology


title: The development of the Supplemental Nutrition Assistance Program enrollment accessibility (SNAP-Access) score

abstract:
BackgroundThe Supplemental Nutrition Assistance Program (SNAP) is a federally funded public benefit providing critical food assistance to millions of Americans. However, it is typically administered by states, creating potential variation in accessibility and transparency of information about enrollment for people with disabilities.

ObjectiveTo create a method to assess the accessibility and transparency of information about the disability-inclusive process and practices of SNAP enrollment

MethodsData was collected from SNAP landing and enrollment webpages from all 50 U.S. states, the District of Columbia, and New York City from June-August 2021. Based on key principles of universal design and accessibility, scores were determined for each SNAP program across three areas: flexibility in the enrollment process (6 points), efficiency of finding information about enrollment on SNAP websites (6 points), and the accessibility of SNAP webpages (6 points). Total scores were the sum of these sub-categories (18 points maximum).

ResultsOf the 52 SNAP programs assessed, mean scores were 10.66 (SD=2.51) for the total score, 2.67 (SD=0.91) for flexibility in the enrollment process, 3.32 (SD=1.19) for efficiency of finding information about enrollment on SNAP websites, and 4.67 (SD=1.72) for the accessibility of SNAP webpage. A total of 0 SNAP programs received the maximum score (6 points) on flexibility, 2 programs the maximum on efficiency, and 31 programs the maximum on accessibility.

ConclusionsWe found differences in the accessibility, flexibility, and efficiency of SNAP program enrollment information available on SNAP websites and outline much room for improvement across all three of these areas.

category: health policy


title: SARS-CoV-2 Omicron disease burden in Australia following border reopening: a modelling analysis

abstract:
BackgroundCountries with high COVID-19 vaccination rates have seen the SARS-CoV-2 Omicron variant result in rapidly increasing case numbers. This study evaluated the impact on the health system which may occur following introduction of the Omicron variant into Western Australia following state border reopening. We aimed to understand the effect of high vaccine coverage levels on the population health burden in the context of lower vaccine effectiveness against the Omicron variant, the impact of a third dose booster regime, and ongoing waning of vaccine-induced immunity. Originally scheduled for 5th February 2022, the Western Australian border was opened on 3rd March 2022, we also aimed to determine the impact of delaying border reopening on the COVID-19 health burden and whether the West Australian health system would be able to manage the resulting peak demand.

MethodsAn agent-based model was used to evaluate changes in the COVID-19 health burden resulting from different border openings, at monthly intervals. We assumed immunity was derived from vaccination with the BNT162b2 Pfizer BioNTech vaccine and waned at observed rates from the UK. The model was calibrated against outbreaks in two other Australian states, Queensland and South Australia, both of which were in a similar situation to Western Australia with negligible COVID-19 transmission prior to Omicrons introduction. Age-specific infections generated by the model, together with recent UK data, permitted resulting outbreak health burden to be quantified, in particular peak ICU demand.

ResultsOverall population immunity in Western Australia is shown to peak and then plateau for a period of 5 months, between February and June 2022, resulting in a similar health burden if the border is reopened prior to June 2022. For an opening date of 5th March 2022, hospitalisations are predicated to peak at 510 beds, 51 of which will be in ICU, with a total of 383 deaths. If the border reopened on 5th June 2022, hospitalisations are expected to peak with 750 beds required, 75 of which would be in ICU, and a total of 478 deaths. With a total surge capacity of 52 fully staffed ICU beds, West Australian hospitals are predicted to have adequate ICU capacity for future COVID-19 demands if border reopening occurs prior to May 2022.

ConclusionsOur results show that with extremely high SARS-CoV-2 vaccination rates in Western Australian, and documented vaccine-induced vaccine waning rates, the overall population immunity in Western Australia will be at its highest in the period of February 2022 to June 2022. Opening the Western Australian border prior to the end this period will result in the lowest health burden in comparison to opening in June 2022 or later. With a border reopening of 3rd March 2022 announced by the Western Australian government, our data for a 5th March 2022 opening date may be used to predict the progression of this resulting outbreak. These data show expected peak demand of 510 hospital beds, 51 of which will be in ICU, with a total of 383 deaths. With a surge capacity of 52 ICU beds, it is expected that the Western Australian hospital system will be able to handle the additional load during the peak of the wave.

category: infectious diseases


title: The impact of introduction of the 10-valent pneumococcal conjugate vaccine (PCV10) on pneumococcal carriage in Nigeria

abstract:
BackgroundPneumococcal Conjugate Vaccines (PCVs) reduce the burden of pneumococcal disease by reducing nasopharyngeal acquisition and transmission of serotypes in the vaccines (vaccine-serotypes). Following introduction of the 10-valent PCV (PCV10) in Nigeria, we assessed the population-level impact of PCV introduction on pneumococcal carriage.

MethodsWe conducted annual cross-sectional carriage and vaccination coverage surveys between 2016 and 2020 in rural and urban sites in Nigeria. We recruited a random sample of residents and used WHO-recommended laboratory methods to identify pneumococcal serotypes. We modelled prevalence ratios for the change in annual carriage prevalence using log-binomial regression, and explored the association between vaccination coverage in children <5 years and changes in the population-level vaccine-serotype carriage.

FindingsWe enrolled 4,684 and 3,653 participants for the carriage surveys and 2,135 and 1,106 children for the coverage surveys in the rural and urban sites, respectively. Carriage prevalence of vaccine-serotypes declined steadily with increasing levels of PCV10 coverage among children aged <5 years. From 2016 to 2020, coverage with three doses of PCV10 increased from 7% to 59% and from 15% to 81% in the rural and urban sites, respectively. Prevalence ratios for the annual change in vaccine-serotype carriage in participants aged <5 years and [≥]5 years were 0.84 (95% CI:0.79-0.89) and 0.86 (95%CI:0.80-0.89) in the rural, and 0.69 (95% CI:0.62-0.77), and 0.83 (95% CI:0.74-0.93) in the urban sites.

ConclusionsWe found significant reduction in vaccine-serotype carriage at a population level following a steady increase in PCV10 coverage, indicating direct and indirect vaccine effects.


title: Safety of praziquantel in persons with and without schistosomiasis: systematic review and meta-analysis

abstract:
Millions of praziquantel doses have been delivered in schistosomiasis endemic populations through preventive chemotherapy. However, no comprehensive assessment of short and long-term safety has been conducted. This systematic review assessed safety of praziquantel in persons with and without schistosome infections who received praziquantel treatment.

MethodsWe identified relevant studies (published, unpublished, in press or preprint) that assessed safety of praziquantel without language restriction. We searched MEDLINE, EMBASE, CINAHL, and LILACS from 1978 to 31st October 2021, using well-formulated and piloted search strategy. We also searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2021), mRCT, Google Scholar, Hinari and Africa Journals Online. References of relevant studies were checked and experts were contacted for additional studies. One author searched and managed the search output. Two authors selected studies, extracted data and assessed quality of the included studies for risk of bias. Activities at all stages were checked independently by a third reviewer. Discrepancies were resolved through discussion among the authors. Data were analysed with RevMan v5.4 and STATA v17. Binary outcomes were reported as risk ratio using random-effects model and continuous outcomes as mean difference, all presented with their 95% confidence intervals. P-value was set at 0.05. Heterogeneity was assessed using I2-static and where possible sensitivity analysis was conducted. When pooling of data was not possible, we presented data in a narrative synthesis and as tables.

Main resultsThe search retrieved 3202 studies of which 134 met the inclusion criteria; 94 (70.1%) were conducted in Africa, 17 (12.7%) in Asia, 15 (11.2%) in the Americas (14 from Brazil), 4 (3.0%) in the Middle East and 3 (2.2%) in Europe. Praziquantel mostly resulted in mild-to-moderate and transient adverse events, however, majority of the included studies had design issues, including very short follow-up times (mostly few hours) for assessing incidence of adverse events. Less than <10% of the studies reported severe or serious adverse events. The subgroup analyses of twenty studies comparing school age children (SAC) and adults, and involved over one million participants found no difference in the nature of adverse events, but SAC experienced higher incidence than adults: headache (RR 3.07, 95% CI 2.32 to 4.06, twenty studies, I2 = 98%, p < 0.00001), dizziness (RR 1.80, 95% CI 1.36 to 2.37, p = 0.0001), vomiting (RR 2.43, 95% CI 1.87 to 3.14, I2 = 98%; p < 0.00001), four time for abdominal pain (RR 3.97, 95% CI 3.09 to 5.10, I2 = 96%, p < 0.00001), nausea (RR 1.67, 95% CI 1.32 to 2.12, I2 = 97%, p < 0.0001), general discomfort (RR 1.32, 95% CI 1.03 to 1.68, I2 = 97%, p < 0.00001), fever (RR 4.78, 95% CI 3.04 to 7.52, I2 = 98%, p < 0.00001), diarrhoea (RR 1.41, 95% CI 1.12 to 1.78, I2 = 92%, p < 0.00001), itching (RR 2.42, 95% CI 1.58 to 3.70, I2 = 93%, p <0.0001) and breathing difficulty (RR 2.46, 95% CI 1.41 to 4.29, I2 = 92%, p = 0.002). There was no statistically significant difference in incidence of swelling. Some of the studies that assessed safety in pregnant women reported serious events including miscarriages, foetal deaths and congenital anomalies, but the evidence is incoclusive given the limited numbers. Some studies reported praziquantel-related visual adverse events, but evidence is limited and remains inconclusive. There was paucity of data on long term adverse events, and events in co-morbidity, polypharmacy, co-infection with taeniasis. Generally, adverse events research in this area lacked methodological rigour.

ConclusionsThe evidence generated from this review involving millions of people and millions of doses from different geographic locations with mostly mild-to-moderate and transient adverse events shows praziquantel is safe. However, given that the primary studies included in the review had design issues, including over 95% assessing adverse events over very short follow-up times, means serious long-term adverse events would have been missed. Also, the fact that some pregnant women who received praziquantel experienced serious events including miscarriages, foetal deaths and congenital anomalies calls for caution in the inclusion of pregnant women, particularly in their first trimester, in preventive chemotherapy campaigns. Additionally, the studies that reported severe visual adverse events raise safety concerns. Praziquantel is now offered repeatedly in endemic communities and the fact that in some settings up to 90% of those without infection could be offered the drug and the fact that there was no study that compared safety between infected and non-infected recipients, warrants further research. Evidence on safety in pregnant women and their foetuses, co-morbidity, polypharmacy, co-infection with taeniasis, as well as co-administration with drugs used in other preventive chemotherapy programmes, remain inconclusive and further research with long follow-up that should include blood chemistry analysis to provide additional evidence on long term safety, is warranted. This systematic review has exposed the lack of methodological rigour in adverse events studies and recommends future research should use robust and standardized design, methods, conduct and reporting.


title: Duration of vaccine effectiveness against SARS-CoV2 infection, hospitalisation, and death in residents and staff of Long-Term Care Facilities (VIVALDI): a prospective cohort study, England, Dec 2020-Dec 2021

abstract:
BackgroundLong-term care facilities (LTCF) have been prioritised for vaccination, but data on potential waning of vaccine effectiveness (VE) and the impact of booster doses in this vulnerable population remains scarce.

MethodsWe included residents and staff from 331 LTCFs enrolled in VIVALDI (ISRCTN 14447421), who underwent routine PCR testing between Dec 8, 2020 - Dec 11, 2021 in a Cox proportional hazards regression, estimating VE against SARS-CoV2 infection, COVID-19-related hospitalisation, and COVID-19-related death after 1-3 vaccine doses, stratifying by previous SARS-CoV2 exposure.

ResultsFor 15,518 older residents, VE declined from 50{middle dot}7% (15{middle dot}5, 71{middle dot}3) to 17{middle dot}2% ([~]23{middle dot}9, 44{middle dot}6) against infection; from 85{middle dot}4% (60{middle dot}7, 94{middle dot}.6) to 54{middle dot}3% (26{middle dot}2, 71{middle dot}7) against hospitalisation; and from 94{middle dot}4% (76{middle dot}4, 98{middle dot}7) to 62{middle dot}8% (32{middle dot}9, 79{middle dot}4) against death, when comparing 2-12 weeks and [≥]12 weeks after two doses. For 19,515 staff, VE against infection declined slightly from 50{middle dot}3% (32{middle dot}7, 63{middle dot}3) to 42{middle dot}1% 29{middle dot}5, 52{middle dot}4). High VE was restored following a third dose, with VE of 71{middle dot}6% (53{middle dot}5, 82{middle dot}7) and 78{middle dot}3% (70{middle dot}1, 84{middle dot}3) against infection and 89{middle dot}9% (80{middle dot}0, 94{middle dot}6) and 95{middle dot}8% (50{middle dot}4, 99{middle dot}6) against hospitalisation, for residents and staff respectively; and 97{middle dot}5% (88{middle dot}1, 99{middle dot}5) against death for residents.

InterpretationSubstantial waning of VE is observed against all outcomes in residents from 12 weeks after a primary course of AstraZeneca or mRNA vaccines. Boosters restore protection, and maximise immunity across all outcomes. These findings demonstrate the importance of boosting and the need for ongoing surveillance of VE in this vulnerable cohort.

FundingUK Government Department of Health and Social Care.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE and medRxiv for studies reporting vaccine effectiveness (VE) over time after two or three doses against SARS-CoV2 infection, COVID-19-related hospitalisation, or COVID-19-related death amongst staff or residents of long-term care facilities (LTCFs), that were published between Jan 1, 2020, and December 21, 2021. We used variations of the search terms "COVID-19" OR "SARS-CoV-2" AND "vaccine effectiveness" OR "vaccine efficacy" AND "care homes" OR "long term care facilities".

We identified 8 articles reporting two-dose data from LTCFs, including 1 peer-reviewed paper from Israel, 1 preprint from Denmark, 1 preprint from Norway, 1 peer-reviewed paper from France, two peer-reviewed papers from Spain, 1 peer-reviewed paper from the USA, and 1 preprint from England; however none of these studies examined waning of protection over time after two doses. Five studies (mRNA vaccines 3-4 weeks interval) reported short-term two-dose VE of 49-71% in residents, and 82-90% in staff. Two-dose VE was reported to be 75-88% against hospitalisation, 87-97% against death, and 86% against either outcome. An English study of residents (Pfizer or AstraZeneca, 8-12 week interval) reported 73% VE against infection and noted VE waning from 7 weeks after the first dose, but did not examine waning after the second dose. All of these studies were set prior to emergence of the Delta variant and did not examine waning of immunity due to short lengths of follow-up after Dose 2. Only one study (USA) compared Pfizer/Moderna two-dose VE against infection in LTCF residents before (67{middle dot}5% [60{middle dot}1-73{middle dot}5%]) and during (53{middle dot}1% [49{middle dot}1-56{middle dot}7%]) Delta variant predominance; however, authors could not access vaccination dates therefore did not account for any waning of immunity over time; they also did not examine any severe clinical outcomes.

We identified only one correspondence piece from Israel (Pfizer 3-4 week interval) describing the benefit of a third  booster dose in LTCFs; it reported relative rate reductions of 71% for infection and 80%, for hospitalisation in the period after booster roll-out. However, individual-level VE estimates by time since vaccination were not reported, and adjustment for prior infection was not undertaken.

Overall, there was a paucity of data on non-mRNA vaccines, waning of immunity over time after two doses, and VE following a third (booster) dose in LTCF populations, which we address in this study.

Added value of this studyWe report findings from a prospective cohort study that includes 15,518 residents and 19,515 staff from 331 LTCFs across England, who underwent routine PCR testing 2-3 times per month, looking at SARS-CoV2 vaccine effectiveness over 12 months (Dec 8, 2020-Dec 11, 2021), which is the longest duration of follow-up of any study within this vulnerable cohort. We evaluated the effectiveness of first, second, and booster vaccine doses of AstraZeneca, Pfizer, and Moderna against infection, hospitalisation, and death over the 12 months when the Alpha and Delta variants were dominant. Our findings affirm that complete vaccination with two doses of AstraZeneca or mRNA vaccines offers moderate protection against infection, and high protection against severe clinical outcomes, however this protection declines over time, particularly for residents. A third booster dose of an mRNA vaccine restores, and indeed maximises, VE to 71{middle dot}6% (53{middle dot}5, 82{middle dot}7) and 78{middle dot}3% (70{middle dot}1, 84{middle dot}3) against infection, and 89{middle dot}9% (80{middle dot}0, 94{middle dot}6) and 95{middle dot}8% (50{middle dot}4, 99{middle dot}6) against hospitalisation, for residents and staff respectively, and to 97{middle dot}5% (88{middle dot}1, 99{middle dot}5) against death for residents, with similar protection offered after the third dose irrespective of primary course type.

This is the first study to examine and describe waning of immunity over a one-year period, as well as vaccine effectiveness of a booster dose, in a large cohort of LTCF staff and residents.

Implications of all the available evidenceTaken together, our findings indicate high short-term immunity against SARS-CoV2 infection and very high immunity against severe clinical outcomes of COVID-19 for LTCF residents and staff following vaccination. However substantial waning in vaccine-derived immunity is seen beyond 3 months, irrespective of vaccine type, suggesting the need for regular boosting to maintain protection in this vulnerable cohort. Although this analysis took place in the pre-Omicron period, these trends of waning immunity over time are likely to be generalisable across variants, carrying important implications for long-term vaccination policy in LTCFs. Ongoing surveillance in this vulnerable cohort remains crucial, in order to describe further changes in vaccine-induced immunity, particularly in the context of new variants.


title: Identification and Quantification of Bioactive Compounds Suppressing SARS-CoV-2 Signals in Wastewater-based Epidemiology Surveillance

abstract: Recent SARS-CoV-2 wastewater-based epidemiology (WBE) surveillance have documented a positive correlation between the number of COVID-19 patients in a sewershed and the level of viral genetic material in the wastewater. Efforts have been made to use the wastewater SARS-CoV-2 viral load to predict the infected population within each sewershed using a multivariable regression approach. However, reported clear and sustained variability in SARS-CoV-2 viral load among treatment facilities receiving industrial wastewater have made clinical prediction challenging. Several classes of molecules released by regional industries and manufacturing facilities, particularly the food processing industry, can significantly suppress the SARS-CoV-2 signals in wastewater by breaking down the lipid-bilayer of the membranes. Therefore, a systematic ranking process in conjugation with metabolomic analysis was developed to identify the wastewater treatment facilities exhibiting SARS-CoV-2 suppression and identify and quantify the chemicals suppressing the SARS-COV-2 signals. By ranking the viral load per diagnosed case among the sewersheds, we successfully identified the wastewater treatment facilities in Missouri, USA that exhibit SARS-CoV-2 suppression (significantly lower than 5 x 1011 gene copies/reported case) and determined their suppression rates. Through both untargeted global chemical profiling and targeted analysis of wastewater samples, 40 compounds were identified as candidates of SARS-CoV-2 signal suppression. Among these compounds, 14 had higher concentrations in wastewater treatment facilities that exhibited SARS-CoV-2 signal suppression compared to the unsuppressed control facilities. Stepwise regression analyses indicated that 4-nonylphenol, palmitelaidic acid, sodium oleate, and polyethylene glycol dioleate are positively correlated with SARS-CoV-2 signal suppression rates. Suppression activities were further confirmed by incubation studies, and the suppression kinetics for each bioactive compound were determined. According to the results of these experiments, bioactive molecules in wastewater can significantly reduce the stability of SARS-CoV-2 genetic marker signals. Based on the concentrations of these chemical suppressors, a correction factor could be developed to achieve more reliable and unbiased surveillance results for wastewater treatment facilities that receive wastewater from similar industries.

category: epidemiology


title: Associations between maternal infections during pregnancy and childhood IQ scores using the ALSPAC birth cohort

abstract: Maternal prenatal infections have been linked to childrens neurodevelopment and cognitive outcomes. It remains unclear, however, whether infections occurring during specific vulnerable gestational periods can affect childrens cognitive outcomes. The study aimed to examine maternal infections in each trimester of pregnancy and associations with childrens verbal, performance, and total IQ scores. The ALSPAC birth cohort was used to investigate associations between maternal infections in pregnancy and childhood IQ outcomes. Infection data from mothers and cognition data from children were included with the final study sample size comprising 7,410 mother-child participants. Regression analysis was used to examine links between maternal infections occurring at each trimester of pregnancy and childrens cognitive IQ scores at 18 months, 4 years, and 8 years. Infections in the third trimester were significantly associated with decreased verbal IQ at age 4 (p<.05, adjusted R2 = .004); decreased verbal IQ (p<.01, adjusted R2 = .001), performance IQ (p<.01, adjusted R2 = .0008), and total IQ at age 8 (p<.01, adjusted R2 = .001). Results suggest that later maternal infections could have a latent effect on cognitive development, only emerging when cognitive load increases over time, though magnitude of effect appears to be small. Performance IQ may be more vulnerable to trimester-specific exposure to maternal infection as compared to verbal IQ. Future research could include examining potential mediating mechanisms on childhood cognition, such as possible moderating effects of early childhood environmental factors, and if effects persist in future cognitive outcomes.


title: Accumulation of dihydrosphingolipids and neutral lipids is related to steatosis and fibrosis damage in human and animal models of non-alcoholic fatty liver disease

abstract:
BackgroundDihydrosphingolipids are lipid molecules biosynthetically related to ceramides. An increase in ceramides is associated with enhanced fat storage in the liver and inhibition of their synthesis is reported to prevent the appearance of steatosis in animal models. However, the precise association of dihydrosphingolipids with non-alcoholic fatty liver disease (NAFLD) is yet to be established. We employed a diet-induced NAFLD mouse model to study the association between this class of compounds and disease progression.

MethodsMice were fed a high-fat diet enriched in cholesterol and supplemented with glucose and fructose up to 40 weeks. A mouse subgroup was treated with carbon tetrachloride to accelerate fibrosis development. Animals were sacrificed at different time-points to reproduce the full spectrum of histological damage found in human disease, including steatosis (NAFL) and steatohepatitis (NASH) with and without significant fibrosis. Blood and liver tissue samples were obtained from patients (n=195) whose NAFLD severity was assessed histologically. Lipidomic analysis was performed using liquid chromatography-tandem mass spectrometry.

ResultsTriglyceride, cholesterol ester and dihydrosphingolipid levels were increased in the liver of model mice in association with the degree of steatosis. Dihydroceramide concentrations increased with the histological severity of the disease in liver samples of mice (0.024 {+/-} 0.003 vs 0.049 {+/-} 0.005, non-NAFLD vs NASH-fibrosis, p<0.0001) and patients (0.105 {+/-} 0.011 vs 0.165 {+/-} 0.021, p=0.0221). Several dihydroceramide and dihydrosphingomyelin species were increased in plasma of NAFLD patients and correlated with accumulation of liver triglycerides.

ConclusionsDihydrosphingolipids accumulate in the liver in response to increased free fatty acid overload and are correlated with progressive histological damage in NAFLD. The increase in dihydrosphingolipids is related to upregulation of hepatic expression of enzymes involved in de novo synthesis of ceramides.

HIGHLIGHTSO_LINeutral lipids and dihydrosphingolipids accumulate in liver in correlation with the histological severity of NAFLD in both mice and humans.
C_LIO_LIThe ceramide pathway is stimulated to alleviate the free fatty acid excess in liver of NAFLD models.
C_LIO_LIAppearance of significant fibrosis is associated with reduced concentrations of neutral lipids but not dihydrosphingolipids in a mouse model of NAFLD.
C_LI

category: gastroenterology


title: Preliminary Rasch analysis of the Multidimensional Assessment of Interoceptive Awareness in adults with stroke

abstract:
PurposeThe Multidimensional Assessment of Interoceptive Awareness (MAIA) measures interoceptive body awareness, which includes aspects such as attention regulation, self-regulation, and body listening. Our purpose was to validate the MAIA in adults with stroke using Rasch Measurement Theory.

MethodsThe original MAIA has 32 items grouped into eight separately scored subscales that measure aspects of body awareness. Using Rasch Measurement Theory, we evaluated the unidimensionality of the entire scale and investigated person and item fit, person separation reliability, targeting, local item dependence, and principal components analysis of residuals.

ResultsForty-one adults with chronic stroke (average 3.8 years post-stroke, 13 women, and average age, 57{+/-}13 years) participated in the study. Overall fit (X2=62.26, p=0.26) and item fit were obtained after deleting 3 items and rescoring 26 items. One participant did not fit the model (2.44%). There were no floor (0.00%) or ceiling effects (0.00%). Local item dependence was found in 42 pairs. The person separation reliability was 0.91, and the person mean location was 0.06{+/-}1.12 logits.

ConclusionsThe MAIA demonstrated good targeting and reliability, as well as good item and person fit in adults with chronic stroke. A study with a larger sample size is needed to validate our findings.

category: rehabilitation medicine and physical therapy


title: Distinct immune-effector and metabolic profile of CD8+ T Cells in patients with autoimmune polyarthritis induced by therapy with immune-checkpoint inhibitors

abstract:
ObjectivesRheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI-therapy improves CD8+ T cell (CD8) function, but CD8 contribute to chronic inflammation in autoimmune arthritis (AA). Thus, we studied whether immune-functional and metabolic changes in CD8 explain the development of musculoskeletal irAE in ICI-treated patients.

MethodsPeripheral CD8 obtained from ICI-treated patients with and without musculoskeletal irAEs and from AA-patients with and without history of malignancy were stimulated in media containing 13C-labeled glucose with and without Tofacitinib. Changes in metabolism, immune-mediator release, expression of effector cell-surface molecules, and inhibition of tumor cell growth were quantified.

ResultsCD8 from irAE patients showed significantly lower frequency and expression of cell-surface molecules characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and pro-inflammatory immune-mediators compared to CD8 from ICI-patients who did not develop irAE. This was accompanied by a lower glycolytic rate. Gene-expression analysis of pre-ICI-treated CD8 revealed over 30 differentially expressed transcripts in patients who later developed musculoskeletal irAEs. In vitro Tofacitinib treatment did not significantly change the immune-metabolic profile nor the capacity to inhibit the growth of the human lung-cancer cell-line H838.

ConclusionsOur study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE have a distinct immune-effector and metabolic profile from those that remain irAE-free. This specific irAE profile overlaps with the one observed in CD8 from AA-patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs.

Key messages

What is already known about this subject?O_LIImmune-checkpoint inhibition (ICI) therapies have a high success rate regarding progression free and overall survival of cancer patients. However, up to 20% of the ICI-treated patients develop musculoskeletal immune-related adverse events (irAE) that are often associated with severely reduced quality of life.
C_LIO_LITo avoid precocious ICI-treatment termination, strategies to treat rheumatic irAE have to be simultaneously efficient in curbing musculoskeletal symptoms without interfering with the antitumoral therapy.
C_LIO_LICD8+ T cells play a pivotal role both in arthritis pathogenesis and antitumoral responses.
C_LI

What does this study add?O_LIImmuno-functional and metabolic analysis of peripheral CD8+ T cells from patients with musculoskeletal irAEs revealed that they share a common profile with those from patients with chronic autoimmune polyarthritis (AA) but are distinct from ICI-treated patients who remained irAE-free.
C_LIO_LICD8+ T cells from irAE patients treated in vitro with the JAK-pathway inhibitor Tofacitinib still maintained the capacity to release cytokines and cytolytic molecules, express immune-effector cell surface molecules, and prevent the growth of a human lung-cancer cell line.
C_LI

How might this impact on clinical practice or future developments?O_LIThe specific immuno-functional and metabolic profile in rheumatic irAEs and its overlap to AA-profile is a potential starting point for a better understanding of the pathogenesis and identification of ICI-patients at risk of developing an irAE.
C_LIO_LIJAK inhibitors may expand the thus far limited therapeutic armamentarium to cope with severe, refractory and / or chronical rheumatic irAEs.
C_LI

category: rheumatology


title: The Social Factors, Epigenomics, and Lupus in African American Women (SELA) study: protocol for an observational mechanistic study examining the interplay of multiple individual and social factors on lupus outcomes in a health disparity population

abstract:
IntroductionDespite the disproportional impact of systemic lupus erythematosus (SLE) on historically marginalized racial and ethnic communities, the individual and sociocultural factors underlying these health disparities remain elusive. We report the design and methods for a study aimed at identifying the epigenetic mechanisms by which risk and resiliency social factors affect gene function and thereby influence SLE in a health disparity population.

Methods and analysisThe Social Factors, Epigenomics, and Lupus in African American Women (SELA) study is a cross-sectional, case-control study involving the Medical University of South Carolina, Emory University, and Wake Forest School of Medicine. A total of 600 self-reported African American females will be invited to participate. All participants will respond to questionnaires that capture detailed sociodemographic and medical history, validated measures of racial discrimination, vicarious racism stress, social support, healthcare utilization and lost productivity, as well as disease activity and damage for cases. Physician-reported disease activity will also be incorporated Participants will choose if they wish to receive their genetic ancestry estimates and be involved in research. Blood samples are required to provide serum, plasma, PBMCs counts, DNA and RNA. The primary goals of SELA are to identify variation in DNA methylation (DNAm) associated with self-reported exposure to racial discrimination and exposure to social support, to evaluate whether social DNAm sites affect gene expression, to identify the synergistic effects of social factors on DNAm changes on SLE, and to develop a social factors-DNAm predictive model for disease outcomes. This study was approved by and will be conducted in cooperation with the Sea Island Families Project Citizen Advisory Committee.

Discussion and disseminationSELA will respond to the pressing need to identify the regulatory mechanisms through which social exposures influence SLE in a health disparity population, clarify the interplay and underlying mechanism by which various positive and negative social determinants of health influence epigenomic variation, and how the resulting biological changes may contribute to the lupus health disparity. Results will be published and shared with patients and the community. These findings may inform the development of psychosocial interventions that prevent or mitigate risk exposures, and services or interventions that promote positive exposures. Development of these novel treatments and preventative interventions, as informed by the results of this study, is paramount to the closure of the health disparities gap.


title: Parkinson's disease causality and heterogeneity: a proteogenomic view

abstract:
Pathogenesis and clinical heterogeneity in Parkinsons disease (PD) have been evaluated from genetic, pathological, and clinical perspective. Technology allowing for high-throughput proteomic analyses in cerebrospinal fluid (CSF) has opened new opportunities to scrutinize this heterogeneity. This is to date the most comprehensive proteomics profiling in CSF of PD patients and controls, both in terms of subjects (n=1103) and proteins (n=4135).

Combining CSF aptamer-based proteomics with genetics across all samples we determined the protein quantitative trait loci (pQTLs) linking genetic variants with protein abundance in CSF. Analyzing pQTLs together with summary statistics from the largest PD genome wide association study (GWAS) led us to identify 68 potential causal proteins by Mendelian randomization. The top PD causal protein, GPNMB, has colocalization support and has been reported to be upregulated in the substantia nigra of PD patients.

We also examined three subcohorts of PD patients: LRRK2 variant carriers (LRRK2+), GBA variant carriers (GBA+) and idiopathic PD patients, each with their respective controls. The second goal was to identify proteomic differences between PD patients and controls within and between the three subcohorts. Statistical analyses revealed six proteins differentially expressed when comparing GBA+ PD patients with unaffected GBA+ controls, seven proteins when comparing LRRK2+ PD patients with unaffected LRRK2+ controls and 23 proteins when comparing idiopathic PD patients with healthy controls who did not carry any severe PD mutations.

Furthermore a hypothesis-free stratification of idiopathic PD patients based on their proteomic profile revealed two protein modules based on the co-expression network structure. Based on these modules, cluster analysis revealed two patient endotypes for idiopathic PD.

Differences in the CSF proteomic signature between subcohorts and between idiopathic endotypes, as well as causal targets identified using both proteomics and genetics may together influence the way we approach the identification of potential therapeutic targets in PD.


title: Digital gait biomarkers, but not clinical ataxia scores, allow to capture 1-year longitudinal change in Spinocerebellar ataxia type 3 (SCA3)

abstract: Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time-frames (e.g. one year). We present the first multi-center longitudinal gait analysis study in spinocerebellar ataxias (SCAs). We performed a combined cross-sectional (n=28) and longitudinal (1-year interval, n=17) analysis in SCA3 subjects (including 7 pre-ataxic mutation carriers). Longitudinal analysis revealed significant change in gait measures between baseline and 1-year follow-up, with high effect sizes (stride length variability: p=0.01, effect size rprb=0.66; lateral sway: p=0.007, rprb=0.73). Sample size estimation for lateral sway reveals a required cohort size of n=43 for detecting a 50% reduction of natural progression, compared to n=240 for the clinical ataxia score SARA. These measures thus present promising motor biomarkers for upcoming interventional studies.


title: Deciphering the heterogeneous niche in the tumor progression of hepatocellular carcinoma: a Spatial single-cell landscape and multi-omics atlas analysis

abstract: Hepatocellular carcinoma (HCC) is an invasive disease which is characteristic with highly heterogeneous molecular phenotype, rich blood supply, and unique immune niche, therefore it is of great significance to explore the tumor heterogeneous niche and clonal evolution progress of these malignant cells. Based on the advance in single-cell technology, spatial transcriptome technology, and Oxford nanopore technology, this study innovatively reconstructed and delineated the heterogeneity of the HCC tumor niche and its tumor progression pattern. Our results showed that the copy number variation (CNV) of cells in cancer lesions and liver cirrhosis lesions of the same patient is basically the same and is mainly regulated by transcription factors such as TP53, HOXA7, FOXN3, and PPARG, suggests that malignant cells of common origin gradually evolve into different lesions in a very rare numbers of different CNVs, which are mainly regulated by expression patterns and mediate the heterogeneity between the tumor and cirrhosis lesions. Angiogenesis-related genes (SREBF1, ZNF585A, and HOXB5) may mediate communication between HCC subpopulations and endothelial cells via exosomes, thereby contributing to the angiogenic niche before HCC metastasis. In addition, numerous CNVs were found in patients with early recurrent HCC, and these mutated genes is the potential niche genes for the early tumor recurrence. In summary, this study provides a general transcriptional landscape of the ecological structure of HCC, systematically maps the molecular, cellular, and spatial composition of different HCC cell niches, and provides a scientific and theoretical basis at the molecular and cellular levels for personalized and accurate treatment strategies for HCC.

category: oncology


title: Higher polygenic risk for melanoma is associated with improved survival

abstract:
BackgroundAlthough there are well-known prognostic factors for survival from cutaneous melanoma (CM) such as primary tumour thickness and stage of the tumour at diagnosis, the role of germline genetic factors in determining survival is not well understood.

ObjectiveTo perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS.

MethodsWe conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia (MIA; 5,762 patients with melanoma; 800 deaths from melanoma) and UK Biobank (UKB: 5,220 patients with melanoma; 241 deaths from melanoma). The GWAS were adjusted for age, sex and the first ten genetic principal components, and combined in a fixed-effects inverse-variance-weighted meta-analysis. Significant (P<5x10-8) results were investigated in the Leeds Melanoma Cohort (LMC; 1,947 patients with melanoma; 370 melanoma deaths). We also developed a CM-susceptibility PRS using a large independent GWAS meta-analysis (23,913 cases, 342,870 controls). The PRS was tested for an association with MSS in the MIA and UKB cohorts, with replication in the LMC.

ResultsTwo loci were significantly associated with MSS in the meta-analysis of MIA and UKB with lead SNPs rs41309643 (G allele frequency 1.6%, hazard ratio [HR] 2.09, 95% confidence interval [CI] 1.61-2.71, P=2.08x10-8) on chromosome 1, and rs75682113 (C allele frequency 1.8%, HR=2.38, 95% CI=1.77--3.21, P=1.07x10-8) on chromosome 7. While neither SNP replicated (P>0.05) in the LMC, rs75682113 was significantly associated in the combined discovery and replication sets and requires confirmation in additional cohorts.

After adjusting for age at diagnosis, sex and the first ten principal components, a one standard deviation increase in the CM-susceptibility PRS was associated with improved MSS in the discovery meta-analysis (HR=0.88, 95% CI=0.83--0.94, P=6.93x10-5; I2=88%). The association with the PRS was not replicated (P > 0.05) in LMC, but remained significantly associated with MSS in the meta-analysis of the discovery and replication results.

ConclusionWe found two loci potentially associated with MSS, and evidence that increased germline genetic susceptibility to develop CM may be associated with improved MSS.


title: The effect of focused muscle contraction therapy on chronic pain and Brodmann Area activity in former National Football League players

abstract: NFL players have a traumatic injury rate approaching 100%; chronic pain with decreased concentration occur commonly. This study examined the role of a novel focused muscle contraction therapy for the treatment of chronic pain and identified its impact on brain activity. Chronic pain was assessed by numerical score, neuropathic component, and impact on daily activities in 8 retired players. Brain activity was characterized by QEEG with low-resolution electromagnetic tomography analysis and functional measures of visual and auditory attention. Focused muscle contraction muscle therapy administered twice weekly for 6 months was tapered to twice monthly by 12 months. Brodmann Areas (BA) 4 and 9, known to associate with chronic pain, showed values outside the clinically normal range; mean pain duration was 16.5 {+/-} 12.9 years. At 6 months, 5/8 subjects reported pain scores of 0. High beta wave activity was seen in BA 19, 21, 29, 30, and 39, affecting auditory, visual, and body perceptions. Clinically relevant improvements were observed in auditory attention and visual stamina. Pain relief was sustained through 18 months of follow-up. Focused muscle contraction therapy appears to redirect brain activity to new areas of activity which are associated with long-lasting relief of chronic pain and its detriments. This study was registered with clinicaltrial.gov #NCT04822311.

category: pain medicine


title: The impact of the one child policy on China's infant mortality from 1970-1989: A quasi-experimental study

abstract:
BackgroundChinas One Child Policy (OCP), enforced in 1980, was the largest fertility control policy in human history, and its effects are still widely debated. Previous analyses of the OCP have focused on population reduction and sex ratios, among others. This study evaluates the impact of the OCP on infant mortality in China using quasi-experimental methods.

MethodsCountry-level panel data for China and 106 other countries were extracted from the World Bank data repository for the years 1970-1989. The primary outcome was infant mortality rate (IMR) defined as deaths among children <1 year of age per 1000 live births. The impact of the OCP was estimated using uncontrolled and controlled interrupted time series (ITS) designs that control for within group time varying characteristics. Models were further adjusted for a comprehensive set of covariates and corrected for first-order autocorrelation. Countries included in the control groups were identified using the method of synthetic controls and propensity score matching (PSM). Valid control groups reduced threats from selection bias and unobserved time invariant confounders.

ResultsAdjusting for GDP per capita, GDP growth, womens education, and population density, IMR decreased on average by 2.5 deaths per 1,000 annually before the OCP was enforced in China. The pre-OCP trends in IMR moved in tandem across China, synthetic and PSM controls, validating the parallel trends assumption. After the OCP, the trend in IMR in China increased by 2.24 (95% CI 1.39-3.09) per year, compared to the IMR trend in the pre-OCP period, comparing differences in China to synthetic controls. Results were similar and confirmed across PSM (1.96, 0.56-3.37) and uncontrolled ITS (2.14, 1.39-2.89) models. No significant immediate level change in IMR was observed in the controlled ITS models.

ConclusionsThe reduction in IMR slowed down significantly after the OCP was enforced in China. The slowdown is likely due to a relative increase in the ratio of the IMR of females to males suggesting that practices such as female infanticide, abandonment, and neglect, stemming from a strong son preference were primary contributors. Coercive policies to reduce fertility can have unintended consequences.


title: Vaccine-induced antibody level predicts the clinical course of breakthrough infection of COVID-19 caused by delta and omicron variants: a prospective observational cohort study

abstract:
BackgroundOmicron variant viruses spread rapidly, even in individuals with high vaccination rates. This study aimed to determine the utility of the antibody against the spike protein level as a predictor of the disease course of COVID-19 in vaccinated patients.

MethodsBetween 11 December 2021 and 10 February 2022, we performed a prospective observational cohort study in South Korea, which included patients infected with delta -and -omicron variants. Multivariable logistic regression analysis to determine the association between antibody levels and the outcomes was conducted.The relationship between antibody levels and cycle threshold (Ct) values was confirmed using a generalised linear model.

ResultsFrom 106 vaccinated patients (39 delta and 67 omicron), the geometric mean titres of antibodies in patients withfever ([≥]37.5 {degrees}C), hypoxia ([≤]94% of SpO2), pneumonia, C-reactive protein (CRP) elevation (>8 mg/L), or lymphopenia (<1,100 cells/L) were 1,201.5 U/mL, 98.8 U/mL, 774.1 U/mL, 1,335.1 U/mL, and 1,032.2 U/mL, respectively. Increased antibody levels were associated with a decrease in the fever occurrence (adjusted odds ratio [aOR], 0.23; 95% confidence interval [CI], 0.12-0.51), hypoxia (aOR, 0.23; 95% CI, 0.08-0.7), CRP elevation (aOR, 0.52; 95% CI, 0.29-0.0.94), and lymphopenia (aOR, 0.57; 95% CI, 0.33-0.98). Ct values showed a positive correlation between antibody levels (P =0.02).

ConclusionAntibody levels are predictive of the clinical course of COVID-19 in vaccinated patients with delta and omicron variant infections. Our data highlight the need for concentrated efforts to monitor patients with SARS-CoV-2 infection who are at risk of low antibody levels.

SummaryIn this prospective observation cohort study, antibody level predicts clinical course of breakthrough infection of COVID-19. Fever (aOR 0.23[0.12-0.51], hypoxia (aOR 0.23[0.08-0.7]), CRP elevation(aOR 0.52[0.29-0.0.94] and lymphopenia (aOR 0.57[0.33-0.98]) were inversely correlated with antibody levels.


title: Bacterial culture use, etiology and antibiotic susceptibility of common bacterial infections in Indonesian hospitals in 2019

abstract:
ObjectivesTo describe the use of bacterial cultures, and the etiology and antibiotic susceptibility of common high-priority bacteria isolated from hospitalized patients in Jakarta, Indonesia.

MethodsWe conducted a hospital-wide cross-sectional study of all inpatients receiving systemic antibiotic treatment (WHO ATC J01) in six hospitals in 2019, capturing routine data on antibiotic treatment and cultures. We reported bug-drug combinations for Escherichia coli and the ESKAPE group of bacteria.

Results562 patients (52% women, median age 46 years) had 587 diagnoses, with pneumonia (258, 44%) most common. One or more culture specimens were taken in 38% (215/562) overall, a sputum culture in 25% (64/258) of pneumonia patients; and a blood culture in 52% (16/31) of sepsis patients. 50% of positive blood culture results were reported after 4 days. From 670 culture specimens, 279 bacteria were isolated, 214 (77%) were Gram-negative, including Klebsiella pneumoniae (70, 25%), Pseudomonas aeruginosa (36, 13%), and E. coli (21, 11%). Resistance included third-generation cephalosporin-resistant K. pneumoniae (77%), E. coli (65%) and Enterobacter spp (81%); carbapenem-resistant K. pneumoniae (26%), P. aeruginosa (24%), E. coli (33%), Acinetobacter spp (57%), and Enterobacter spp (60%); and meticillin-resistant S. aureus (71%). Vancomycin-resistant S. aureus (0%) and Enterococcus faecalis (12%) were uncommon. Multi-drug resistance was 30% for K. pneumoniae, 29% for P. aeruginosa, 49% for E. coli, 42% for Acinetobacter spp, and 71% for S. aureus.

ConclusionsIn Indonesian hospitals, bacterial cultures were underused and antibiotic resistance is at alarming levels. Enhanced context-specific infection prevention, diagnostic and antibiotic stewardship interventions are urgently needed.


title: Methadone Distribution Increased from 2010 to 2019 for Opioid Use Disorder Treatment in the US

abstract:
ObjectivesTo identify US prescription trends in methadone distribution for OUD from 2010 to 2020.

MethodsThe weight of methadone in grams distributed to OTPs per state was derived from the US Drug Enforcement Administrations Automated Reports and Consolidated Ordering System. Methadone was adjusted for state population and compared across all fifty states and Washington DC from 2010 to 2020.

ResultsThe overall distribution of methadone to OTPs significantly (P < 0.0001) increased from 2010 to 2019 (+61.0%) and from 2015 to 2020 (+26.22%). The states with the highest percent change from 2010 to 2020 were Montana (+897.02%), Alaska (+421.11%), and Vermont (+353.67%). In contrast with prior increase of distribution, from 2019 (pre-COVID-19 pandemic) to 2020 (during pandemic), there was no significant change in the distribution of methadone to OTPs (-0.09%). Ohio (+26.02%) significantly increased while Alabama (-21.96%), New Hampshire (-24.13%) and Florida (-28.97%) significantly decreased methadone relative to the national mean.

ConclusionsThis investigation revealed two trends related to methadone distribution in the US: increased utilization over the past decade and a plateau in utilization from 2019 to 2020. Policies are needed to remove access barriers to methadone treatment during the COVID-19 pandemic in order to reduce the worsening crisis of opioid overdoses in the US.

category: addiction medicine


title: Long COVID and its associated factors among COVID survivors in the community from a middle-income country: an online cross-sectional study

abstract:
IntroductionPatients with COVID-19 usually recover and return to normal health, however some patients may have symptoms that last for weeks or even months after recovery. This persistent state of ill health is known as Long COVID if it continues for more than 12 weeks and are not explained by an alternative diagnosis. Long Covid has been overlooked in low and middle income countries. Therefore, we conducted an online survey among the COVID-19 survivors in the community to explore their Long COVID symptoms, factors associated with Long COVID and how Long COVID affected their work.

MethodsThis was a cross sectional study conducted from July to September 2021, during the implementation of a nationwide movement control order (MCO). Data was collected using the REDCap electronic data capture tool. The questionnaire was distributed in social and news media. The questionnaire covers information such as socio-demographic characteristics, existing comorbidities, self-perception on health, information on the acute COVID-19 condition and treatment received, symptoms and duration of post-COVID condition and effects on occupation. Results: A total of 732 COVID-19 survivors responded. There were slightly more females (58.7%), younger and more highly educated respondents. More than half of them were overweight or obese and about two third were free of comorbidities. Among these respondents, about 56% were without or with mild symptoms during their acute COVID-19 conditions. A total of 21.1% of the respondents reported to experience Long COVID. The most commonly reported symptoms for Long COVID were fatigue, brain fog, depression, anxiety, insomnia, arthralgia or myalgia. Females had 58% higher odds (95% CI: 1.02, 2.45) of experiencing Long COVID. Patients with moderate and severe levels of acute COVID-19 symptoms had OR of 3.01 (95% CI: 1.21, 7.47) and 3.62 (95% CI: 1.31, 10.03) respectively for Long COVID.

ConclusionThis study provides additional insight on the symptoms and duration of post-COVID symptoms as well as the associated factors with Long COVID among COVID-19 survivors in Malaysia. Recognition of Long COVID and its associated factors is important in planning prevention, rehabilitation, clinical management to improve recovery and long-term COVID-19 outcomes.


title: Disentangling the effect of measures, variants and vaccines on SARS-CoV-2 Infections in England: A dynamic intensity model

abstract: In this paper, we estimate the path of daily SARS-CoV-2 infections in England from the beginning of the pandemic until the end of 2021. We employ a dynamic intensity model, where the mean intensity conditional on the past depends both on past intensity of infections and past realised infections. The model parameters are time-varying and we employ a multiplicative specification along with logistic transition functions to disentangle the time-varying effects of non-pharmaceutical policy interventions, of different variants and of protection (waning) of vaccines/boosters. We show that earlier interventions and vaccinations are key to containing an infection wave. We consider several scenarios that account for more infectious variants and different protection levels of vaccines/boosters. These scenarios show that, as vaccine protection wanes, containing a new wave in infections and an associated increase in hospitalisations in the near future will require further booster campaigns and/or non-pharmaceutical interventions.


title: Amputation in Kingdom of Saudi Arabia: Etiology, Characteristics and Clinical status from a Large Tertiary Rehabilitation Center

abstract:
IntroductionLimb amputation significantly impacts the patients physical, emotional, and social life. Multiple etiological factors may lead to limb amputation. Unfortunately, there is limited data about amputation in Saudi Arabia. Since Sultan Bin Abdulaziz Humanitarian City (SBAHC) is a tertiary centre receiving such patients, we collected data from ten years to look at the etiology, characteristics, and clinical impact of amputations in the Kingdom.

MethodsA retrospective study of 1409 amputee patients data at SBAHC collected over ten years included demographic variables, etiology, site, level, and type of amputation. We also collected Functional independent measurement (FIM) scores for 618 patients.

ResultMales constitute the majority of amputees (75.7%) and the average age in males was higher in males compared to females (45 vs 36 years respectively, p<0.001). Vascular diseases (42.3%) and Trauma (36.8%) were the leading cause of amputation in this cohort. Diabetes mellitus was the most frequent comorbidity (40.5%), followed by hypertension (26.2%). Transtibial amputations were the most typical (22.58%), followed by trans-femoral amputation (14.12%). Traumatic trans-femoral amputation was more prevalent among young adults than traumatic trans-tibial amputation. Trauma-related amputation cases were highest in the age group of 21-30 years (69.2%), while vascular related amputations were highest in the age group of 70 and above years (89.5%). FIM scores improved significantly in locomotion (33.6%) followed by transfer (30.6%) and self-care (16.4%) at six-month post discharge compared to admission (all p-values<0.01).

ConclusionVascular pathology arising due to chronic diseases is the primary risk factor that may lead to amputation and warrant primary and secondary prevention programs. Seatbelt enforcement can significantly decrease amputation related to Road Traffic Accidents, which has been the second most familiar cause of amputation.


title: A Pilot Validation Study Comparing FIBI, a Slide-Free Imaging Method, with Standard FFPE H&E Tissue Section Histology for Primary Surgical Pathology Diagnosis

abstract:
IntroductionDigital pathology whole slide images (WSI) have been recently approved by the FDA for primary diagnosis in clinical surgical pathology practices. These WSI are generated by digitally scanning standard formalin-fixed and paraffin-embedded (FFPE) H&E-stained tissue sections mounted on glass microscope slides. Novel imaging methods are being developed that can capture the surface of tissue without requiring prior fixation, paraffin embedding, or tissue sectioning. One of these methods, FIBI (Fluorescence Imitating Brightfield Imaging), an optically simple and low-cost technique, was developed by our team and used in this study.

Methods100 de-identified surgical pathology samples were obtained from the UC Davis Health Pathology Laboratory. Samples were first digitally imaged by FIBI, and then embedded in paraffin, sectioned at 4 {micro}m, mounted on glass slides, H&E stained, and scanned using the Aperio/Leica AT2 scanner. The resulting digital images from both FIBI and H&E scan sets were uploaded to PathPresenter and viewed in random order and modality (FIBI or H&E) by each of 4 reading pathologists. After a 30-day washout, the same 100 cases, in random order, were presented in the alternate modality to what was first shown, to the same 4 reading pathologists. The data set consisted, therefore, of 100 reference diagnoses and 800 study pathologist reads (400 FIBI and 400 H&E). Each study read was compared to the reference diagnosis for that case, and also compared to that readers diagnosis across both modalities for each case. Categories of concordance, minor and major discordance were adjudicated by the study team based on established criteria.

ResultsThe combined category, concordance or minor discordance, was scored as "no major discordance." The overall agreement rate (compared to the reference diagnosis), across 800 reads, was 97.9%. This consisted of 400 FIBI reads at 97.0% vs. reference and 400 H&E reads vs. reference at 98.8%. Minor discordances (defined as alternative diagnoses without clinical treatment or outcome implications) were 6.1% overall, 7.2% for FIBI and 5.0% for HE.

ConclusionsPathologists without specific experience or training in FIBI imaging interpretation can provide accurate diagnosis from FIBI slide-free images. Concordance/discordance rates are similar to published rates for comparisons of WSI to standard light microscopy of glass slides for primary diagnosis that led to FDA approval. The present study was more limited in scope but suggests that a follow-on formal clinical trial is feasible. It may be possible, therefore, to develop a slide-free, non-destructive approach for primary pathology diagnosis. Such a method promises improved speed, reduced cost, and better conservation of tissue for advanced ancillary studies.

category: pathology


title: The changing impact of vaccines in the COVID-19 pandemic

abstract: The Omicron wave has left a global imprinting of immunity which changes the COVID landscape. In this study, we simulate six hypothetical variants emerging over the next year and evaluate the impact of existing and improved vaccines. We base our study on South Africas infection- and vaccination-derived immunity. Our findings illustrate that variant-chasing vaccines will only add value above existing vaccines in the setting where a variant emerges if we can shorten the window between variant introduction and vaccine deployment to under three weeks, an impossible time-frame without significant NPI use. This strategy may have global utility, depending on the rate of spread from setting to setting. Broadly neutralizing and durable next-generation vaccines could avert over three-times as many deaths from an immune-evading variant compared to existing vaccines. Our results suggest it is crucial to develop next-generation vaccines and redress inequities in vaccine distribution to tackle future emerging variants.


title: KNOWLEDGE OF AND PRACTICES AROUND ZOONOTIC DISEASES AMONGST ACTORS IN THE LIVESTOCK TRADE IN THE LAKE VICTORIA CRESCENT ECOSYSTEM IN EAST AFRICA

abstract:
BackgroundZoonotic diseases pose a direct threat to health and undercut livelihoods in the communities in which they occur. A combination of anthropogenic, animal, and ecosystem activities drives the emergence and re-emergence of zoonotic diseases. Consequently, One Health approaches are necessary to alleviate disease impacts. To be effective, understanding peoples Knowledge, Attitudes, and Practices concerning these disease threats are essential for their prevention, control, and eventual elimination. Livestock traders interact closely with livestock, which puts these traders at high risk of infection and creates conditions by which they may spread zoonotic pathogens through the animals they trade. It is, thus, essential to examine practices among actors involved in livestock trade to understand how well to mitigate these risks in a non-pastoral production system.

MethodsBusia County was selected for this study because it is a predominantly crop-producing area, with cross-border (between Kenya and Uganda) trade in livestock. A qualitative study was conducted among the actors in the livestock trade on their knowledge, attitudes, and practices that may contribute to the spread, control, and prevention of zoonotic disease transmission. A thematic analysis framework was used to categorize and synthesize data from In-depth interviews (IDIs) and the Key informant interviews(KIIs).

ResultsWhereas participants could list the signs of zoonotic diseases, they could not identify these diseases by name, which, demonstrates insufficient knowledge of zoonosis. Brucellosis, Foot and Mouth Disease (FMD), and Anthrax were broadly mentioned as diseases of importance by many actors this shows that they are the common livestock diseases in the area. The actors identified sick animals by checking for dropped ears, mass mucus production; diarrhea; bloody urinal discharge; and general animal activity levels, an animal that is not actively eating or walking will be a sign of sickness. To manage the spread of these diseases, they wash their animals, isolate sick animals from the rest of the stock; vaccinate their animals against certain diseases as preventive practices, they also seek help from animal health professionals for the sick animals as curative practices. The practices of skinning dead animals before burying them and the consumption of dead carcasses risk the increase of zoonotic disease transmission. These practices are drawn from cultural values and beliefs about the curses and potential loss of entire stock if livestock is unceremoniously disposed of upon death, irrespective of the cause.

Conclusions and recommendationsLivestock actors have agency in the prevention and elimination of zoonotic diseases, hence, they need to be involved when developing intervention programs and policies for the extension services. Training these actors as a continuum of animal health workers blends lay and professional knowledge, which alongside their intense contact with large numbers of animals, becomes a critical disease surveillance tool this may also play a role in supporting state actors in disease surveillance and response. There is an urgent need to increase awareness of zoonoses within livestock keepers and traders, these campaigns, need should deploy multi-disciplinary teams with an understanding of human health, animal health, and social scientists so that the risky but deeply rooted traditional practices like skinning and eating dead animals can be minimized.


title: Tau, β-amyloid, and glucose metabolism following service-related Traumatic Brain Injury in Vietnam war veterans: The AIBL-VETS study

abstract:
Traumatic Brain Injury (TBI) is common amongst military veterans and has been associated with an increased risk of dementia. It is unclear if this is due to increased risk for Alzheimers disease (AD) or other mechanisms. This case control study sought evidence for AD, as defined by the 2018 NIA-AA research framework1, by measuring tau, {beta}-amyloid and glucose metabolism using positron emission tomography (PET) in veterans with service-related TBI.

Seventy male Vietnam war veterans -- 40 with TBI (aged 68.0{+/-}2.5 years) and 30 controls (aged 70.1{+/-}5.3 years) -- with no prior diagnosis of dementia or mild cognitive impairment underwent {beta}-amyloid (18F-Florbetaben), tau (18F-Flortaucipir) and 18F-FDG PET. The TBI cohort included 15 participants with mild, 16 with moderate, and 9 with severe injury. {beta}-amyloid level was calculated using the Centiloid (CL) method and tau was measured by Standardized Uptake Value Ratios (SUVR) using the cerebellar cortex as reference region. Analyses were adjusted for age and APOE-e4. The findings were validated in an independent cohort from the ADNI-DOD study.

There were no significant nor trending differences in {beta}-amyloid or tau levels or 18F-FDG uptake between the TBI and control groups before and after controlling for covariates. The {beta}-amyloid and tau findings were replicated in the ADNI-DOD validation cohort and persisted when the AIBL-VETS and ADNI-DOD cohorts were combined (114 TBI vs 87 controls in total). These findings suggest that TBI is not associated with the later life accumulation of the neuropathological markers of AD.


title: Semi-automatic segmentation of the fetal brain from Magnetic Resonance Imaging

abstract: Template-based segmentation techniques have been used for targeting deep brain structures in fetal MR images. In this study, two registration algorithms were compared to determine the optimal strategy of segmenting subcortical structures in T2-weighted images acquired during the third trimester of pregnancy. Adult women with singleton pregnancies (n=9) ranging from 35-39 weeks gestational age were recruited. Fetal MRI were performed on 1.5 T and 3 T scanners. Automatic fetal brain segmentation and volumetric reconstruction algorithms were performed on all subjects using the NiftyMIC software. An atlas of cortical and subcortical structures (36 weeks gestation) was registered into native space using ANTs (Automatic Normalization Tools) and FLIRT (FMRIBs linear image registration tool). The cerebellum and thalamus were manually segmented. Dice coefficients were calculated to validate the reliability of automatic methods and to compare the performance between ANTs (nonlinear) and FLIRT (affine) registration algorithms compared to the gold-standard manual segmentations. The Dice-kappa values for the automated labels were compared using the Wilcoxon test. Comparing cerebellum and thalamus masks against the manually segmented masks, the median Dice-kappa coefficients for ANTs and FLIRT were 0.76 (interquartile range [IQR]= 0.56-0.83) and 0.65 (IQR=0.5-0.73), respectively. The Wilcoxon test (Z=4.9, P<0.01) indicated that the ANTs registration method performed better than FLIRT for the fetal cerebellum and thalamus. We found that a nonlinear registration method, provided improved results compared to an affine transformation. Nonlinear registration methods may be preferable for subcortical segmentations in MR images acquired in third-trimester fetuses.

category: obstetrics and gynecology


title: Effect of working from home on the association between job demands and psychological distress

abstract:
PurposeLimited information is available about the association between workplace psychosocial factors and general mental health status among workers during the COVID-19 pandemic. This study examined how working from home affected the association between job demands and psychological distress (PD).

MethodA cross-sectional online survey was conducted in December 2020 (N=27,036). The dependent variable (PD) was assessed using the Kessler Psychological Distress Scale. Job demands were assessed using the Job Content Questionnaire. Working from home was determined by participants responses to the question: "Do you currently work from home?" We used a two-level regression analysis adjusted for prefecture; each individual-level variable at level 1 was nested into each prefecture at level 2, stratified by working from home or not.

ResultsOverall, 21.3% of participants worked from home. The interaction between working from home and job demands was significant. Job demands were positively associated with PD. The stratified analysis showed the associations were weaker among employees who worked from home compared with those who did not.

ConclusionThe association between job demands and PD may be weakened by working from home.

category: occupational and environmental health


title: The Association of Scoliosis Properties with Spinal Cord Tethering: A Statistical Model for Prognostication

abstract:
ObjectiveTo evaluate the relationship between the structural measures of scoliosis and underlying spinal cord tethering (SCT) and proposing a statistical prognostication model.

Study designCross-sectional.

SettingAcademic healthcare center

Methods128 definite scoliosis cases that were candidates for corrective surgery were enrolled. Anterior-posterior whole column digital radiographs and whole-spine MRI (supine for all samples and adjuvant prone MRI for suspected cases with tight filum terminal) were performed. Univariate and multiple logistic regression were used for the analysis of association and interaction. Association of SCT with structural features of scoliosis -Cobb angle, convexity, and type (idiopathic and congenital)- age, and sex were assessed.

ResultsNone of the study variables showed a statistical association with SCT in univariable and multiple logistic regressions. After inclusion of Cobb angle-convexity-type interaction, higher Cobb angle, idiopathic scoliosis, dextrosoliosis, and male gender had a significant effect. Stratification for convexity discovered a positive association of Cobb angle and SCT in idiopathic patients with dextroscoliosis (1.02 [1.01-1.03], 0.049). In contrast, in congenital cases, the rate of SCT decreased by higher left-sided Cobb angles but it was not statistically significant (0.94 [0.88-1.01], 0.104).

ConclusionThe risk of spinal cord tethering was not zero in any of the subgroups and no SCT-free group could be detected. Conventional MRI should be preoperatively performed for every case of scoliosis and thoroughly examined for signs of tethering. Clear imaging of patients at higher risk of SCT should not be decisive and further workup should be utilized before proceeding with reconstructive surgery.

category: orthopedics


title: Cellular and humoral immune response to a third dose of BNT162b2 COVID-19 vaccine - a prospective observational study

abstract:
BackgroundSince the introduction of various vaccines against SARS-CoV-2 at the end of 2020, rates of infection have continued to climb worldwide. This led to the establishment of a third dose vaccination in several countries, known as a booster. To date, there has been little real-world data about the immunological effect of this strategy.

MethodsWe compared the humoral- and cellular immune response before and after the third dose of BioNTech/Pfizer vaccine BNT162b2, following different prime-boost regimes. Humoral immunity was assessed by determining anti-SARS-CoV-2 binding antibodies using a standardized quantitative assay. In addition, neutralizing antibodies were measured using a commercial surrogate ELISA-assay. Interferon-gamma release was measured after stimulating blood-cells with SARS-CoV-2 specific peptides using a commercial assay to evaluate the cellular immune response.

ResultsThe median antibody level increased significantly after the third dose to 2663.1 BAU/ml vs. 101.4 BAU/ml (p < 0.001) before administration of the boosting dose. This was also detected for neutralizing antibodies with a binding inhibition of 99.68% {+/-} 0.36% vs. 69.06% {+/-} 19.88% after the second dose (p < 0.001).

96.3% of the participants showed a detectable T-cell-response after the third dose with a mean interferon-gamma level of 2207.07 mIU/ml {+/-} 1905 mIU/ml.

ConclusionThis study detected a BMI-dependent increase after the third dose of BNT162b2 following different vaccination protocols, whereas all participants showed a significant increase of their immune response. This, in combination with the limited post-vaccination-symptoms underlines the potential beneficial effect of a BNT162b2-boosting dose.


title: Time-Varying Death Risk After SARS-CoV-2-Infection in Swedish Long-Term Care Facilities

abstract:
BackgroundThe case fatality rate of SARS-CoV-2 has been high among residents of long-term care (LTC) facilities. It is unknown whether there is also higher mortality after the first month from documented infection.

MethodsWe extended the follow-up period to 8 months of a previous, retrospective cohort study based on the Swedish Senior Alert register. 3731 LTC residents infected with SARS-CoV-2 were matched to 3731 uninfected controls using time-dependent propensity scores on age, sex, body mass index, health status, comorbidities, and prescription medication use. In a sensitivity analysis, residents were also matched on geographical region and time of Senior Alert registration.

ResultsMedian age was 87 years (65% women). Excess mortality was highest 5 days after documented infection (hazard ratio 19.1; 95% confidence interval [CI], 14.6-24.8); subsequently excess mortality decreased rapidly. After the second month, mortality rate became lower in infected residents than in controls. Median survival of uninfected controls was 577 days (1.6 years), much lower than national life expectancy in Sweden at age 87 (5.05 years in men, 6.07 years in women). During days 61-210 of follow-up, hazard ratio for death was 0.41 (95% CI, 0.34-0.50) (0.76 (95% CI, 0.62-0.93) in the sensitivity analysis).

ConclusionsNo excess mortality was observed in LTC residents who survived acute SARS-CoV-2 infection (the first month). Life expectancy of uninfected residents was much lower than that of the general population of same age and sex. This difference should be taken into account in calculations of years of life lost among LTC residents.

Key messagesO_LISARS-CoV-2 infection sharply increased mortality risk among residents of long-term care (LTC) facilities in the first month.
C_LIO_LIThe mortality risk in infected residents of LTC facilities rapidly returned to baseline and dropped below the mortality risk of uninfected controls after the first month.
C_LIO_LIThe mortality rate remained lower in infected residents than in uninfected controls for 8 months of follow-up.
C_LIO_LINo excess mortality was observed in LTC residents who survived the acute SARS-CoV-2 infection.
C_LIO_LILoss of life-years in infected residents of LTC facilities is much lower than suggested for age- and sex- general population life tables.
C_LI


title: Time-varying death risk after SARS-CoV-2-infection in Swedish long-term care facilities


title: Arterial Oxygen and Carbon Dioxide Tension and Acute Brain Injury in Extracorporeal Cardiopulmonary Resuscitation Patients: Analysis of the Extracorporeal Life Support Organization Registry

abstract:
ObjectiveAcute brain injury remains common after extracorporeal cardiopulmonary resuscitation. Using a large international multicenter cohort, we investigated the impact of peri-cannulation arterial oxygen (PaO2) and carbon dioxide (PaCO2) on ABI occurrence.

DesignRetrospective cohort study.

SettingData in the Extracorporeal Life Support Organization Registry from 2009 to 2020.

PatientsAdult patients ([≥]18 years old) who underwent extracorporeal cardiopulmonary resuscitation.

InterventionsNone.

Measurements and Main ResultsOf 3,125 patients with extracorporeal cardiopulmonary resuscitation (median age=58, 69% male), 488 (16%) experienced at least one form of acute brain injury, which included ischemic stroke, intracranial hemorrhage, seizures, and brain death. 217 (7%) experienced ischemic stroke and 88 (3%) experienced intracranial hemorrhage. The registry collects two blood gas data pre- (6 hours before) and on- (24 hours after) extracorporeal membrane oxygenation (ECMO) cannulation. Blood gas parameters were classified as: hypoxia (<60mmHg), normoxia (60-119mmHg), and mild (120-199mmHg), moderate (200-299mmHg), and severe hyperoxia ([≥]300mmHg); hypocarbia (<35mmHg), normocarbia (35-44mmHg), mild (45-54mmHg) and severe hypercarbia ([≥]55mmHg). In multivariable logistic regression analysis, pre-ECMO hypoxia (aOR=1.46, 95%CI: 1.03-2.08, p=0.04) and on-ECMO severe hyperoxia (aOR=1.55, 95%CI: 1.02-2.36, p=0.04) were associated with composite ABI. Also, on-ECMO severe hyperoxia was associated with intracranial hemorrhage (aOR=1.88, 95%CI: 1.02-3.47, p=0.04) and in-hospital mortality (aOR=3.51, 95%CI: 1.98-6.22, p<0.001). Pre- and on-ECMO PaCO2 levels were not significantly associated with composite ABI or mortality, though mild hypercarbia pre- and on-ECMO were protective of ischemic stroke and intracranial hemorrhage, respectively.

ConclusionsEarly severe hyperoxia ([≥]300mmHg) on ECMO was a significant risk factor for acute brain injury and mortality for patients undergoing extracorporeal cardiopulmonary resuscitation. Careful consideration should be given in early oxygen delivery in ECPR patients who are at risk of reperfusion injury.

category: cardiovascular medicine


title: Correlates of circulating extracellular vesicle cargo with key clinical features of type 1 diabetes

abstract: Type 1 diabetes (T1D) is a heterogeneous disease with a slower evolution in individuals diagnosed at older ages. There are no validated clinical or laboratory biomarkers to predict the rate of insulin secretion decline either before or after the clinical onset of the disease, or the rate of progression to chronic complications of the disease. This pilot study aimed to characterize the proteomic and phosphoproteomic landscape of circulating extracellular vesicles (EVs) across a range of obesity in carefully matched established T1D and control subjects. We used archived serum samples from 17 human subjects (N=10 with T1D and N=7 normal healthy volunteers) from the ACME study (NCT03379792). EVs were isolated using EVtrap(R) technology (Tymora). Mass spectrometry-based methods were used to detect the global circulating EV proteome and phosphoproteome. Differential expression, coexpression network (WGCNA), and pathway enrichment analyses were implemented. The detected proteins and phosphoproteins were highly enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 differentially expressed EV proteins and 15 differentially expressed EV phosphoproteins were identified, with 8 upregulated EV proteins (i.e., CD63, RAB14, VCP, BSG, FLNA, GNAI2, LAMP2, and EZR) and 1 downregulated EV phosphoprotein (i.e., TUBA1B) listed among the top 100 ExoCarta proteins. This suggests that T1D could indeed modulate EV biogenesis and secretion. Enrichment analyses of both differentially expressed EV proteins and EV phosphoproteins identified associations of upregulated features with neutrophil, platelet, and immune response functions, as well as prion disease and other neurodegenerative diseases, among others. On the other hand, downregulated EV proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential novel key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, and phosphorylated S100A9, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others. This study demonstrates the potential of EV proteomic and phosphoproteomic signatures to provide insight into the pathobiology of type 1 diabetes and its complications.

category: endocrinology


title: Immortal time bias in older vs younger age groups: a simulation study with application to a population-based cohort of patients with colon cancer

abstract:
BackgroundIn observational studies, the risk of immortal time bias (ITB) increases with the likelihood of early death, itself increasing with age. We investigated how age impacts the magnitude of ITB when estimating the effect of surgery on one-year overall survival (OS) in patients with stage IV colon cancer aged 50-74 and 75-99 in England.

MethodUsing simulations, we compared estimates from a time-fixed exposure model to three methods addressing ITB: time-varying exposure, delayed entry, and landmark methods. We then estimated the effect of surgery on one-year OS using a national population-based cohort of patients derived from the CORECT-R resource.

ResultsIn simulations, the magnitude of ITB was larger among older patients when their probability of early death increased or treatment was delayed. The bias was corrected using the methods addressing ITB. When applied to CORECT-R data, these methods yielded smaller effects than the time-fixed exposure approach but effects were similar in both age groups.

ConclusionITB must be addressed in all longitudinal studies, particularly, when investigating the effect of an exposure on an outcome in different groups of people (e.g., age groups) with different distributions of exposure and outcomes.


title: The Microbiome in Adult Acute Appendicitis

abstract:
Acute appendicitis is a common acute surgical emergency; however, the pathogenesis of adult appendicitis remains poorly understood. The microbiome is increasingly thought to play a key role in inflammatory disease of the bowel and similarly, may play a role in appendicitis.

AimThis study aimed to characterize the microbiome of adult acute appendicitis in a prospective cohort.

MethodWe recruited 60 adults with acute appendicitis and 20 healthy controls. Rectal swabs were taken from each patient. After DNA extraction, 16S rRNA amplicon sequencing was carried out for analysis of diversity and taxonomic abundance.

ResultsPhylogenetic sequencing of the samples indicated that there is a difference between the microbial composition of those with acute appendicitis and healthy controls, with a statistically significant decrease in alpha diversity in rectal swabs of appendicitis patients compared to healthy controls. At the genus level, we saw an increased abundance of potential pathogens, e.g. Parvimonas and Acinetobacter, and a decrease in commensal taxa such as Faecalibacterium, Blautia and Lachnospiraceae in appendicitis patients compared to healthy controls.

ConclusionAn imbalance in the gut microbiome may contribute to the pathogenesis of adult acute appendicitis.


title: Cov2clusters: genomic clustering of SARS-CoV-2 sequences

abstract:
BackgroundThe COVID-19 pandemic remains a global public health concern. Advances in sequencing technologies has allowed for high numbers of SARS-CoV-2 whole genome sequence (WGS) data and rapid sharing of sequences through global repositories to enable almost real-time genomic analysis of the pathogen. WGS data has been used previously to group genetically similar viral pathogens to reveal evidence of transmission, including methods that identify distinct clusters on a phylogenetic tree. Identifying clusters of linked cases can aid in the regional surveillance and management of the disease. In this study, we present a novel method for producing stable genomic clusters of SARS-CoV-2 cases, cov2clusters, and compare the sensitivity and stability of our approach to previous methods used for phylogenetic clustering using real-world SARS-CoV-2 sequence data obtained from British Columbia, Canada,

ResultsWe found that cov2clusters produced more stable clusters than previously used phylogenetic clustering methods when adding sequence data through time, mimicking an increase in sequence data through the pandemic. Our method also showed high sensitivity when compared to epidemiologically informed clusters.

ConclusionsOur new approach allows for the identification of stable clusters of SARS-CoV-2 from WGS data. Producing high-resolution SARS-CoV-2 clusters from sequence data alone can a challenge and, where possible, both genomic and epidemiological data should be used in combination.

category: public and global health


title: Comparison of radiation dose and cancer risk between conventional polychromatic imaging and gemstone spectral imaging in computed tomography (CT) examination: a phantom study

abstract: This study aims to measure the radiation doses and estimate the associated lifetime attributable risks (LARs) of cancer incidence resulted from gemstone spectral imaging (GSI) and conventional polychromatic imaging (CPI) in computed tomography (CT) examinations. Organ doses were measured using an adult phantom and thermoluminescent dosimeters. Four scans, including head CT, thorax CT, abdomen CT and pelvis CT, were performed on the phantom. LARs of cancer incidence were estimated for Chinese population and US population. The effective doses of thorax CT was the highest. With CPI, it was 7.94 mSv for females, and 7.74 mSv for males. With GSI, it was 6.81 mSv for females, and 7.69 mSv for males. With GSI, the corresponding LARs for males and females aged 20-70 years were less than 0.062% and 0.154%, respectively. With CPI, these values were less than 0.074% and less than 0.171%, respectively. The LARs decreased in both US population and Chinese population when exposed age increased, with thorax scan causing the highest risk. GSI does not increased radiation exposure or cancer risk compared to CPI. These findings may allow the application of GSI in patients referred for CT.

category: radiology and imaging