bluuebunny/crossref_metadata_2025 huggingface dataset:
Polygenic Health Index, General Health, Pleiotropy, Embryo Selection and Disease Risk
Authors: Widen Erik , Lello Louis , Raben Timothy G. , Tellier Laurent C. A. M. , Hsu Stephen D. H.
Published: June 2022

We construct a polygenic health index as a weighted sum of polygenic risk scores for 20 major disease conditions, including, e.g., coronary artery disease, type 1 and 2 diabetes, schizophrenia, etc. Individual weights are determined by population-level estimates of impact on life expectancy. We validate this index in odds ratios and selection experiments using unrelated individuals and siblings (pairs and trios) from the UK Biobank. Individuals with higher index scores have decreased disease risk across almost all 20 diseases (no significant risk increases), and longer calculated life expectancy. When estimated Disability Adjusted Life Years (DALYs) are used as the performance metric, the gain from selection among 10 individuals (highest index score vs average) is found to be roughly 4 DALYs. We find no statistical evidence for antagonistic trade-offs in risk reduction across these diseases. Correlations between genetic disease risks are found to be mostly positive and generally mild. These results have important implications for public health and also for fundamental issues such as pleiotropy and genetic architecture of human disease conditions.
Experiences of mental health and wellbeing support for NHS staff during the COVID-19 pandemic: a reflexive thematic analysis
Authors: Clarkson Corinne , Scott Hannah R. , Hegarty Siobhan , Souliou Emilia , Bhundia Rupa , Gnanapragasam Sam , Docherty Mary Jane , Raine Rosalind , Stevelink Sharon A. M. , Greenberg Neil , Hotopf Matthew , Wessely Simon , Madan Ira , Rafferty Anne Marie , Lamb Danielle
Published: June 2022

Staff in the National Health Service (NHS) have been placed under considerable strain during the COVID-19 pandemic; whilst NHS Trusts provide a variety of health and wellbeing support services, there has been little research investigating staff perceptions of these services. Moreover, the research that does exist typically includes only clinical staff, despite a large proportion of patient-facing NHS workers being in non-clinical roles. We interviewed forty-eight clinical and non-clinical healthcare workers from eighteen NHS Trusts in England about their experiences of workplace health and wellbeing support during the pandemic. Reflexive thematic analysis identified that perceived stigma around help-seeking, and staffing shortages due to wider socio-political contexts such as austerity, were barriers to using support services. Visible, caring leadership at all levels (CEO to line managers), peer support, easily accessible services, and clear communication about support offers were enablers. Our evidence suggests Trusts should have active strategies to improve help-seeking. This could involve providing all staff with regular reminders about support options, in a variety of formats (e.g. email, posters, mentioned in meetings), and easily remembered single points of access, delivered by a mix of in-house and externally-provided services, to cater for those more and less concerned about stigma and confidentiality. In addition, managers at all levels should be trained and supported to feel confident to speak about mental health with staff, with formal peer support facilitated by building in time for this during working hours. As others have pointed out, this will require long-term strategic planning to address workforce shortages.
Detecting CTP Truncation Artifacts in Acute Stroke Imaging from the Arterial Input and the Vascular Output Functions
Authors: de la Rosa Ezequiel , Sima Diana M. , Kirschke Jan S. , Menze Bjoern , Robben David
Published: June 2022

Background

Current guidelines for CT perfusion (CTP) in acute stroke suggest acquiring scans with a minimal duration of 60-70 s. But even then, CTP analysis can be affected by truncation artifacts. Conversely, shorter acquisitions are still widely used in clinical practice and are usually sufficient to reliably estimate lesion volumes. We aim to devise an automatic method that detects scans affected by truncation artifacts.

Methods

Shorter scan durations are simulated from the ISLES’18 dataset by consecutively removing the last CTP time-point until reaching a 10 s duration. For each truncated series, perfusion lesion volumes are quantified and used to label the series as unreliable if the lesion volumes considerably deviate from the original untruncated ones. Afterwards, nine features from the arterial input function (AIF) and the vascular output function (VOF) are derived and used to fit machine-learning models with the goal of detecting unreliably truncated scans. Methods are compared against a baseline classifier solely based on the scan duration, which is the current clinical standard. The ROC-AUC, precision-recall AUC and the F1-score are measured in a 5-fold cross-validation setting.

Results

Machine learning models obtained high performance, with a ROC-AUC of 0.964 and precision-recall AUC of 0.958 for the best performing classifier. The highest detection rate is obtained with support vector machines (F1-score = 0.913). The most important feature is the AIFcoverage, measured as the time difference between the scan duration and the AIF peak. In comparison, the baseline classifier yielded a lower performance of 0.940 ROC-AUC and 0.933 precision-recall AUC. At the 60-second cutoff, the baseline classifier obtained a low detection of unreliably truncated scans (F1-Score = 0.638).

Conclusions

Machine learning models fed with discriminant AIF and VOF features accurately detected unreliable stroke lesion measurements due to insufficient acquisition duration. Unlike the 60s scan duration criterion, the devised models are robust to variable contrast injection and CTP acquisition protocols and could hence be used for quality assurance in CTP post-processing software.
Meta-Analysis of Genome-Wide Association Studies of Hoarding Symptoms in 27 537 Individuals
Authors: Strom Nora I. , Smit Dirk J.A. , Silzer Talisa , Iyegbe Conrad , Burton Christie L. , Pool René , Lemire Mathieu , Crowley James J. , Hottenga Jouke-Jan , Ivanov Volen Z. , Larsson Henrik , Lichtenstein Paul , Magnusson Patrik , Rück Christian , Schachar Russell , Wu Hei Man , Meier Sandra M. , Crosbie Jennifer , Arnold Paul D. , Mattheisen Manuel , Boomsma Dorret I. , Mataix-Cols David , Cath Danielle
Published: June 2022

Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27 537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we found a significant contribution of common genetic factors to HS, as indicated by substantial SNP-based twin-heritability estimates ranging between 26% and 48% and a SNP-heritability of 11% for one sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a “gene discovery zone”. To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.
Trends in Clinical Validation and Usage of Food and Drug Administration (FDA)-Cleared Artificial Intelligence (AI) Algorithms for Medical Imaging
Authors: Khunte Mihir , Chae Allison , Wang Richard , Jain Rishubh , Sun Yujuan , Sollee John R. , Jiao Zhicheng , Bai Harrison X.
Published: June 2022

Objective

The objective of this study is to examine the current landscape of FDA-approved AI medical imaging devices and identify trends in clinical validation strategy.

Materials and Methods

We conducted a retrospective study that analyzed data extracted from the American College of Radiology (ACR) Data Science Institute AI Central database as of November 2021 to identify trends in FDA clearance of AI products related to medical imaging. Product and clinical validation information of each device was gathered from their respective public 510(k) summary or de novo request submission, depending on their type of authorization.

Results

Overall, the database included a total of 151 AI algorithms that were cleared by the FDA between 2008 and November 2021. Out of the 151 FDA summaries reviewed, 97 (64.2%) reported the use of clinical data to validate their device. Of these 151 summaries, 81 (53.6%) reported the total number of patient cases used during validation, with the average number of cases being 799 (SD: 1363) and the range of cases spanning from 15 to 9122. A total of 51 (33.8%) AI devices characterized their clinical data as multicenter, 3 (2.0%) as single-center, and the remaining 97 (64.2%) did not specify. The ground truth used for clinical validation was specified in 78 (51.6%) FDA summaries.

Discussion and Conclusion

A wide breadth of AI algorithms have been developed for medical imaging. Most of the devices’ FDA summaries mention their use of clinical data and patient cases for device validation, emphasizing their utility in real clinical practice.
Antimicrobial Prescribing Practices at Dermatology Outpatient Departments in Tertiary Care Hospitals: A multi-centered, Cross Sectional Study
Authors: Sultana Nagina , Ferdoush Jannatul , Johora Fatema , Towfiq Hossain Sharif Mohammad , Hossain Arifa
Published: June 2022

Background

The purpose of this study is to evaluate antimicrobial prescribing behaviors in the dermatology outpatient department.

Methods

This multi-centered, cross-sectional study was conducted at dermatology outpatient department of three tertiary care hospitals in Chittagong division, Bangladesh during the period October, 2021 to April, 2022.

Results

During the study period, 463 prescriptions were obtained. Over half of the participants were female (57%) and between the ages of 21 to 40 years. The majority of patients were diagnosed with eczema (19%), acne (17%), and scabies (15%). Most commonly prescribed antimicrobials was Azithromycin (22%), followed by Permethrin (16%) and Erythromycin (7%). In most cases, antimicrobials were recommended for more than two weeks (60%). Nearly half of the antimicrobials (53 %) were recommended as combination of systemic and topical route.

Conclusion

Current study found that dermatologists frequently recommended broad-spectrum antimicrobials for extended periods of time, which may lead to antimicrobial resistance. There is a need for continuing medical education on the appropriate use of antimicrobials, which will result in the effective management of skin diseases.
Evaluating multiple next-generation sequencing derived tumor features to accurately predict DNA mismatch repair status
Authors: Walker Romy , Georgeson Peter , Mahmood Khalid , Joo Jihoon E. , Makalic Enes , Clendenning Mark , Como Julia , Preston Susan , Joseland Sharelle , Pope Bernard J. , Hutchinson Ryan , Kasem Kais , Walsh Michael D. , Macrae Finlay A. , Win Aung K. , Hopper John L. , Mouradov Dmitri , Gibbs Peter , Sieber Oliver M. , O’Sullivan Dylan E. , Brenner Darren R. , Gallinger Steven , Jenkins Mark A. , Rosty Christophe , Winship Ingrid M. , Buchanan Daniel D.
Published: June 2022

Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. We assessed tumor features, individually and in combination, in whole-exome sequenced (WES) colorectal cancers (CRCs) and in panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) for their accuracy in detecting dMMR. CRCs (n=300) with WES, where MMR status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, MSISensor), COSMIC tumor mutational signatures (TMS) and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for 1) individual features, 2) Lasso statistical model and 3) an additive feature combination approach. Panel sequenced tumors (29 CRCs, 22 ECs, 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided >80% dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3%. The additive feature approach with ≥3/6 of MSMuTect, MANTIS, MSIseq, MSISensor, INDEL count or TMS ID2+ID7 achieved 99.7% accuracy. For the panel sequenced tumors, the additive feature combination approach of ≥3/6 achieved accuracies of 100%, 95.5% and 100%, for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs, however, an approach combining tumor features may improve dMMR prediction in both WES and panel sequenced data across tissue types.
Attitudes of the US general public towards Monkeypox
Authors: Malik Amyn A. , Winters Maike S. , Omer Saad B.
Published: June 2022

While the Monkeypox outbreak is growing, little is known about the general public’s levels of knowledge, their trusted sources of information and attitudes towards a Monkeypox vaccine. In our representative survey of the US general public, we find that almost half the respondents (47%) feel that their knowledge level about Monkeypox is poor or very poor. The most trusted sources of information about the outbreak are healthcare professional and officials, but also known doctors and researchers with a large online following. Being vaccinated against COVID-19 was a strong predictor of willingness to receive a Monkeypox if recommended (adjusted Odds Ratio 32.1, 95% Confidence Interval 16.7-61.7). Our findings point to the urgent need for clear communication.
Digital reconstruction of infraslow activity in human intracranial ictal recordings using a deconvolution-based inverse filter
Authors: Lee Somin , Henry Julia , Tryba Andrew K. , Esengul Yasar , Warnke Peter , Wu Shasha , van Drongelen Wim
Published: June 2022

Infraslow activity (ISA) is a biomarker that has recently become of interest in the characterization of seizure recordings. Recent data from a small number of studies have suggested that the epileptogenic zone may be identified by the presence of ISA. Investigation of low frequency activity in clinical seizure recordings, however, has been hampered by technical limitations. EEG systems necessarily include a high-pass filter early in the measurement chain to remove large artifactual drifts that can saturate recording elements such as the amplifier. This filter unfortunately attenuates legitimately seizure-related low frequencies, making ISA difficult to study in clinical EEG recordings. In this study, we present a deconvolution-based digital inverse filter that allows recovery of attenuated low frequency activity in intracranial recordings of temporal lobe epilepsy patients. First, we show that the unit impulse response (UIR) of an EEG system can be characterized by differentiation of the system’s step response. As proof of method, we present several examples that show that the low frequency component of a high-pass filtered signal can be restored by deconvolution with the UIR. We then demonstrate that this method can be applied to biologically relevant signals including clinical EEG recordings obtained from seizure patients. Finally, we discuss how this method can be applied to study ISA to identify and assess the seizure onset zone.
Host microRNAs are differentially expressed in EBV+ Post-transplant Lymphoproliferative Disorder solid-organ transplant recipients
Authors: Sen Ayantika , Enriquez Jeanna , Rao Mahil , Glass Marla , Balachandran Yarl , Syed Sharjeel , Twist Clare J. , Weinberg Kenneth , Boyd Scott D. , Bernstein Daniel , Trickey Amber , Gratzinger Dita , Tan Brent , Lapasaran Mary Gay , Robien Mark A. , Brown Merideth , Armstrong Brian , Desai Dev , Mazariegos George , Chin Clifford , Fishbein Thomas , Venick Robert S. , Tekin Akin , Zimmermann Heiner , Trappe Ralf U. , Anagnostopoulos Ioannis , Esquivel Carlos.O. , Martinez Olivia M. , Krams Sheri M.
Published: June 2022

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Predisposing factors include primary Epstein-Barr virus (EBV) infection, reactivation of EBV in recipient B cells, and decreased T cell immunity due to immunosuppression. Previously, we demonstrated that EBV infection markedly reshapes the microRNA (miR) landscape in EBV+ B cell lines leading to increased IL-10 production. To establish the miRNAome of PTLD tumors we analyzed formalin-fixed, paraffin-embedded shavings of tumor tissues obtained from EBV+ PTLD SOT recipients by microarray analysis and quantitative PCR. The miRNAome of EBV+ PTLD tumors were distinctly different from EBV-PTLD tumors with reduced expression of miRs-17, 19 and 106a, and 194 among EBV+ PTLD tumors. miRs-17, 19, 106a, 155, and 194 were quantitated in the plasma and extracellular vesicles (EVs) from EBV+ PTLD+ SOT recipients and matched transplant controls. The plasma and EV levels of miRs-17, 19, 106a and 194 trended lower in the EBV+ PTLD+ group compared to matched controls, with miR-17 (plasma), miR-19 (EVs) and 106a (plasma and EVs) being significantly reduced. Importantly, the cell free miRs were contained primarily within the EVs. Further studies on the diagnostic, mechanistic, and therapeutic potential of these miRs in PTLD are warranted.
Kinetics of neutralising antibodies against Omicron variant in Vietnamese healthcare workers after primary immunisation with ChAdOx1-S and booster with BNT162b2
Authors: Van Vinh Chau Nguyen , Nguyet Lam Anh , Dung Nguyen Thanh , Quang Vo Minh , Truong Nguyen Thanh , Toan Le Mau , Hung Le Manh , Huy Man Dinh Nguyen , Khoa Dao Bach , Phong Nguyen Thanh , Ngoc Nghiem My , Thao Huynh Phuong , Bich Ty Dinh Thi , Thanh Pham Ba , Han Ny Nguyen Thi , Thanh Le Kim , Thuy Cao Thu , Anh Nguyen To , Thu Hong Nguyen Thi , Truc Nhu Le Nguyen , Yen Lam Minh , Thwaites Guy , Thanh Tran Tan , Tan Le Van ,   OUCRU COVID-19 Research Group
Published: June 2022

We studied the development and persistence of neutralising antibodies against SARS-CoV-2 ancestral strain, and Delta and Omicron (BA.1 and BA.2) variants in Vietnamese healthcare workers (HCWs) up to 15 weeks after booster vaccination. We included 47 HCWs with different pre-existing immune statuses (group 1 (G1): n=21, and group 2 (G2): n=26 without and with prior breakthrough Delta variant infection, respectively). The study participants had completed primary immunisation with ChAdOx1-S and booster vaccination with BNT162b2. Neutralising antibodies were measured using a surrogate virus neutralisation assay. Of the 21 study participants in G1, neutralising antibodies against ancestral strain, Delta variant, BA.1 and BA.2 were (almost) abolished at month 8 after the second dose, but all had detectable neutralising antibodies to the study viruses at week two post booster dose. Of the 26 study participants in G2, neutralising antibody levels to BA.1 and BA.2 were significantly higher than those to the corresponding viruses measured at week 2 post breakthrough infection and before the booster dose. At week 15 post booster vaccination, neutralising antibodies to BA.1 and BA.2 dropped significantly, with more profound changes observed in those without breakthrough Delta variant infection. Booster vaccination enhanced neutralising activities against ancestral strain and Delta variant, as compared to those induced by primary vaccination. These responses were maintained at high levels for at least 15 weeks. Our findings emphasise the importance of the first booster dose in producing cross-neutralising antibodies against Omicron variant. A second booster dose might be needed to maintain long-term protection against Omicron variant.
Impact of COVID-19 vaccination on long COVID: a systematic review and meta-analysis
Authors: Byambasuren Oyungerel , Stehlik Paulina , Clark Justin , Alcorn Kylie , Glasziou Paul
Published: June 2022

Background

The impact of COVID-19 vaccination on preventing or treating long COVID is unclear. We aim to assess the impact of COVID vaccinations administered (i) before and (ii) after acute COVID-19, including vaccination after long COVID diagnosis, on the rates or symptoms of long COVID.

Methods

We searched PubMed, Embase, Cochrane COVID-19 trials, and Europe PMC for preprints from 1 Jan 2020 to 16 Feb 2022. We included trials, cohort, and case control studies reporting on long COVID cases and symptoms with vaccine administration both before and after COVID-19 diagnosis as well as after long COVID diagnosis. Risk of bias was assessed using ROBINS-I.

Results

We screened 356 articles and found no trials, but 6 observational studies from 3 countries (USA, UK, France) that reported on 442,601 patients. The most common long COVID symptoms studied include fatigue, cough, loss of smell, shortness of breath, loss of taste, headache, muscle ache, trouble sleeping, difficulty concentrating, worry or anxiety, and memory loss or confusion. Four studies reported data on vaccination before SARS-CoV-2 infection, of which three showed statistically significant reduction in long COVID: the odds ratio of developing long COVID with one dose of vaccine ranged between OR 0.22 to 1.03; with two doses OR 0.51 to 1; and with any dose OR 0.85 to 1.01. Three studies reported on post-infection vaccination with odds ratios between 0.38 to 0.91. The high heterogeneity between studies precluded any meaningful meta-analysis. Studies failed to adjust for potential confounders such as other protective behaviours, and missing data, thus increasing the risk of bias, and decreasing the certainty of evidence to low.

Discussion

Current studies suggest that COVID-19 vaccinations may have protective and therapeutic effects on long COVID. However, more robust comparative observational studies and trials are urgently needed to clearly determine effectiveness of vaccines in prevention and treatment of long COVID.
Ethnic inequalities in patient satisfaction with primary health care in the UK: evidence from recent General Practitioner Patient Surveys (GPPS)
Authors: Magadi John Paul , Magadi Monica Akinyi
Published: June 2022

Aims and objectives

This paper aims to improve understanding of factors that contribute to persistent ethnic disparities in patient satisfaction in the UK. The specific objectives are to (i) examine ethnic differences in patient satisfaction with their primary care in the UK; (ii) establish recent trends in patient satisfaction by ethnicity; and (iii) examine factors that contribute to ethnic differences in patient satisfaction.

Data and methods

The study is based on secondary analysis of recent General Practitioner Patient Survey (GPPS) datasets of 2019, 2020 and 2021. Descriptive bivariate analysis was used to examine ethnic differences in patient satisfaction across the three years. This was followed with multilevel linear regression, with General Practice (GP) at level-1 and Clinical Commissioning Group (CCG) at level-2 to identify factors contributing to ethnic differences in patient satisfaction.

Results

The findings show consistent negative correlations between the proportion of patients reporting good (very or fairly good) overall experience and each of the ethnic minority groups. Further examination of the distribution of patient satisfaction by ethnicity, based on combined ethnic minority groups, depicted a clear negative association between ethnic minority group and patient satisfaction at both GP and CCG level. Multilevel regression analysis identified several service-related factors (especially ease of using GP website and being treated with care and concern) that largely explained the ethnic differences in patient satisfaction. Of all factors relating to patient characteristics considered in the analysis, none was significant after controlling for GP service-related factors.

Conclusions

Ethnic minority patients in the UK continue to consistently report lower satisfaction with their primary health care in recent years. This is largely attributable to supply (service related) rather than demand (patient characteristics) factors. These findings have important implications for health care system policy and practice at both GP and CCG levels in the UK.
Association of Complement C3 Inhibitor Pegcetacoplan with Photoreceptor Degeneration Beyond Areas of Geographic Atrophy
Authors: Pfau Maximilian , Schmitz-Valckenberg Steffen , Ribeiro Ramiro , Safaei Reza , McKeown Alex , Fleckenstein Monika , Holz Frank G.
Published: June 2022

Preservation of photoreceptors beyond areas of retinal pigment epithelium atrophy is a critical treatment goal in eyes with geographic atrophy (GA) to prevent vision loss. Thus, we assessed the association of treatment with the complement C3 inhibitor pegcetacoplan with optical coherence tomography (OCT)-based photoreceptor laminae thicknesses in this post hoc analysis of the FILLY trial (NCT02503332).

Retinal layers in OCT were segmented using a deep-learning-based pipeline and extracted along evenly spaced contour-lines surrounding areas of GA. The primary outcome measure was change from baseline in (standardized) outer nuclear layer (ONL) thickness at the 5.16°-contour-line at month 12.

Participants treated with pegcetacoplan monthly had a thicker ONL along the 5.16° contour-line compared to the pooled sham arm (mean difference [95% CI] +0.29 z-score units [0.16, 0.42],P<.001). The same was evident for eyes treated with pegcetacoplan every other month (+0.26 z-score units [0.13, 0.4],P<.001). Additionally, eyes treated with pegcetacoplan exhibited a thicker photoreceptor inner segment layer along the 5.16°-contour-line at month 12.

These findings suggest that pegcetacoplan could slow GA progression and lead to a lesser thinning of photoreceptor layers beyond the GA boundary. Future trials in earlier disease stages, i.e., intermediate AMD, aiming to slow photoreceptor degeneration warrant consideration.
Effectiveness of Subcutaneous Casirivimab and Imdevimab Relative to no COVID-19 Antibody Treatment Among Patients Diagnosed With COVID-19 in the Ambulatory Setting
Authors: Jalbert Jessica J. , Hussein Mohamed , Mastey Vera , Sanchez Robert J. , Wang Degang , Murdock Dana , Farinas Laura , Bussey Jonathan , Duart Carlos , Hirshberg Boaz , Weinreich David M. , Wei Wenhui
Published: June 2022

Importance

Data on real-world effectiveness of subcutaneous (SC) administration of casirivimab and imdevimab (CAS+IMD) for treatment of COVID-19 are limited.

Objective

To assess effectiveness of SC CAS+IMD vs no COVID-19 antibody treatment among patients diagnosed with COVID-19 in ambulatory settings during the Delta-dominant period prior to Omicron emergence.

Design

Retrospective cohort study.

Setting

Encrypted linked data between Komodo Health closed claims database and CDR Maguire Health & Medical database.

Participants

Patients with COVID-19 in ambulatory settings between August 1, 2021 and October 30, 2021 treated with SC CAS+IMD were exact- and propensity score-matched to up to 5 untreated patients who were treatment-eligible under the Emergency Use Authorization (EUA)

Exposure

Subcutaneous CAS+IMD.

Main Outcomes and Measures

Composite endpoint of 30-day all-cause mortality or COVID- 19-related hospitalization. Kaplan-Meier estimators were used to calculate composite risk overall and across subgroups including age, COVID-19 vaccination status, immunocompromised, and elevated risk defined as age ≥ 65 years or 55-64 years with body mass index ≥ 35 kg/m2, type 2 diabetes, chronic obstructive pulmonary disease, or chronic kidney disease. Cox proportional- hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).

Results

Among 13 522 patients treated with SC CAS+IMD, 12 972 (95.9%) were matched to 41 848 EUA-eligible untreated patients; patients were 57-58% female, with mean age between 50 and 52 years. The 30-day composite outcome risk was 1.9% (95% CI, 1.7-2.2; 247 events) and 4.4% (95% CI, 4.2-4.6; 1822 events) in the CAS+IMD-treated and untreated cohorts, respectively; CAS+IMD treatment was associated with a 49% lower risk (aHR 0.51; 95% CI, 0.46-0.58). Treatment was also associated with a 67% lower 30-day risk of all-cause mortality (aHR 0.33, 95% CI, 0.18-0.60). Treatment effectiveness was consistent regardless of vaccination status and across subgroups, including those at elevated risk (aHR 0.51, 95% CI 0.42-0.60) or immunocompromised (aHR 0.34, 95% CI 0.17-0.66).

Conclusions and Relevance

Subcutaneous treatment with CAS+IMD is effective for reducing all-cause mortality or COVID-19-related hospitalization in patients diagnosed with COVID-19 and managed in real-world outpatient settings during the Delta-dominant period. Effectiveness is maintained among immunocompromised, vaccinated, and elevated risk patients.
Leveraging serology testing to identify children at risk for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the RECOVER program
Authors: Mejias Asuncion , Schuchard Julia , Rao Suchitra , Bennett Tellen D. , Jhaveri Ravi , Thacker Deepika , Bailey L. Charles , Christakis Dimitri A. , Pajor Nathan M. , Razzaghi Hanieh , Forrest Christopher B. , Lee Grace M.
Published: June 2022

The impact of post-acute sequelae of SARS-CoV-2 infection (PASC) in children is underrecognized. We developed an EHR-based algorithm across eight pediatric institutions to identify children with COVID-19 based on serology testing from 3/2020 through 4/2022 who had not been identified by PCR. Overall, serology tests were used 100-fold less than PCR. Seroprevalence of IgG anti-nucleocapsid antibodies remained stable, while rates of positive IgG anti-spike antibodies increased in teenagers after COVID-19 vaccine approval. Through data harmonization and after excluding 1,410 serology test results that may have been influenced by vaccines, we identified 2,714 children that were COVID-19 positive exclusively by serology. These patients were frequently tested as inpatients (24% vs. 2%), had chronic conditions more frequently (37% vs 24%), and a MIS-C diagnosis (23% vs. <1%) compared with PCR-positive children. Identification of children that could have been paucisymptomatic, not tested, or missed is critical to define the burden of PASC in children.
Naturally-acquired Immunity Dynamics against SARS-CoV-2 in Children and Adolescents
Authors: Patalon Tal , Saciuk Yaki , Ohayon Hadad Hanit , Perez Galit , Peretz Asaf , Ben-Tov Amir , Gazit Sivan
Published: June 2022

Objectives

There are paucity of studies examining naturally acquired immunity against SARS-CoV-2 in children and adolescents, though they are generally the last group to be afforded the vaccine, and a significant portion of them are still unvaccinated. This study examined the duration of protection conferred by a previous SARS-CoV-2 infection amongst children and adolescents.

Design

A retrospective study, applying two complementary approaches: a matched test-negative case control design and a retrospective cohort design.

Setting

Nationally centralized database of Maccabi Healthcare Services, an Israeli national health fund that covers 2.5 million people.

Participants

The study population included between 293,743 and 458,959 individuals (depending on the model), 5-18 years of age, who were unvaccinated SARS-CoV-2 naïve persons or unvaccinated convalescent patients.

Main outcomes and measures

Analyses focused on the period of July 1 to December 13, 2021, a Delta-dominant period in Israel. We evaluated three SARS-CoV-2-related outcomes: (1) documented PCR confirmed infection or reinfection, (2) COVID-19 and (3) severe COVID-19.

Results

Overall, children and adolescents who were previously infected acquired durable protection against reinfection (symptomatic or not) with SARS-CoV-2 for at least 18 months. Importantly, no COVID-19 related deaths were recorded in either the SARS-CoV-2 naïve group or the previously infected group. Effectiveness of naturally-acquired immunity against a recurrent infection reached 89.2% (95% CI: 84.7%-92.4%) three to six months after first infection, mildly declining to 82.5% (95% CI, 79.1%-85.3%) nine months to one year after infection, then remaining rather steady for children and adolescents for up to 18 months, with a slight non-significant waning trend. Additionally, we found that ages 5-11 exhibited no significant waning of naturally acquired protection throughout the outcome period, whereas waning protection in the 12-18 age group was more prominent, but still mild.

Conclusions

Children and adolescents who were previously infected with SARS-CoV-2 remain protected against reinfection to a high degree for 18 months. Policy decision makers should consider when and if convalescent children and adolescents should be vaccinated. Nonetheless, further research is needed to examine naturally acquired immunity against emerging variants, including the Omicron.
Forecasting waiting lists for elective procedures and surgery in England: a modelling study
Authors: Nepogodiev Dmitri , Acharya Radhika , Chaudhry Daoud , Glasbey James C , Harris Benjamin , Li Elizabeth , Jolly Kate , Bhangu Aneel
Published: June 2022

Introduction

The aim of this study was to forecast the total need for elective procedures in England by 2030.

Methods

We used publicly available activity data from NHS Digital to estimate procedure- level shortfalls in elective procedures performed during the pandemic period (January 2020 to March 2022) compared to what would be expected based on pre-pandemic trends. We also estimated the procedure-level composition of the NHS waiting list immediately preceding the pandemic (December 2019). The total need for elective procedures in March 2022 was calculated by summing the pandemic shortfall with the pre-pandemic NHS waiting list. We projected the need for elective procedures through to January 2030 for four scenarios: current capacity (surgical volume remains at the same level as in February-March 2022), pessimistic scenario (elective procedure volume increases to pre-pandemic levels by July 2023 followed and remains at this level until 2030), central scenario (elective procedure volume returns to pre-pandemic levels by December 2022 followed by a 2% increase per year), optimistic scenario (elective procedure volume returns to pre-pandemic levels by December 2022 followed by a 4% increase per year)

Results

We estimated the total need for elective procedures in England in March 2022 was 4,347,469. Of these 4,347,469 patients, 3,304,513 (76.0%) were on a hidden waiting list. The greatest need was for General Surgery (1,522,366), Orthopaedics (976,875), and Ophthalmology (391,683). The procedures with the greatest need were sigmoidoscopy and colonoscopy (568,838), gastroscopy (447,830), cataract surgery (314,790), lower limb joint replacement (224,363), and interventional cardiology (349,300). We projected that at current capacity, the total number of elective procedures needed would increase to 14,608,195 by 2030. In the pessimistic scenario, elective procedure volume total elective procedures needed would increase to 8,507,087, in the central scenario it would increase to 5,420,999, and in the optimistic scenario it would decrease to 2,584,664 procedures.

Discussion

The estimate of 4.3 million elective procedures needed in England is considerably higher than the official NHS waiting list, reflecting a large hidden waiting list. Even in the most optimistic scenarios there will be a substantially larger waiting list in 2030 than pre-pandemic.
A Bayesian hierarchical approach to account for reporting uncertainty, variants of concern and vaccination coverage when estimating the effects of non-pharmaceutical interventions on the spread of infectious diseases
Authors: Rehms Raphael , Ellenbach Nicole , Rehfuess Eva , Burns Jacob , Mansmann Ulrich , Hoffmann Sabine
Published: June 2022

Coronavirus disease (COVID-19) has highlighted both the shortcomings and value of modelling infectious diseases. Infectious disease models can serve as critical tools to predict the development of cases and associated healthcare demand and to determine the set of non-pharmaceutical interventions (NPI) that is most effective in slowing the spread of the infectious agent. Current approaches to estimate NPI effects typically focus on relatively short time periods and either on the number of reported cases, deaths, intensive care occupancy or hospital occupancy as a single indicator of disease transmission. In this work, we propose a Bayesian hierarchical model that integrates multiple outcomes and complementary sources of information in the estimation of the true and unknown number of infections while accounting for time-varying under-reporting and weekday-specific delays in reported cases and deaths, allowing us to estimate the number of infections on a daily basis rather than having to smooth the data. Using information from the entire course of the pandemic, we account for the spread of variants of concern, seasonality and vaccination coverage in the model. We implement a Markov Chain Monte Carlo algorithm to conduct Bayesian inference and estimate the effect of NPIs for 20 European countries. The approach shows good performance on simulated data and produces posterior predictions that show a good fit to reported cases, deaths, hospital and intensive care occupancy.
Dissected subgroups predict the risk of recurrence of stage II colorectal cancer and select rational treatment
Authors: Wang Fulong , Lu Shixun , Zhou Xin , Di Xiaotang , Wu Rujia , Chen Gong , Tian Sun
Published: June 2022

Background

Stage II colorectal cancer(CRC) patients after surgery alone have a five-year survival rate of ∼60-80%; the incremental benefit of adjuvant chemotherapy is <5%. Predicting risk of recurrence and selecting effective personalized adjuvant drugs for stage II CRC using formalin-fixed, paraffin-embedded(FFPE) samples is a major challenge.

Methods

1319 stage II CRC patients who enrolled in 2011-2019 at Sun Yat-sen University Cancer Center were screened. RNAseq data of FFPE tumor samples of 222 stage II MSS CRC patients(n.recurrence=47, n.norecurrence=175, median follow-up=41 months) were used to develop a method TFunctionalProg for dissecting heterogeneous subgroups of recurrence, predicting risk of recurrence and proposing adjuvant drugs.

Results

TFunctionalProg showed significant predictive values in 222 stage II MSS CRCs. The TFunctionalProg low-risk group had significantly better RFS (validation set (HR=4.78, p-value=1e-4, low-risk group three-year RFS=92.6%, high-risk group three-year RFS=59.7%). TFunctionalProg dissected two subgroups of transition states of stage II MSS CRCs at a high risk of recurrence; each state displays distinct levels of hybrid epithelial-mesenchymal traits, cytotoxic cell inhibition and FOLFOX resistance. Based on mechanisms in two subgroups, TFunctionalProg proposed personalized rational adjuvant drug combinations of immunotherapy, chemotherapy and repurposed CNS drugs. The complementary utility of TFunctionalProg and ctDNA-based prognostic biomarkers were presented.

Conclusion

TFunctionalProg was validated using FFPE samples to predict the risk of recurrence and propose rational adjuvant drug combinations for stage II CRCs.
ERBB4 Drives the Proliferation of BRAF-WT Melanoma Cell Lines
Authors: Lucas L.M. , Cullum R.L. , Woggerman J.N. , Dwivedi V. , Markham J.A. , Kelley C.M. , Knerr E.L. , Cook L.J. , Lucas H.C. , Waits D.S. , Ghosh T.M. , Halanych K.M. , Gupta R.B. , Riese D.J.
Published: June 2022

Metastatic skin cutaneous melanomas remain a significant clinical problem. In particular, those melanomas that do not contain a gain-of-functionBRAFallele remain challenging to treat because of the paucity of targets for effective therapeutic intervention. Thus, here we investigate the role of the ERBB4 receptor tyrosine kinase in skin cutaneous melanomas that contain wild-typeBRAFalleles (“BRAFWT melanomas”). We have performedin silicoanalyses of a public repository (The Cancer Genome Atlas - TCGA) of skin cutaneous melanoma gene expression and mutation data (TCGA-SKCM data set). These analyses demonstrate that elevatedERBB4transcription strongly correlates withRASgene orNF1mutations that stimulate RAS signaling. Thus, these results have led us to hypothesize that elevated ERBB4 signaling which cooperates with elevated RAS signaling to driveBRAFWT melanomas. We have tested this hypothesis using commercially availableBRAFWT melanoma cell lines. Ectopic expression of wild-typeERBB4stimulates clonogenic proliferation of the IPC-298, MEL-JUSO, MeWo, and SK-MEL-2BRAFWT melanoma cell lines, whereas ectopic expression of a dominant-negative (K751M)ERBB4mutant allele inhibits clonogenic proliferation of these same cell lines. Ectopic expression of a dominant-negativeERBB4mutant allele inhibits anchorage-independent proliferation of MEL-JUSO cells and ectopic expression of a dominant-negativeERBB2mutant alleles inhibits clonogenic proliferation of MEL-JUSO cells. These data suggest that elevated signaling by ERBB4-ERBB2 heterodimers cooperates with elevated RAS signaling to drive the proliferation of someBRAFWT tumors and that combination therapies that target these two signaling pathways may be effective against theseBRAFWT tumors.
Immediate and Long-Term Effects of Tibial Nerve Stimulation on the Sexual Behavior of Female Rats
Authors: Zimmerman Lauren L. , Mentzelopoulos Georgios , Parrish Hannah , Marcu Vlad I. , Luma Brandon D. , Becker Jill B. , Bruns Tim M.
Published: June 2022

Objectives

There are limited treatment options for female sexual dysfunction (FSD). Percutaneous tibial nerve stimulation (PTNS) has shown improvements in FSD symptoms in neuromodulation clinical studies, but the direct effects on sexual function are not understood. This study evaluated the immediate and long-term effects of PTNS on sexual motivation and receptivity in a rat model of menopausal women. Our primary hypothesis was that long-term PTNS would yield greater changes in sexual behavior than short-term stimulation.

Materials and Methods

In two Experiments, after receiving treatment, we placed ovariectomized female rats in an operant chamber in which the female controls access to a male by nose poking. We used five treatment conditions, which were with or without PTNS and no, partial, or full hormone priming. In Experiment 1, we rotated rats through each condition twice with behavioral testing immediately following treatment for 10 weeks. In Experiment 2, we committed rats to one condition for 6 weeks and tracked sexual behavior over time. We quantified sexual motivation and sexual receptivity with standard measures.

Results

No primary comparisons were significant in this study. In Experiment 1, we observed increased sexual motivation but not receptivity immediately following PTNS with partial hormone priming, as compared to priming without PTNS. In Experiment 2, we observed trends of increased sexual receptivity and some sexual motivation metrics when PTNS was applied long-term with partial hormone priming, as compared to hormone-primed rats without stimulation.

Conclusions

PTNS combined with hormone priming shows potential for increasing sexual motivation in the short-term and sexual receptivity in the long-term in rats. Further studies are needed to examine variability in rat behavior and to investigate PTNS as a treatment for FSD in menopausal women.
Targeted curation of the gut microbial gene content modulating human cardiovascular disease
Authors: Borton Mikayla A. , Shaffer Michael , Hoyt David W. , Jiang Ruisheng , Ellenbogen Jared , Purvine Samuel , Nicora Carrie D. , Eder Elizabeth K. , Wong Allison R. , Smulian A. George , Lipton Mary S. , Krzycki Joseph A. , Wrighton Kelly C.
Published: June 2022

Despite the promise of the gut microbiome to forecast human health, few studies expose the microbial functions underpinning such predictions. To comprehensively inventory gut microorganisms and their gene content that control trimethylamine induced cardiovascular disease, we mined over 200,000 gut-derived genomes from cultivated and uncultivated microbial lineages. Creating MAGICdb (Methylated Amine Gene Inventory of Catabolism database), we designated an atherosclerotic profile for 6,341 microbial genomes that encoded metabolisms associated with heart disease. We used MAGICdb to evaluate diverse human fecal metatranscriptome and metaproteome datasets, demonstrating how this resource eases the recovery of methylated amine gene content previously obscured in microbiome datasets. From the feces of healthy and diseased subjects, we show MAGICdb gene markers predicted cardiovascular disease as effectively as traditional blood diagnostics. This functional microbiome catalog is a public, exploitable resource, enabling a new era of microbiota-based therapeutics.
Non-classical glycosylation determines intracellular trafficking of APP and Aβ production
Authors: Tachida Yuriko , Iijima Junko , Takahashi Kazuto , Suzuki Hideaki , Yamaguchi Yoshiki , Tanaka Katsunori , Nakano Miyako , Takakura Daisuke , Kawasaki Nana , Saito Yuko , Manya Hiroshi , Endo Tamao , Kitazume Shinobu
Published: June 2022

A primary pathology of Alzheimer’s disease (AD) is Aβ deposition in brain parenchyma and blood vessels, the latter being called cerebral amyloid angiopathy (CAA). Parenchymal amyloid plaques presumably originate from neuronal Aβ precursor protein (APP), but vascular amyloid deposits’ origins remain unclear. Endothelial APP expression in APP-knock-in mice was recently shown to expand CAA pathology, highlighting endothelial APP’s importance. Furthermore, two types of endothelial APP—with and without O-glycans—have been biochemically identified, but only the former is cleaved for Aβ production, indicating the critical relationship between APP O-glycosylation and processing. Here, we analyzed APP glycosylation and its intracellular trafficking in neurons and endothelial cells. Although protein glycosylation is generally believed to precede cell surface trafficking, which was true for neuronal APP, we unexpectedly observed that APP lacking O-glycans is externalized to the endothelial cell surface and transported back to the Golgi apparatus, where it then acquires O-glycans. Knockdown of genes encoding enzymes initiating APP O-glycosylation significantly reduced Αβ production, suggesting this non-classical glycosylation pathway contributes to CAA pathology and is a novel therapeutic target.