bluuebunny/crossref_metadata_2025 huggingface dataset:
Necrotic Granulomatous Inflammation after Use of Small Intestine Submucosa Matrix for Recurrent Compression Neuropathy
Authors: Koenig Zachary A. , Burns Jack C. , Hayes John D.
Published: June 2022

Various techniques exist for treating recurrent carpal and ulnar tunnel syndrome, but AxoGuard nerve wrap has shown promising results for treatment of compression neuropathies when used in conjunction with neurolysis and tenosynovectomy. Prior results demonstrate no safety concerns, and there have not been any reported cases of infection, persistent inflammation, or recurrent perineural fibrosis. A 41-year-old, right-hand-dominant woman experienced repeated bouts of carpal and ulnar tunnel syndromes, which were treated with a small intestine submucosa matrix wrap around the median and ulnar nerves in the wrist. Here, we report a case of necrotic granulomatous inflammation 2.5 months after AxoGuard xenograft nerve wrap was placed around the median and ulnar nerves. As a salvage, NuShield placental allograft was wrapped around the median nerve, which has shown promising results at several months follow-up. Placental allograft nerve wraps represent a useful tool in compression neuropathy resistant to autografts, xenografts, and revision decompression operations.
Effect of Optic Disc Tilt on the Measurement of Peripapillary Vessel Density Using Optical Coherence Tomography Angiography
Authors: Han Ye Eun , Sung Kyung Rim
Published: June 2022

Précis:

Eyes with tilted disc (TD) had significantly lower peripapillary vessel density (pVD) and lower long-term measurement reproducibility in optical coherence tomography angiography (OCTA). After adjusting for confounding factors, disc tilt still contributed to the reduction of pVD in most sectors.

Purpose:

The purpose of this study was to investigate the effect of optic disc tilt on the measurement of sectoral pVD by OCTA and on the long-term measurement reproducibility.

Materials and Methods:

This retrospective observational case-control study included 70 healthy eyes. Average and 8-sector pVDs and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were obtained from OCTA at 2 visits at 1-year intervals. The disc tilt was quantified by ovality ratio (the longest/shortest disc diameter) on fundus photography, with a TD defined as an ovality ratio ≥1.3. pVD and pRNFL thickness of each sector were compared in the TD and nontilted disc (NTD) groups. Long-term reproducibility was assessed by the intraclass correlation coefficients (ICCs) for both groups. Factors associated with pVD were evaluated by univariable and multivariable linear regression analyses.

Results:

Thirty-five eyes each had TD and NTD. Average pVD was lower in the TD than in the NTD group (47.0%±3.5% vs. 51.7%±2.8%, P<0.001), as were pVDs in all 8 sectors. The long-term reproducibilities of average and sectoral pVD measurements were lower in the TD (ICC: 0.46–0.83) than in the NTD (ICC: 0.67–0.96) group. Disc tilt was significantly associated with pVD in average and all sectors except for nasal inferior sector after adjusting for axial length, pRNFL thickness, and signal strength index of OCTA image.

Conclusion:

OCTA-measured pVD and the long-term reproducibility were lower in eyes with TD than NTD. These findings should be considered when interpreting OCTA-measured pVD.
Role of Transbronchial Lung Cryobiopsy in the Diagnosis of Interstitial Lung Disease
Authors: Zayed Yazan , Alzghoul Bashar N. , Hyde Ryan , Wadood Zerka , Banifadel Momen , Khasawneh Majd , Maharrey Phillip Brandon , Saker Haneen , Harden Christopher , Barnes Gabrielle , Gomez-Manjarres Diana , Patel Divya , Faruqi Ibrahim , Mehrad Borna , Mehta Hiren J.
Published: June 2022

Background:

Diagnosis of interstitial lung disease (ILD) is based on multidisciplinary team discussion (MDD) with the incorporation of clinical, radiographical, and histopathologic information if available. We aim to evaluate the diagnostic yield and safety outcomes of transbronchial lung cryobiopsy (TBLC) in the diagnosis of ILD.

Methods:

We conducted a meta-analysis by comprehensive literature search to include all studies that evaluated the diagnostic yields and/or adverse events with TBLC in patients with ILD. We calculated the pooled event rates and their 95% confidence intervals (CIs) for the diagnostic yield by MDD, histopathologic diagnostic yield, and various clinical adverse events.

Results:

We included 68 articles (44 full texts and 24 abstracts) totaling 6386 patients with a mean age of 60.7±14.1 years and 56% men. The overall diagnostic yield of TBLC to achieve a definite or high-confidence diagnosis based on MDD was 82.3% (95% CI: 78.9%-85.2%) and histopathologic diagnosis of 72.5% (95% CI: 67.7%-76.9%). The overall rate of pneumothorax was 9.6% (95% CI: 7.9%-11%), while the rate of pneumothorax requiring drainage by a thoracostomy tube was 5.3% (95% CI: 4.1%-6.9%). The rate of moderate bleeding was 11.7% (95% CI: 9.1%-14.9%), while the rate of severe bleeding was 1.9% (95% CI: 1.4%-2.6%). The risk of mortality attributed to the procedure was 0.9% (95% CI: 0.7%-1.3%).

Conclusion:

Among patients with undiagnosed or unclassified ILD requiring tissue biopsy for diagnosis, transbronchial cryobiopsy represents a reliable alternative to surgical lung biopsy with decreased incidence of various clinical adverse events.
Drug Induced Diabetes Mellitus in Pediatric Acute Lymphoblastic Leukemia: Approach to Diagnosis and Management
Authors: Handattu Koushik , Sharma Lokesh K. , Vijayasekharan Kalasekhar , Bhat K. Vasudeva , Aroor Shrikiran , Sudhanshu Siddhnath
Published: June 2022

Corticosteroids and l-asparaginase used in the treatment of pediatric acute lymphoblastic leukemia (ALL) can cause drug-induced diabetes mellitus (DIDM). DIDM can lead to dyselectrolytemia, a higher risk of infections including cellulitis, bacteremia, fungemia, and a higher incidence of febrile neutropenia and may have an impact on the outcome of ALL. Literature on the management of DIDM among children with ALL is sparse and the diagnostic criteria for pediatric diabetes should be carefully applied considering the acute and transient nature of DIDM during ALL therapy. Insulin remains the standard of care for DIDM management and the choice of Insulin regimen (stand-alone Neutral Protamine Hagedorn or basal bolus) should be based on the type and dose of steroids used for ALL and the pattern of hyperglycemia. A modest glycemic control (postmeal 140 to 180 mg/dL, premeal <140 mg/dL) to prevent complications of hyperglycemia, as well as hypoglycemia, would be the general approach. This review is intended to suggest evidence-based practical guidance in the diagnosis and management of DIDM during pediatric ALL therapy.
Case Report: 2-Year-old With Wilms Tumors, Familial Heterozygous DIS3L2 Mutation, and Cutis Marmorata Telangiectatica Congenita
Authors: Friedman Cameron D. , DeBrosse Suzanne , Mitchell Anna , Horn Joanna , Merrill Michelle
Published: June 2022

Biallelic variants in DI3SL2 cause Perlman Syndrome, associated increased risk for Wilms tumor. Cutis Marmorata Telangiectatica Congenita (CMTC) is a rare congenital disorder characterized by cutaneous vascular anomalies. We report a 2-year-old boy with both Wilms tumor and CMTC. Genetic testing, prompted by his complex presentation, revealed 1 somatic mutation and 1 familial germline mutation in the DIS3L2 gene, suggesting a 2-hit causation of Wilms tumor. Separately, a single GNA11 somatic mutation was identified to explain the CMTC. We suggest that genetic testing for germline mutations associated with Wilms tumor susceptibility be considered even in cases without known family history.
Efficacy of Teicoplanin Lock Therapy in the Treatment of Port-related Coagulase-negative Staphylococci Bacteremia in Pediatric Oncology Patients
Authors: Okur Acar Sultan , Tahta Neryal , Böncüoğlu Elif , Odaman Al Işik , Kiymet Elif , Gözmen Salih , Demirağ Bengü , Karapinar Tuba H. , Oymak Yeşim , Vergin Canan , Devrim İlker
Published: June 2022

The number of studies evaluating teicoplanin lock therapy in coagulase-negative staphylococcus-associated catheter infection in pediatric malignancies is limited. The aim of this study was to evaluate the efficacy of teicoplanin lock therapy in pediatric cancer cases. Twenty-two patients with coagulase-negative staphylococcus-associated totally implantable venous access device infection, who had undergone teicoplanin closure treatment, were included in the study. Demographic data, number of lock treatment days, and treatment success data were obtained from the medical files of the patients. Fourteen of the patients (63.6%) had acute lymphocytic leukemia, 3 (13.6%) had acute myelocytic leukemia, and 5 (22.7%) had solid cancer. The median neutrophil count was 240×103/μL (interquartile range: 0 to 1195×103/μL). Between patients with and without catheter removal, no statistically significant difference was found in terms of baseline C-reactive protein, absolute neutrophil count, and the day of starting systemic teicoplanin treatment (P>0.05). The overall port survival rate of teicoplanin lock therapy was 72.7%. Within an average of 4 days, negative cultures of 16 (72.7%) patients whose catheters had not been removed were obtained. In conclusion, we suggest that teicoplanin lock therapy is an effective and safe treatment for catheter-related infections, caused by methicillin-resistant coagulase-negative staphylococcus.
Protocol for a Randomized Multiple Center Trial of Conservative Versus Liberal Oxygenation Targets in Critically Ill Children (Oxy-PICU): Oxygen in Pediatric Intensive Care
Authors: Chang Irene , Thomas Karen , O'Neill Gutierrez Lauran , Peters Sam , Agbeko Rachel , Au Carly , Draper Elizabeth , Jones Gareth A. L. , Major Lee Elliot , Orzol Marzena , Pappachan John , Ramnarayan Padmanabhan , Ray Samiran , Sadique Zia , Gould Doug W. , Harrison David A. , Rowan Kathryn M. , Mouncey Paul R. , Peters Mark J.
Published: June 2022

OBJECTIVES:

Oxygen administration is a fundamental part of pediatric critical care, with supplemental oxygen offered to nearly every acutely unwell child. However, optimal targets for systemic oxygenation are unknown. Oxy-PICU aims to evaluate the clinical effectiveness and cost-effectiveness of a conservative peripheral oxygen saturation (Spo
2) target of 88–92% compared with a liberal target of more than 94%.

DESIGN:

Pragmatic, open, multiple-center, parallel group randomized control trial with integrated economic evaluation.

SETTING:

Fifteen PICUs across England, Wales, and Scotland.

PATIENTS:

Infants and children age more than 38 week-corrected gestational age to 16 years who are accepted to a participating PICU as an unplanned admission and receiving invasive mechanical ventilation with supplemental oxygen for abnormal gas exchange.

INTERVENTION:

Adjustment of ventilation and inspired oxygen settings to achieve an Spo
2 target of 88–92% during invasive mechanical ventilation.

MEASUREMENTS and MAIN RESULTS:

Randomization is 1:1 to a liberal Spo
2 target of more than 94% or a conservative Spo
2 target of 88–92% (inclusive), using minimization with a random component. Minimization will be performed on: age, site, primary reason for admission, and severity of abnormality of gas exchange. Due to the emergency nature of the treatment, approaching patients for written informed consent will be deferred to after randomization. The primary clinical outcome is a composite of death and days of organ support at 30 days. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support, and discharge outcomes. This trial received Health Research Authority approval on December 23, 2019 (reference: 272768), including a favorable ethical opinion from the East of England—Cambridge South Research Ethics Committee (reference number: 19/EE/0362). Trial findings will be disseminated in national and international conferences and peer-reviewed journals.
Pre-exposure Prophylaxis Discontinuation During the COVID-19 Pandemic Among Men Who Have Sex With Men in a Multisite Clinical Cohort in the United States
Authors: Goedel William C. , Rogers Brooke G. , Li Yu , Nunn Amy S. , Patel Rupa R. , Marshall Brandon D. L. , Mena Leandro A. , Ward Lori M. , Brock J. Benjamin , Napoleon Siena , Zanowick-Marr Alexandra , Curoe Kate , Underwood Ashley , Johnson Catrell J. , Lockwood Khadijra R. , Chan Philip A.
Published: June 2022

Background:

The coronavirus disease 2019 (COVID-19) pandemic continues to put strain on health systems in the United States, leading to significant shifts in the delivery of routine clinical services, including those offering HIV pre-exposure prophylaxis (PrEP). We aimed to assess whether individuals discontinued PrEP use at higher rates during the COVID-19 pandemic and the extent to which disruptions to usual clinical care were mitigated through telehealth.

Methods:

Using data from an ongoing prospective cohort of men who have sex with men (MSM) newly initiating PrEP in 3 mid-sized cities (n = 195), we calculated the rate of first-time discontinuation of PrEP use in the period before the COVID-19 pandemic and during the COVID-19 pandemic and compared these rates using incidence rate ratios (IRRs). Furthermore, we compared the characteristics of patients who discontinued PrEP use during these periods with those who continued to use PrEP during both periods.

Results:

Rates of PrEP discontinuation before the COVID pandemic and during the COVID-19 pandemic were comparable [4.29 vs. 5.20 discontinuations per 100 person-months; IRR: 1.95; 95% confidence interval (CI): 0.83 to 1.77]. Although no significant differences in the PrEP discontinuation rate were observed in the overall population, the rate of PrEP discontinuation increased by almost 3-fold among participants aged 18–24 year old (IRR: 2.78; 95% CI: 1.48 to 5.23) and by 29% among participants covered by public insurance plans at enrollment (IRR: 1.29; 95% CI: 1.03 to 5.09). Those who continued to use PrEP were more likely to have had a follow-up clinical visit by telehealth in the early months of the pandemic (45% vs. 17%).

Conclusions:

In this study, rates of PrEP discontinuation were largely unchanged with the onset of the COVID-19 pandemic. The use of telehealth likely helped retain patients in PrEP care and should continue to be offered in the future.
Implementation of a digital early warning score (NEWS2) in a cardiac specialist and general hospital settings in the COVID-19 pandemic: A qualitative study
Authors: Alhmoud Baneen , Bonnici Timothy , Patel Riyaz , Melley Daniel , Hicks Louise , Banerjee Amitava
Published: June 2022

Objectives

To evaluate implementation of EHR-integrated NEWS2 in a cardiac care setting and a general hospital setting in the COVID-19 pandemic.

Design

Thematic analysis of qualitative semi-structured interviews with purposefully sampled nurses and managers, as well as online surveys.

Settings

Specialist cardiac hospital (St Bartholomew’s Hospital) and General teaching hospital (University College London Hospital).

Participants

Eleven nurses and managers from cardiology, cardiac surgery, oncology, and intensive care wards (St Bartholomew’s) and medical, haematology and intensive care wards (UCLH) were interviewed and sixty-seven were surveyed online.

Results

Three main themes emerged: (i) Implementing NEWS2 challenges and supports; (ii) Value of NEWS2 to alarm, escalate, particularly during the pandemic; and (iii) Digitalisation: EHR integration and automation. The value of NEWS2 was partly positive in escalation, yet there were concerns by nurses who undervalued NEWS2 particularly in cardiac care. Challenges, like clinicians’ behaviours, lack of resources and training and the perception of NEWS2 value, limit the success of this implementation. Changes in guidelines in the pandemic have led to overlooking NEWS2. EHR integration and automated monitoring are improvement solutions that are not fully employed yet.

Conclusion

Whether in specialist or general medical settings, the health professionals implementing EWS in healthcare face cultural and systems related challenges to adopting NEWS2 and digital solutions. The validity of NEWS2 in specialised settings and complex conditions is not yet apparent and requires comprehensive validation. EHRs integration and automation are powerful tools to facilitate NEWS2 if its principles are reviewed and rectified, and resources and training are accessible. Further examination of implementation from the cultural and automation domains are needed.
Impact of clonal hematopoiesis on atherosclerotic cardiovascular disease according to low-density lipoprotein cholesterol levels
Authors: Lee Heesun , Song Han , Koh Youngil , Park Hyo Eun , Yoon Ji Won , Kim Min Joo , Chung Soie , Bae Jung Ho , Choi Seung Ho , Choi Su-Yeon , Koo Bon-Kwon
Published: June 2022

Background

Clonal hematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of hematopoietic stem cells with age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the pathogenic mechanism of CHIP in atherosclerotic cardiovascular disease (ASCVD) development is not yet fully understood.

Methods

In a cohort comprising 4,300 asymptomatic Korean participants aged 40–79 years, we investigated the risks associated with ASCVD by CHIP and the interplay of CHIP with other traditional risk factors for developing ASCVD. Using coronary computed tomography angiography (CCTA), we noninvasively assessed the changes in coronary arteries to evaluate CHIP-associated atherosclerosis.

Results

CHIP was present in 368 participants (8.6%). The most commonly mutated genes in CHIP included DNMT3A, TET2, and ASXL1. During follow-up (median, 4.7 years), 18 ASCVD cases (4.9%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (p<0.001). The presence of CHIP was associated with an increased risk of ASCVD (adjusted hazard ratio [HR] 2.54, 95% confidence interval [CI] 1.48–4.37, p<0.001) after adjusting for other conventional cardiovascular risk factors. Particularly, in participants with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD development (adjusted HR 4.18, 95% CI 1.99–8.77, p<0.001), demonstrating a significant synergism between CHIP and LDL cholesterol (S-index, 4.61; 95% CI 1.04–20.57, p=0.045). Serial CCTAs supported our findings by displaying de novo measurable coronary atherosclerosis with unstable plaque and in proximal lesions only in CHIP carriers with high LDL cholesterol.

Conclusion

The presence of CHIP was significantly associated with the risk of ASCVD through synergy with LDL cholesterol in the general population, which might promote the early stage of coronary atherosclerosis.
Anti-vascular endothelial growth factor for diabetic macular edema: a Bayesian network analysis
Authors: Wang Xianhuai , Guo Xinyu , Li Tianhui , Sun Xincheng
Published: June 2022

Aims

Comparison of the efficacy of six Anti- vascular endothelial growth drugs in the treatment of diabetic macular edema

Methods

This network meta-analysis has been registered on the PROSPERO platform (CRD42022295684).A comprehensive search of eight databases without language restrictions.PubMed, EMBASE, Web of Science, Cochrane Library, CBM, CNKI, VIP, and Wanfang were used to search for randomized controlled trials on anti- vascular endothelial growth factor of diabetic macular edema, no language restrictions and publication time restrictions. According to the inclusion and exclusion criteria, literatures were screened, data were extracted and literature quality was evaluated, and the mean changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT) were obtained. Using the Gemtc 1.0-1 package in R 4.1.2 to call the JAGS and the Markov Chain-Monte Card (MC-MC) method for Bayesian network meta-analysis. Risk of bias was assessed using RevMan 5.3. Stata 14.0 draws funnel plots to assess publication bias.

RESULTS

Sixteen studies including 3651 eyes were included, all with treatment follow-up over 6 months. The overall heterogeneity in the network analysis was low(I²=0), and there was no inconsistency. For the efficacy of reducing CMT, ranking according to the cumulative probability: Faricimab (0.9) > Brolucizumab (0.87) > Aflibercept (0.58) > Conbercept (0.37) > Ranibizumab (0.29)>Bevacizumab (0), but there was no statistically significant difference between Conbercept and Faclibercept, Aflibercept, and Buloxizumab. For the efficacy of improving BCVA, ranking according to the cumulative probability: Conbercept (0.87) > Faricimab (0.79) > Aflibercept (0.61) > Brolucizumab (0.51) > Ranibizumab (0.2)>Bevacizumab (0.02), but there was no statistically significant difference between Conbercept and Faclibercept, Aflibercept, and Brolucizumab.
The evolving scenario of COVID-19 in hemodialysis patients
Authors: Esposito Pasquale , Picciotto Daniela , Cappadona Francesca , Russo Elisa , Falqui Valeria , Conti Novella Evelina , Parodi Angelica , Mallia Laura , Cavagnaro Sara , Battaglia Yuri , Viazzi Francesca
Published: June 2022

Background

‘Coronavirus disease 2019 (COVID-19) is a rapidly changing disease. So, in this study, we evaluated the evolution of COVID-19 presentation and course in hemodialysis patients (HD).

Methods

We retrospectively compared clinical data and outcomes of HD patients affected by COVID-19 during the first pandemic waves of 2020 (from March to December 2020-Group 1) with patients diagnosed with COVID-19 from September 2021 to February 2022 (Group 2), after the full completion of vaccination. Then, we distinguished among them patients responsive (antibody levels > 13 binding antibody units/ml) and unresponsive to the vaccine. We collected data on COVID-19 clinical presentation, laboratory examinations, and outcomes.

Results

Group 1 was constituted of 44 patients (69.3±14.6 years) and Group 2 of 55 patients (67.4±15.3 years). Among Group 2, fifty-two patients (95%) were vaccinated, 43 of them (83%) with three doses. Patients of Group 2, compared with Group 1, were more often asymptomatic (38 vs 10%, p=0.002), and reported less frequent fever and pulmonary involvement. At diagnosis, the Group 2 showed a significantly higher number of lymphocytes (0.97±0.45 vs 0.69±0.35 cells x109/L, p=0.008) and lower levels of circulating IL-6 (16±13.3 vs 41±39.4 pg/ml, p=0.002). Moreover, in Group 2, inflammatory parameters significantly improved after a few days from diagnosis. Patients of Group 2 presented a lower hospitalization rate (12.7 vs 38%, p=0.004), illness duration (18.8±7.7 vs 29.2±19.5 days, p=0.005), and mortality rate (5.4 vs 25%, p= 0.008). Finally, responders to the vaccination (80% of the vaccinated patients) compared with non-responders showed a reduction in infection duration and hospitalization (5 vs 40%, p=0.018).

Conclusions

COVID-19 presentation and course in HD patients have improved over time after the implementation of vaccine campaigns. However, due to the evolving nature of the disease, active surveillance is necessary.
Estimating the contribution of subclinical tuberculosis disease to transmission – an individual patient data analysis from prevalence surveys
Authors: Emery Jon C. , Dodd Peter J. , Banu Sayera , Frascella Beatrice , Garden Frances L. , Horton Katherine C. , Hossain Shahed , Law Irwin , van Leth Frank , Marks Guy B. , Nguyen Hoa Binh , Nguyen Hai Viet , Onozaki Ikushi , Quelapio Maria Imelda D. , Richards Alexandra S , Shaikh Nabila , Tiemersma Edine W. , White Richard G , Zaman Khalequ , Cobelens Frank , Houben Rein MGJ
Published: June 2022

Background

Individuals with bacteriologically confirmed pulmonary tuberculosis disease (TB) that do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis (Mtb) transmission is unknown, especially compared to individuals who report symptoms at time of diagnosis (clinical TB). Relative infectiousness can be approximated by cumulative infections in household contacts, but such data are rare.

Methods and Findings

We reviewed the literature to identify studies where surveys of Mtb infection were linked to population surveys of TB disease. We collated individual population data for analysis and used literature on the relative durations of subclinical and clinical TB to estimate relative infectiousness through a cumulative hazard model, accounting for sputum-smear status. Relative prevalence of subclinical and clinical disease in high burden settings was used to estimate the contribution of subclinical TB to global Mtb transmission.

We collated data on 414 index cases and 789 household contacts from three prevalence surveys (Bangladesh, Philippines, Viet Nam) and one case-finding trial in Viet Nam. The odds ratio of household infection prevalence was 1.2 (0.6-2.3, 95% Confidence Interval). Adjusting for duration of disease, we found a per-unit-time infectiousness of subclinical TB relative to clinical TB of 1.93 (0.62-6.18, 95% Prediction Interval (PrI)). 14 countries across Asia and Africa provided data on relative prevalence of subclinical and clinical TB, suggesting an estimated 68% (27-92%, 95% PrI) of global transmission is from subclinical TB.

Conclusions

Our results suggest that subclinical TB contributes substantially to transmission and needs to be diagnosed and treated for effective progress towards TB elimination.
Right Or Left: Laterality Incidence Of Billed Plantar Fasciitis Plus Foot Pain
Authors: Kezelian Harry A. , Qadri Ali A. , Chakrabortty Shushovan , Gupta Deepak
Published: June 2022

Background

Footedness and its potential role still remains largely underexplored in terms of laterality of lower extremity diseases.

Materials and Methods

Podiatric medicine patients’ electronic health/medical records were explored based on International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes billed from October 1, 2015-September 30, 2021 for pain in right foot (ICD-10-CM Diagnosis Code M79.671) as well as for plantar fasciitis (ICD-10-CM Diagnosis Code M72.2) vs. for pain in left foot (ICD-10-CM Diagnosis Code M79.672) as well as for plantar fasciitis (ICD-10-CM Diagnosis Code M72.2).

Results

During the six-year period, 1077 patients were only billed for pain in right foot vs. 921 patients were only billed for pain in left foot (p=0.0005) but only 362 patients with pain in right foot were concurrently billed for plantar fasciitis while only 372 patients with pain in left foot were concurrently billed for plantar fasciitis (p=0.71).

Conclusion

Although there was no significance difference between right vs. left plantar fasciitis incidence, the incidental finding of significant difference between right vs. left foot pain incidence warrants future investigations.
Plasma pTau-217 in preclinical Alzheimer’s disease
Authors: Jonaitis Erin M. , Janelidze Shorena , Cody Karly A. , Koscik Rebecca Langhough , Du Lianlian , Chin Nathaniel A. , Mattsson-Carlgren Niklas , Hogan Kirk J. , Christian Bradley T. , Betthauser Tobey J. , Hansson Oskar , Johnson Sterling C.
Published: June 2022

Background and Objectives

An accurate blood test for Alzheimer’s disease (AD) that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention of AD. We assessed the performance of plasma pTau against brain PET markers of amyloid ([11C]-PiB) and tau ([18F]MK-6240), and its utility for predicting longitudinal cognition.

Methods

Samples were analyzed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer’s Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of AD. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma, and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma pTau217 and PET biomarkers of AD, and mixed effects models to understand the ability of plasma pTau217 to predict longitudinal performance on WRAP’s preclinical Alzheimer’s cognitive composite (PACC-3).

Results

The primary analysis included 165 people (108 women; mean age=62.9 ± 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma pTau217 was strongly related to PET-based estimates of concurrent brain amyloid (β̂DVR = 0.83 (0.75, 0.90), p<.001). Concordance was high between plasma pTau217 and both amyloid PET (AUC=0.91, specificity=0.80, sensitivity=0.85, PPV=0.58, NPV=0.94, LR−=5.48) and tau PET (AUC=0.95, specificity=1, sensitivity=0.85, PPV=1, NPV=0.98, LR−=6.47). Higher baseline pTau217 levels were associated with worse cognitive trajectories (β̂pTau=age = -0.07 (-0.09, -0.06), p<.001).

Conclusions and Relevance

In a convenience sample of unimpaired adults, plasma pTau217 levels correlate well with concurrent brain AD pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect AD before clinical signs and thus may disambiguate presymptomatic AD from normal cognitive aging.

Classification of Evidence

This study meets Class III evidential criteria for diagnostic accuracy of plasma pTau217.
Building a Vertically-Integrated Genomic Learning Health System: The Colorado Center for Personalized Medicine Biobank
Authors: Wiley Laura K , Shortt Jonathan A , Roberts Emily R , Lowery Jan , Kudron Elizabeth , Lin Meng , Mayer David A , Wilson Melissa P , Brunetti Tonya M , Chavan Sameer , Phang Tzu L , Pozdeyev Nikita , Lesny Joseph , Wicks Stephen J , Moore Ethan , Morgenstern Joshua L , Roff Alanna N , Shalowitz Elise L , Stewart Adrian , Williams Cole , Edelmann Michelle N , Hull Madelyne , Patton J. Tacker , Axell Lisen , Ku Lisa , Lee Yee Ming , Jirikowic Jean , Tanaka Anna , Todd Emily , White Sarah , Peterson Brett , Hearst Emily , Zane Richard , Greene Casey S , Mathias Rasika , Coors Marilyn , Taylor Matthew RG , Ghosh Debashis , Kahn Michael G , Brooks Ian M , Aquilante Christina L , Kao David , Rafaels Nicholas , Crooks Kristy , Hess Steve , Barnes Kathleen C , Gignoux Christopher R
Published: June 2022

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the Biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has over 200,000 patients with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain Region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped patients across multiple disease domains. Finally, we describe our current efforts towards return of clinical genetic test results including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA and CLIA-certified environment.
Estimation of offspring genetic risk scores using parental genotypes
Authors: Adesomo Adebayo , Workalemahu Tsegaselassie , Givens Matthew , Yandell Mark , Quinlan Aaron , Tristani-Firouzi Martin , Heerboth Sarah , Silver Robert , Blue Nathan
Published: June 2022

Objective

Our objective was to determine whether genetic risk scores (GRSs) of offspring can be accurately estimated from parental DNA.

Methods

Whole genome sequencing data from a cohort of forty-seven multi-generation Utah families were used to extract single nucleotide polymorphism (SNP) data at genetic loci associated with the following traits: birth weight (BW), fasting plasma glucose (FPG), blood pressure (BP), body mass index (BMI), height, and type 2 diabetes (T2D). Offspring GRSs for each trait were estimated from parental single nucleotide polymorphism (SNP) data and compared to actual offspring GRSs. We also assessed offspring GRS estimation using only one parent’s DNA to simulate scenarios when only one genetic parent is available. The primary outcome was the percent error of parental-derived estimated GRS for each trait. An a priori threshold of 10% error was chosen for estimated GRSs to be considered accurate.

Results

Forty-three families with an average of 8.9 ± 1.8 offspring (N = 454 offspring) had parental and offspring SNP data available for GRS calculations. Mean percent errors for estimated offspring GRSs were less than 10% for all traits except for FPG (10.5% ± 8.1%). Percent errors were not significantly different when offspring GRSs were estimated using only one parent’s DNA whether the missing parent was a father or mother. Mean percent error of GRSs decreased exponentially with increasing SNPs per trait, with diminishing improvement in percent error above 500 SNPs.

Conclusion

Parental genetic risk scores can be used to accurately estimate genetic risk scores of offspring. This proof of concept supports further exploration of parental genetic risk scores as a tool for prenatal fetal genetic risk stratification.

Statements

What’s already known about this topic?

Genetic risk scoring is a tool to estimate the probability of development traits or conditions with complex, multifactorial inheritance.

What does this study add?

Offspring genetic risk scores can be accurately estimated using parental DNA. This proof of concept supports further exploration of parental genetic risk scores as a tool for prenatal fetal genetic risk stratification.
Mapping Climate Change’s Impact on Cholera Infection Risk in Bangladesh
Authors: Kruger Sophia E. , Lorah Paul A. , Okamoto Kenichi W.
Published: June 2022

Several studies have investigated howVibrio choleraeinfection risk changes with increased rainfall, temperature, and water pH levels for coastal Bangladesh, which experiences seasonal surges in cholera infections associated with heavy rainfall events. While coastal environmental conditions are understood to influenceV. choleraepropagation within brackish waters and transmission to and within human populations, it remains unknown how changing climate regimes impact the risk for cholera infection throughout Bangladesh. To address this, we developed a random forest species distribution model to predict the occurrence probability of cholera incidence within Bangladesh for 2015 and 2050. Using R, our random forest model was trained on cholera incidence data and spatial environmental raster data at a resolution of 250 square meters. This model was then predicted to environmental data for the training data year (2015) and for 2050. We interfaced R with ArcGIS to develop risk maps for cholera infection for the years 2015 and 2050, proxying infection risk with cholera occurrence probability predicted by the model. The best-fitting model predicted cholera occurrence given elevation and distance to water. We find that although cells of high risk cluster along the coastline predominantly in 2015, by 2050 high-risk areas expand from the coast to inland Bangladesh with all but the northwestern district of Rangpur seeing increased clusters around surface water. Mapping the geographic distribution of cholera infections given projected environmental conditions provides a valuable tool for guiding proactive public health policy tailored to areas most at risk of future disease outbreaks.
Structure-based discovery of a novel small-molecule inhibitor of TEAD palmitoylation with anticancer activity
Authors: Gridnev Artem , Maity Subhajit , Misra Jyoti R.
Published: June 2022

The paralogous oncogenic transcriptional coactivators YAP and TAZ are the distal effectors of the Hippo signaling pathway, which play a critical role in cell proliferation, survival and cell fate specification. The core kinase cascade of the Hippo signaling pathway phosphorylates YAP/TAZ and restrict its activity by promoting cytoplasmic sequestration and degradation. Unphosphorylated YAP/TAZ translocates into the nucleus and associates with the TEA domain (TEAD1-4) transcription factors to regulate their target genes. They are frequently misregulated in most human cancers, where they contribute to multiple aspects of tumorigenesis including growth, metabolism, metastasis and chemo/immunotherapy resistance. Thus, they provide a critical point for therapeutic intervention. However, due to their intrinsically disordered structure, they are challenging to target directly. Since YAP/TAZ exerts oncogenic activity by associating with the TEAD1-4 transcription factors, to regulate target gene expression, YAP activity can be controlled indirectly by regulating TEAD1-4. Interestingly, TEADs undergo autopalmitoylation, which is essential for their stability and function. The palmitic acid occupies a hydrophobic pocket in TEAD1-4, and small-molecule inhibitors that bind to this site can render them unstable, and allosterically inhibit their interaction with YAP/TAZ and chromatin. Here we combined structure-based virtual ligand screening with biochemical and cell biological studies and identified a novel small-molecule that inhibits TEAD palmitoylation and stability. Further, it affects YAP-TEAD interaction and inhibits YAP transcriptional activity and impairs proliferation, colony formation and migration of breast and ovarian cancer cells.
Performance estimation of two in-house ELISA assays for COVID-19 surveillance through the combined detection of anti-SARS-CoV-2 IgA, IgM, and IgG immunoglobulin isotypes
Authors: Ramírez-Reveco Alfredo , Velázquez Gerardo , Aros Christopher , Navarrete Gabriela , Villarroel-Espindola Franz , Navarrete Maritza , Fica Alberto , Plaza Anita , Castro Natalia , Verdugo Claudio , Acosta-Jamett Gerardo , Verdugo Cristóbal
Published: June 2022

The main objective of this study was to estimate the performance, under local epidemiological conditions, of two in-house ELISA assays for the combined detection of anti-SARS-CoV-2 IgA, IgM, and IgG immunoglobulins. A total of 94 serum samples were used for the assessment, where 44 corresponded to sera collected before the pandemic (free SARS-CoV-2 antibodies), and 50 sera were collected from confirmed COVID-19 patients admitted to the main public hospital in the city of Valdivia, southern Chile. The Np and RBD proteins were separately used as antigens (Np and RBD ELISA, respectively) to assess their diagnostic performance. A receiver operating characteristic (ROC) analysis was performed to estimate the optical density (OD) cut-off that maximized the sensitivity (Se) and specificity (Sp) of the ELISA assays. Np ELISA had a mean Se of 94% (95% CI = 83.5 – 98.8%) and a mean Sp of 100% (95% CI = 92.0 – 100%), with an OD 450 nm positive cut-off value of 0.88. On the other hand, RBD ELISA presented a mean Se of 96% (95% CI = 86.3 – 99.5%) and a mean Sp of 90% (95% CI = 78.3 – 97.5%), with an OD 450 nm positive cut off value of 0.996. Non-significant differences were observed between the Se distributions of Np and RBD ELISAs, but the latter presented a significant lower Sp than Np ELISA. In parallel, collected sera were also analyzed using a commercial lateral flow chromatographic immunoassay (LFCI), to compare the performance of the in-house ELISA assays against a commercial test. The LFCI had a mean sensitivity of 94% (95% CI = 87.4 – 100%) and a mean specificity of 100% (95% CI = 100 – 100%). When compared to Np ELISA, non-significant differences were observed on the performance distributions. Conversely, RBD ELISA had a significant lower Sp than the LFCI. Although, Np ELISA presented a similar performance than the commercial test, this was 2.5 times cheaper than the LFCI assay. Thus, the in-house Np ELISA could be a suitable alternative tool, in resource limited environments, for the surveillance of SARS-CoV-2 infection, supporting further epidemiological studies.
Genome wide association neural networks (GWANN) identify genes linked to family history of Alzheimer’s disease
Authors: Ghose Upamanyu , Sproviero William , Winchester Laura , Amin Najaf , Zhu Taiyu , Newby Danielle , Ulm Brittany S. , Papathanasiou Angeliki , Shi Liu , Liu Qiang , Fernandes Marco , Adams Cassandra , Albukhari Ashwag , Almansouri Majid , Choudhry Hani , van Duijn Cornelia , Nevado-Holgado Alejo
Published: June 2022

Augmenting traditional genome wide association studies (GWAS) with advanced machine learning algorithms can allow the detection of novel signals in available cohorts. We introduce “Genome wide association neural networks (GWANN)”, a novel approach that uses neural networks (NNs) to perform a gene-level association study with family history of Alzheimer’s disease (AD). In UK Biobank, we defined cases (n=42,110) as those with AD or family history of AD and sampled an equal number of controls. The data was split into an 80:20 ratio of training and testing samples, and GWANN was trained on the former followed by identifying associated genes using its performance on the latter. Our method identified 18 genes to be associated with family history of AD.APOE,BIN1, SORL1, ADAM10, APH1B,andSPI1have also been identified by previous AD GWAS.PCDH9, NGR3, ROR1, LINGO2, SMYD3,andLRRC7were among the new genes that have been previously associated with neurofibrillary tangles or phosphorylated tau. Furthermore, there is evidence for differential transcriptomic or proteomic expression between AD and healthy brains for 11 of the 12 new genes. A series of post-hoc analyses resulted in a significantly enriched protein-protein interaction network (P-value<1×10−16), and enrichment of relevant disease and biological pathways such as focal adhesion (P-value=1×10−4), extracellular matrix organisation (P-value=1×10−4), Hippo signalling (P-value=7×10−4), Alzheimer’s disease (P-value=3×10−4), impaired cognition (P-value=4×10−3), and autism spectrum disorders (P-value=1×10−2). Applying NNs for GWAS illustrates their potential to complement existing algorithms and methods and enable the discovery of new associations without the need to expand existing cohorts.
Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy
Authors: Sand Ilana Katz , Gnjatic Sacha , Krammer Florian , Tuballes Kevin , Carreño Juan Manuel , Satyanarayan Sammita , Filomena Susan , Staker Erin , Tcheou Johnstone , Miller Aaron , Fabian Michelle , Safi Neha , Nichols Jamie , Patel Jasmin , Krieger Stephen , Tankou Stephanie , Horng Sam , Klineova Sylvia , Beck Erin , Merad Miriam , Lublin Fred
Published: June 2022

Importance

People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants.

Objective

Evaluate humoral and cellular immune responses to third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays.

Design

Observational study evaluating immunological response to third COVID-19 vaccine dose in volunteers treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated.

Setting

Mount Sinai Hospital

Participants

People treated with anti-CD20 therapy or S1PR modulators and healthy volunteers

Exposure

Treatment with anti-CD20 therapy, S1PR modulator, or neither

Main outcomes and measures

Serum neutralizing antibodies and ex vivo T cell responses against SARS-CoV-2 antigens.

Results

This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P<0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p<0.001) and were not significantly “boosted” by a third injection.

Conclusions and Relevance

Participants on immunomodulators had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.
Platelet findings in 22q11.2 Deletion Syndrome correlate with disease manifestations but do not correlate with GP1b surface expression
Authors: Campbell Ian M. , Crowley T. Blaine , Jobaliya Chintan , Bailey Alice , McGinn Daniel E. , Gaiser Kimberly , Bassett Anne , Gur Raquel E. , Morrow Bernice , Emanuel Beverly S. , Franco Aime T. , French Deborah , Zackai Elaine H. , McDonald-McGinn Donna M. , Lambert Michele P.
Published: June 2022

Prior studies have demonstrated that patients with chromosome 22q11.2 deletion syndrome (22q11.2DS) have lower platelet counts (PC) compared to non-deleted populations. They also have an increased mean platelet volume. The mechanism for this has been postulated to be haploinsufficiency of the GPIBB gene. We examined platelet parameters, deletion size and factors known to influence counts, including status of thyroid hormone and CHD, in a population of 825 patients with 22q11.2DS. We also measured surface expression of GPIB-IX complex by flow cytometry. The major determinant of PC was deletion status of GP1BB, regardless of surface expression or other factors. Patients with nested distal chromosome 22q11.2 deletions (those with GP1BB present) had higher PCs than those with proximal deletions where GP1BB is deleted. Patients with 22q11.2DS also demonstrated an accelerated PC decrease with age, occurring in childhood. These data demonstrate that genes within the proximal deletion segment drive PC differences in 22q11.2DS and suggest that PC reference ranges may need to be adjusted for age and deletion size in 22q11.2DS populations. Bleeding did not correlate with either platelet count or GP1b expression. Further studies into drivers of expression of GP1b and associations with severe thrombocytopenia and immune thrombocytopenia are needed to inform clinical care.