bluuebunny/crossref_metadata_2025 huggingface dataset:
A Systematic Review of New Approaches to Sexually Transmitted Infection Screening Framed in the Capability, Opportunity, Motivation, and Behavior Model of Implementation Science
Authors: Footman Alison , Dagama Dorris , Smith Catherine Hogan , Van Der Pol Barbara
Published: May 2021

Chlamydia and gonorrhea are 2 of the most common bacterial sexually transmitted infections (STIs) worldwide. Rising chlamydia and gonorrhea rates along with increased closing of STI clinics has led many to seek STI testing in clinical settings such as urgent cares and walk-in clinics. However, with competing priorities, providing effective and efficient STI care can be difficult in these settings. This has left a growing need for the implementation of novel STI screening programs in other clinical settings. This review summarizes previous studies that have evaluated the clinical implementation of chlamydia and gonorrhea screening programs in these settings. Literature from January 2015 to February 2020 regarding the implementation or evaluation of STI screening programs in clinical settings was reviewed. Constructs from the Capability, Opportunity, Motivation, and Behavior model were used to organize results, as this model can aid in identifying specific strategies for behavior/process change interventions. We found that multiple STI screening programs have been implemented and evaluated in 5 different countries and multiple health care facilities including sexual health clinics, urgent cares, walk-in clinics, and university health clinics. When implementing new STI screening programs, sample-first, test-and-go services and molecular point-of-care (POC) testing approaches were found to be effective in increasing screening and reducing costs and time to treatment. At the health care systems level, these programs can help reduce STI screening costs and generate additional revenue for clinics. At the provider level, clear communication and guidance can help clinical and administrative staff in adopting new screening programs. Finally, at the patient level, new programs can reduce time to treatment and travel costs in visiting clinics multiple times for testing and treatment services.
Expression and Mutation Alterations of ZMYM4 Gene in Gastric and Colonic Cancers
Authors: Moon Seong Won , Son Hyun Ji , Chae Jeesoo , Yoo Nam Jin , An Chang Hyeok , Lee Sug Hyung
Published: May 2021

ZMYM4 is a zinc finger protein, whose cancer-related functions are partially known (cell shape maintenance and cell death). In this study, we analyzed 4 sites of mononucleotide repeats in the coding sequence of ZMYM4 in gastric (GC) and colonic cancers (CC). Seven of the 32 high microsatellite instability (MSI-H) GCs (21.9%) and 23 of 113 MSI-H CCs (20.4%) harbored ZMYM4 frameshift mutations with no significant difference between the 2 organs (P>0.05). There was no ZMYM4 frameshift mutations in microsatellite-stable GCs and CCs. We also identified that 6 of 16 MSI-H CCs (37.5%) exhibited intratumoral heterogeneity of the ZMYM4 frameshift mutations. In both GC and CC with MSI-H, ZMYM4 expression in ZMYM4-mutated cases was significantly lower than that in ZMYM4-nonmutated cases. Our study indicates that ZMYM4 is altered at multiple levels (frameshift mutation, mutational intratumoral heterogeneity, and loss of expression), suggesting their relations with MSI-H GC and CC.
Psychiatric Education for Pediatric Emergency Medicine Fellows
Authors: Rudloff James , Wurster Ovalle Victoria , Barzman Drew , Gonzalez-del-Rey Javier
Published: May 2021

Objectives

The number of psychiatric encounters is steadily increasing across all pediatric emergency departments. Based on this growing national crisis, we hypothesized there is a lack of robust education in behavioral/mental health emergencies during pediatric emergency medicine (PEM) fellowship.

Methods

This was a cross-sectional survey of PEM fellowship directors. The survey was submitted to the Pediatric Emergency Medicine Program Director Survey Committee via REDCap to all 83 fellowship directors.

Results

Fifty-five (66%) PEM fellowship directors completed the survey from September 2019 to December 2019. Forty-three (78%) programs provide some type of didactic teaching, although only 7 (13%) programs offer more than 5 hours of didactics over 3 years of fellowship. Six (11%) programs offer electronic resources, 13 (24%) offer simulations in psychiatry, and only 4 (7%) programs require any type of psychiatry rotation. Forty-six (84%) programs do not currently use psychiatric emergencies as a competency for evaluating PEM fellows. Program directors felt significantly more confident in faculty than graduating fellows in the management of numerous diagnoses including agitation (P < 0.001), homicidal ideation (P = 0.044), neuroleptic malignant syndrome (P = 0.006), acute dystonia (P < 0.001), and heroin overdose (P = 0.022). Ninety-six percent felt online curricula would be helpful to address this knowledge gap.

Conclusions

Despite growing behavioral/mental health needs in the pediatric emergency department, there continues to be opportunity to improve psychiatric education during PEM fellowship. Program directors felt more confident in faculty than graduating fellows with several psychiatric diagnoses. Pediatric emergency medicine fellowship directors expressed a strong interest in online tools to assist in the education of PEM fellows.
Effect of Traditional Plus Virtual Reality Rehabilitation on Prognosis of Stroke Survivors
Authors: Fang Zongwei , Wu Tingting , Lv Meina , Chen Mingrong , Zeng Zhiwei , Qian Jiafen , Chen Wenjun , Jiang Shaojun , Zhang Jinhua
Published: April 2021

Objective

Virtual reality technology has begun to be gradually applied to clinical stroke rehabilitation. The study aimed to evaluate the effect of traditional plus virtual reality rehabilitation on motor function recovery, balance, and activities of daily living in stroke patients.

Method

Studies published in English before October 2020 were retrieved from PubMed, Embase, Web of Science, and the Cochrane Library. This study used RevMan 5.3 software for meta-analysis.

Result

A total of 21 randomized controlled trials were included, which enrolled 619 patients. Traditional plus virtual reality rehabilitation is better than traditional rehabilitation in upper limb motor function recovery measured by Fugl-Meyer Assessment–Upper Extremity (mean difference = 3.49, 95% confidence interval = 1.24 to 5.73, P = 0.002) and manual dexterity assessed by Box and Block Test (mean difference = 6.59, 95% confidence interval = 3.45 to 9.74, P < 0.0001). However, there is no significant difference from traditional rehabilitation in activities of daily living assessed by Functional Independence Measure (mean difference = 0.38, 95% confidence interval = −0.26 to 1.02, P = 0.25) and balance assessed by Berg Balance Scale (mean difference = 2.18, 95% confidence interval = −0.35 to 4.71, P = 0.09).

Conclusions

Traditional plus virtual reality rehabilitation therapy is an effective method to improve the upper limb motor function and manual dexterity of patients with limb disorders after stroke, and immersive virtual reality rehabilitation treatment may become a new option for rehabilitation after stroke.
Major Depression and Survival in People With Cancer
Authors: Walker Jane , Mulick Amy , Magill Nicholas , Symeonides Stefan , Gourley Charlie , Burke Katy , Belot Aurelien , Quartagno Matteo , van Niekerk Maike , Toynbee Mark , Frost Chris , Sharpe Michael
Published: May 2021

Objective

The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study.

Methods

We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis.

Results

Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15–1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11–1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08–1.71), lung cancer (HR = 1.39, 95% CI = 1.24–1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08–2.85). The pooled HR was 1.41 (95% CI = 1.29–1.54, p < .001, I
2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer.

Conclusions

Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study.
Financial Stressors During the Great Recession and Subsequent Risk of Early Mortality
Authors: Bourassa Kyle J.
Published: May 2021

Objective

The Great Recession in 2008 was a period of severe economic upheaval and myriad financial stressors. Financial stress is associated with poorer health, but for whom is this stress the most health-relevant? The current study examined the association between financial stressors and mortality, as well as whether this association varied based on people’s financial status.

Methods

Participants from the Midlife in the United States study (n = 2760) were assessed before (2004–2005) and after (2013–2014) the Great Recession (2008). Mortality status was then tracked from 2013 to 2017.

Results

People who experienced more financial stressors during the Great Recession were at greater risk of early mortality over the 4-year follow-up (hazard ratio [HR] = 1.14 [1.00–1.29], p = .046). This association was moderated by the importance of financial security (B = 0.34 [0.08–0.59], p = .009). Financial stressors were more strongly associated with mortality among people who reported that financial security was important to their well-being (HR = 1.29 [1.08–1.54], p = .006) compared with people who reported it was not (HR = 1.02 [0.82–1.26], p = .89). Household income and subjective financial status did not moderate the association between financial stressors and mortality.

Conclusions

Experiencing financial stressors during the Great Recession was associated with increased mortality over the 4-year follow-up period, particularly for people who reported financial security was important to their well-being. Interventions designed to reduce financial stress to improve health may benefit from targeting people for whom such stressors are particularly important.
The Role of Fgf9 in the Antidepressant Effects of Exercise and Fluoxetine in Chronic Unpredictable Mild Stress Mice
Authors: Xia Jie , Xue Xiangli , Liu Wenbin , Qi Zhengtang , Liu Weina
Published: May 2021

Objective

The neurotrophic hypothesis of depression posits that stress and depression decrease neurotrophic factor expression in brain, whereas antidepressants and exercise can contribute to the blockade of stress effects and produce antidepressant effects. Fibroblast growth factor 9 (FGF9), a member of the fibroblast growth factor (FGF) family, has been reported to be dysregulated in depression. The present study aimed to determine whether and how Fgf9 mediates the antidepressant effects of fluoxetine and exercise in chronic unpredictable mild stress (CUMS) mice.

Methods

Male C57BL/6 mice were exposed to CUMS for 7 weeks. From the fourth week, CUMS-exposed mice were subjected to fluoxetine treatment or swimming exercise for 4 weeks. Forced swim test, tail suspension test, and hole-board test were used to assess behaviors of mice. Real-time polymerase chain reaction was used to examine hippocampal messenger RNA levels of Fgf9, Fgf2, FgfR1, FgfR2, and FgfR3. Western blotting was used to examine the protein levels of Fgf9, protein kinase B (Akt), and phosphorylation of Akt at Ser473 in mouse hippocampus.

Results

Our results demonstrated that CUMS induced depression-like behaviors, which were reversed by fluoxetine treatment and swimming exercise. Moreover, we found that CUMS resulted in a dysregulation of Fgf9, Fgf2, and FgfR2 expression, whereas fluoxetine and swimming restored the FGF expression in CUMS-exposed mice. An analysis of the proteins suggests that the antidepressant effects of fluoxetine and exercise in CUMS-exposed mice were associated with ameliorated Fgf9/Akt signaling.

Conclusions

Our findings have demonstrated that swimming exercise mimics the antidepressant effects of fluoxetine by regulating Fgf9 in CUMS-exposed mice, which may offer new mechanism-based therapeutic targets for depression.
Biopsychosocial Processes of Health and Disease During the COVID-19 Pandemic
Authors: Kop Willem J.
Published: May 2021

The biopsychosocial model provides a useful perspective for understanding the development and characteristics of the COVID-19 pandemic and its anticipated long-term consequences for society as well as individuals. This article provides a biopsychosocial perspective on the COVID pandemic and an editorial comment on the articles in this Special Issue of Psychosomatic Medicine. Based on analysis of the PubMed database, it is shown that the attention to psychological and social factors is 74% higher in COVID-19-related articles compared to all other health-related scientific articles published during the same time-period (between 1/1/2020 and 4/18/2021). Specifically, 18.6% of the ≈123,500 articles addressing COVID-19-related topics also included psychological or social factors in their content vs. 10.7% of articles that did not address COVID-19. The biopsychosocial model is relevant to understanding the interrelationships among risk factors and the multidimensional clinical and psychosocial COVID-19 outcomes. Clinical outcomes directly related to COVID-19 range from severe but rare events (mortality and intensive care treatment) to less severe common outcomes such as positive screening tests for COVID-19 with or without symptoms. In addition, psychosocial outcomes range in severity from frequently observed reduced psychological wellbeing to less common clinical mood and anxiety disorders and, in rare cases, suicidality. The COVID-19 pandemic is characterized by an unusually strong and short-term link between social factors and biological aspects of the disease, without mediating psychological factors. After a review of the articles presented in this Special Issue, this editorial concludes with suggestions for biopsychosocial models in research on COVID-19 and other large-scale health threats.
Prevalence of HIV/hepatitis B and HIV/hepatitis C coinfection among people of East, South, Central and West African ancestry in the United Kingdom
Authors: Hung Rachel , Patel Nisha , Fox Julie , Cosgrove Catherine , Pett Sarah L. , Burns Fiona , Ustianowski Andrew , Rosenvinge Melanie , Bhagani Sanjay , Dusheiko Geoff , Childs Kate , Post Frank A.
Published: April 2021

Regional variability in the prevalence of hepatitis B (HBV) and C (HCV) is reported in sub-Saharan Africa, although data for people with HIV are sparse. We determined the prevalence of HBV/HCV in 2473 people of African ancestry with HIV in the UK. Overall, 6.2% were co-infected with HBV and 1.3% with HCV. Central [adjusted odds ratio (aOR) 2.40 (95% confidence interval (CI) 1.23--4.67) and West [2.10 (1.29–3.41)] African ancestry was associated with HBV and Central [6.98 (2.00–24.43)] African ancestry with HCV.
Special Considerations for Chin Augmentation in the Professional Violinist
Authors: Boustany Ashley N. , Manstein Samuel M. , Lin Samuel J.
Published: May 2021

The extensive training and unique positioning of a stringed instrument (eg, professional violinist) may subject the mandible to compressive forces that may lead to asymmetric micrognathia. Prior cephalometric studies have shown a right-sided facial dominance with an underdeveloped left mandible. Surgical correction must account for occupational demands, as the chin is uniquely load-bearing in violinists. The use of three-dimensional planning with a customized implant facilitates the correction of asymmetries and allows shared decision-making for optimal implant fit. Our case outlines important considerations for alloplastic chin augmentation in violinists.
Patients Undergoing Ileoanal Pouch Surgery Experience a Constellation of Symptoms and Consequences Representing a Unique Syndrome
Authors: Cavallaro Paul , Fearnhead Nicola , Bissett Ian , Brar Mantaj , Cataldo Thomas , Clarke Rasheed , Denoya Paula , Elder Amber Lorraine , Gecse Krisztina , Hendren Samantha , Holubar Stefan , Jeganathan Nimalan , Myrelid Pär , Norton Beth-Anne , Wexner Steven , Wilson Lauren , Zaghiyan Karen , Bordeianou Liliana
Published: May 2021

Objective:

The primary aim was to create a patient-centered definition of core symptoms that should be included in future studies of pouch function.

Background:

Functional outcomes after ileoanal pouch creation have been studied; however, there is great variability in how relevant outcomes are defined and reported. More importantly, the perspective of patients has not been represented in deciding which outcomes should be the focus of research.

Methods:

Expert stakeholders were chosen to correlate with the clinical scenario of the multidisciplinary team that cares for pouch patients: patients, colorectal surgeons, gastroenterologists/other clinicians. Three rounds of surveys were employed to select high-priority items. Survey voting was followed by a series of online patient consultation meetings used to clarify voting trends. A final online consensus meeting with representation from all 3 expert panels was held to finalize a consensus statement.

Results:

One hundred ninety-five patients, 62 colorectal surgeons, and 48 gastroenterologists/nurse specialists completed all 3 Delphi rounds. Fifty-three patients participated in online focus groups. One hundred sixty-one stakeholders participated in the final consensus meeting. On conclusion of the consensus meeting, 7 bowel symptoms and 7 consequences of undergoing ileoanal pouch surgery were included in the final consensus statement.

Conclusions:

This study is the first to identify key functional outcomes after pouch surgery with direct input from a large panel of ileoanal pouch patients. The inclusion of patients in all stages of the consensus process allowed for a true patient-centered approach in defining the core domains that should be focused on in future studies of pouch function.
Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy
Authors: Jin Runsen , Zheng Yuyan , Yuan Ye , Han Dingpei , Cao Yuqin , Zhang Yajie , Li Chengqiang , Xiang Jie , Zhang Zhengyuan , Niu Zhenyi , Lerut Toni , Lin Jules , Abbas Abbas E. , Pardolesi Alessandro , Suda Takashi , Amore Dario , Schraag Stefan , Aigner Clemens , Li Jian , Che Jiaming , Hang Junbiao , Ren Jian , Zhu Lianggang , Li Hecheng
Published: May 2021

Objective:

To determine whether RAL affects perioperative outcomes and long-term efficacy in NSCLC patients, compared with traditional VAL.

Summary of Background Data:

RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated.

Methods:

A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared.

Results:

The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the 2 groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage {830 mL [interquartile range (IQR), 550–1130 mL] vs 685 mL [IQR, 367.5–1160 mL], P = 0.007} and hospitalization costs [$12821 (IQR, $12145–$13924) vs $8009 (IQR, $7014–$9003), P < 0.001] were significantly higher in the RAL group. RAL group had a significantly higher number of LNs harvested [11 (IQR, 8–15) vs 10 (IQR, 8–13), P = 0.02], higher number of N1 LNs [6 (IQR, 4–8) vs 5 (IQR, 3–7), P = 0.005], and more LN stations examined [6 (IQR, 5–7) vs 5 (IQR, 4–6), P < 0.001].

Conclusions:

Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534)
Prehospital evaluation and detection of induced coagulopathy in trauma: The PREDICT study
Authors: Gaessler Holger , Helm Matthias , Kulla Martin , Hossfeld Bjoern , Schmid Uta , Kerschowski Juergen , Bretschneider Ingeborg
Published: May 2021

BACKGROUND

Hemorrhage with trauma-induced coagulopathy (TIC) and hyperfibrinolysis (HF) increases the mortality risk after severe trauma. While TIC at hospital admission is well studied, little is known about coagulopathy at the incident site. The aim of the study was to investigate coagulation disorders already present on scene.

METHODS

In a prospective single-center observational study, blood samples of trauma patients obtained before and at hospital admission were analyzed. Data on rotational thromboelastometry, blood gas analysis, prehospital treatment, injury severity, in-hospital blood transfusions, and mortality were investigated according to the presence of coagulation disorders at the incident site. The patients were divided into three groups according to the presence of coagulation disorders (no coagulopathy, TIC, TIC with HF). In a subgroup analysis, patients with a Trauma-Induced Coagulopathy Clinical Score (TICCS) of ≥10 were investigated.

RESULTS

Between August 2015 and February 2018, 148 patients were enrolled in the study. The mean Injury Severity Score was 22.1, and overall mortality was 7.4%. Trauma-induced coagulopathy and HF were already detectable at the incident site in 18.2% and 6.1%, respectively. Patients with HF had significantly altered circulation parameters with significant changes in pH, hemoglobin, lactate, and base excess at the incident site. In patients with TICCS of ≥10 (14.2%), TIC was detected in 47.6% of the cases and HF in 28.6%. Furthermore, in these patients, blood gas parameters significantly changed and the need for blood transfusion and mortality.

CONCLUSION

Trauma-induced coagulopathy and HF can be detected in severely injured patients even before medical treatment is started. Furthermore, in patients with HF and TICCS of ≥10, blood gas parameters were significantly changed at the incident site.

LEVEL OF EVIDENCE

Prognostic study, level III.
Automatic quantification of brain lesion volume from post-trauma MR Images
Authors: Mistral Thomas , Roca Pauline , Maggia Christophe , Tucholka Alan , Forbes Florence , Doyle Senan , Krainik Alexandre , Galanaud Damien , Schmitt Emmanuelle , Kremer Stéphane , Kastler Adrian , Troprès Irène , Barbier Emmanuel L , Payen Jean-François , Dojat Michel
Published: April 2021

Objectives

The determination of the volume of brain lesions after trauma is challenging. Manual delineation is observer-dependent and time-consuming which inhibits the practice in clinical routine. We propose and evaluate an automated atlas-based quantification procedure (AQP) based on the detection of abnormal mean diffusivity (MD) values computed from diffusion-weighted MR images.

Methods

We measured the performance of AQP versus manual delineation consensus by independent raters in two series of experiments: i) realistic trauma phantoms (n=5) where abnormal MD values were assigned to healthy brain images according to the intensity, form and location of lesion observed in real TBI cases; ii) severe TBI patients (n=12 patients) who underwent MR imaging within 10 days after injury.

Results

In realistic trauma phantoms, no statistical difference in Dice similarity coefficient, precision and brain lesion volumes was found between AQP, the rater consensus and the ground truth lesion delineations. Similar findings were obtained when comparing AQP and manual annotations for TBI patients. The intra-class correlation coefficient between AQP and manual delineation was 0.70 in realistic phantoms and 0.92 in TBI patients. The volume of brain lesions detected in TBI patients was 59 ml (19-84 ml) (median; 25-75th centiles).

Conclusions

our results indicate that an automatic quantification procedure could accurately determine with accuracy the volume of brain lesions after trauma. This presents an opportunity to support the individualized management of severe TBI patients.

Key points

The management of patients with severe traumatic brain injury is complex, and access to objective quantitative information lesion volumes can support clinical decision-making.

An automated delineation procedure was developed to determine the nature and volume of brain lesions post-trauma.

This procedure was based on diffusion weighted MR-imaging to quantify the volume of vasogenic and cellular edema from realistic phantoms and patients with severe traumatic brain injury.

Nature and quantification of the brain lesions volume compared favorably with manual delineation of brain lesions by a panel of experts.
Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium
Authors: Cao Dongfeng , Leong Belinda , Messinger Jeffrey D. , Kar Deepayan , Ach Thomas , Yannuzzi Lawrence A. , Freund K. Bailey , Curcio Christine A.
Published: April 2021

Purpose

By optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Müller glia.

Method

In clinical OCT (61 eyes, 44 AMD patients, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

Results

Trajectories of RPE plume and cellular debris paralleled Müller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Müller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

Conclusion

Gain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Müller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

Précis

Hyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation.
A Prospective Longitudinal Study of Health-Related Quality of Life and Psychological Wellbeing after an Implantable Cardioverter Defibrillator in Patients with Genetic Heart Diseases
Authors: van den Heuvel Lieke M. , Sarina Tanya , Sweeting Joanna , Yeates Laura , Bates Kezia , Spinks Catherine , O’Donnell Catherine , Sears Samuel F. , McGeechan Kevin , Semsarian Christopher , Ingles Jodie
Published: April 2021

Background

Genetic heart diseases often affect young people, can be clinically heterogeneous and pose an increased risk of sudden cardiac death (SCD). The implantable cardioverter defibrillator (ICD) is a lifesaving therapy. Impacts on prospective and long-term psychological and health-related quality of life (HR-QoL) after ICD implant in patients with genetic heart diseases are unknown. We investigate the psychological functioning and HR-QoL over time in patients with genetic heart diseases who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL.

Methods

A longitudinal, prospective study design was used. Patients attending a specialised clinic and diagnosed with a genetic heart disease, for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with five-year follow-up after ICD implant. We measured psychological functioning (Hospital Anxiety Depression Scale, Florida Shock Anxiety Scale), HR-QoL (Short-Form 36v2) and device acceptance (Florida Patient Acceptance Scale).

Results

There were 40 patients with an inherited cardiomyopathy or arrhythmia syndrome included (mean age 46.3 ± 14.2 years; 65.0% males). Mean psychological and HR-QoL measures were within normative ranges during follow-up. After 12 months, 33.3% and 19.4% of participants showed clinically elevated levels of anxiety and depression, respectively. Longitudinal mixed effect analysis showed significant improvements from baseline to first follow-up for the overall cohort, with variability increasing after 36 months. Low education and female gender predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL.

Conclusion

While the majority of patients with a genetic heart disease adjust well to their ICD implant, a subset of patients’ experience poor psychological and HR-QoL outcomes.
Impairment of T cells’ antiviral and anti-inflammation immunities dominates death from COVID-19
Authors: Zhang Luhao , Li Rong , Song Gang , Scholes Gregory D. , She Zhen-Su
Published: April 2021

Clarifying dominant factors determining the immune heterogeneity from non-survivors to survivors is crucial for developing therapeutics and vaccines against COVID-19. The main difficulty is quantitatively analyzing the multi-level clinical data, including viral dynamics, immune response, and tissue damages. Here, we adopt a top-down modelling approach to quantify key functional aspects and their dynamical interplay in the battle between the virus and the immune system, yielding an accurate description of real-time clinical data involving hundreds of patients for the first time. The quantification of antiviral responses demonstrates that, compared to antibodies, T cells play a more dominant role in virus clearance, especially for mild patients (96.5%). Moreover, the anti-inflammatory responses, namely the cytokine inhibition and tissue repair rates, also positively correlate with T cell number and are significantly suppressed in non-survivors. Simulations show that the lack of T cells leads to more significant inflammation, proposing an explanation for the monotonous increase of COVID-19 mortality with age and higher mortality for males. We conclude that T cells play a crucial role in the immunity against COVID-19, which reveals a new direction——improvement of T cell number for advancing current prevention and treatment.
Statistical framework for studying the spatial architecture of the tumor immune microenvironment
Authors: Wilson Christopher , Thapa Ram , Creed Jordan , Nguyen Jonathan , Segura Carlos Moran , Gerke Travis , Schildkraut Joellen , Peres Lauren , Fridley Brooke L.
Published: April 2021

New technologies, such as multiplex immunofluorescence microscopy (mIF), are being developed and used for the assessment and visualization of the tumor immune microenvironment (TIME). These assays produce not only an estimate of the abundance of immune cells in the TIME, but also their spatial locations; however, there are currently few approaches to analyze the spatial context of the TIME. Thus, we have developed a framework for the spatial analysis of the TIME using Ripley’sK, coupled with a permutation-based framework to estimate and measure the departure from complete spatial randomness (CSR) as a measure of the interactions between immune cells. This approach was then applied to ovarian cancer using mIF collected on intra-tumoral regions of interest (ROIs) and tissue microarrays (TMAs) from 158 high-grade serous ovarian carcinoma patients in the African American Cancer Epidemiology Study (AACES) (94 subjects on TMAs resulting in 259 tissue cores; 91 subjects with 254 ROIs). Cox proportional hazard models were constructed to determine the association of abundance and spatial clustering of tumor-infiltrating lymphocytes, cytotoxic T-cells, and regulatory T-cells, and overall survival. We found that EOC patients with high abundance and low spatial clustering of tumor-infiltrating lymphocytes and cytotoxic T-cells in their tumors had the best overall survival. In contrast, patients with low levels of regulatory T-cells but with a high level of spatial clustering (compare to those with a low level of spatial clustering) had better survival. These findings underscore the prognostic importance of evaluating not only immune cell abundance but also the spatial contexture of the immune cells in the TIME. In conclusion, the application of this spatial analysis framework to the study of the TIME could lead to the identification of immune content and spatial architecture that could aid in the determination of patients that are likely to respond to immunotherapies.
Applications of Digital Microscopy and Densely Connected Convolutional Neural Networks for Automated Quantitation of Babesia-Infected Erythrocytes
Authors: Durant Thomas JS , Dudgeon Sarah , McPadden Jacob , Simpson Anisia , Price Nathan , Schulz Wade , Torres Richard , Olson Eben M
Published: April 2021

Background

Clinical babesiosis is diagnosed, and parasite burden is determined, by microscopic inspection of a thick or thin Giemsa-stained peripheral blood smear. However, quantitative analysis by manual microscopy is subject to observer bias, slide distribution errors, statistical sampling error, recording errors, and is inherently burdensome from time management and workflow efficiency standpoints. As such, methods for the automated measurement of percent parasitemia in digital microscopic images of peripheral blood smears could improve clinical accuracy, relative to the predicate method.

Methods

Individual erythrocyte images (shape: 70×70×3) were manually labeled as “parasite” or “normal” and were used to train a model for binary image classification. The best model was then used to calculate percent parasitemia from a clinical validation dataset, and values were compared to a clinical reference value. Lastly, model interpretability was examined using an integrated gradient to identify pixels most likely to influence classification decisions.

Results

The precision and recall of the model during development testing were 0.92 and 1.00, respectively. In clinical validation, the model returned increasing positive signal with increasing mean reference value. However, there were two highly erroneous false positive values returned by the model. Lastly, the model incorrectly assessed three cases well above the clinical threshold of 10%. The integrated gradient suggested potential sources of false positives including rouleaux formations, cell boundaries, and precipitate as deterministic factors in negative erythrocyte images.

Conclusions

While the model demonstrated highly accurate single cell classification and correctly assessed most slides, several false positives were highly incorrect. This project highlights the need for integrated testing of ML-based models, even when models in the development phase perform well.
Estimating the early impact of vaccination against COVID-19 on deaths among elderly people in Brazil: analyses of routinely-collected data on vaccine coverage and mortality
Authors: Victora Cesar , Castro Marcia C , Gurzenda Susie , de Medeiros Arnaldo Correia , França Giovanny , Barros Aluisio J D
Published: April 2021

Background

Vaccination against COVID-19 in Brazil started in January 2021, with health workers and the elderly as the priority groups. We assessed whether there was an impact of vaccinations on the mortality of elderly individuals in a context of wide transmission of the SARS-CoV-2 gamma (P.1) variant.

Methods

By May 27, 2021, 147238,414 COVID-19 deaths had been reported to the Brazilian Mortality Information System. Denominators for mortality rates were calculated by correcting population estimates for all-cause deaths reported in 2020. Proportionate mortality at ages 70-79 and 80+ years relative to deaths at all ages were calculated for deaths due to COVID-19 and to other causes, as were COVID-19 mortality rate ratios relative to individuals aged 0-69 years. Vaccine coverage data were obtained from the Ministry of Health. All results were tabulated by epidemiological weeks 1-19, 2021.

Findings

The proportion of all COVID-19 deaths at ages 80+ years was over 25% in weeks 1-6 and declined rapidly to 12.4% in week 19, whereas proportionate COVID-19 mortality for individuals aged 70-79 years started to decline by week 15. Trends in proportionate mortality due to other causes remained stable. Mortality rates were over 13 times higher in the 80+ years age group compared to that of 0-69 year olds up to week 6, and declined to 5.0 times in week 19. Vaccination coverage (first dose) of 90% was reached by week 9 for individuals aged 80+ years and by week 13 for those aged 70-79 years. Coronavac accounted for 65.4% and AstraZeneca for 29.8% of all doses administered in weeks 1-4, compared to 36.5% and 53.3% in weeks 15-19, respectively.

Interpretation

Rapid scaling up of vaccination coverage among elderly Brazilians was associated with important declines in relative mortality compared to younger individuals, in a setting where the gamma variant predominates. Had mortality rates among the elderly remained proportionate to what was observed up to week 6, an estimated additional 43,802 COVID-related deaths would have been expected up to week 19.
National hospital readiness for COVID-19 in Lesotho: Evidence for oxygen ecosystem strengthening
Authors: Sanders Jill E. , Chakare Tafadzwa , Mapota-Masoabi Lucy , Ranyali-Otubanjo Makhoase , Ramokhele Mareitumetse M. , Rozario Aleisha , McCollum Eric D.
Published: April 2021

The COVID-19 pandemic continues to challenge healthcare systems globally. To understand hospital capacity, including critical oxygen capacity, a pragmatic assessment of all public hospitals in Lesotho was made in July 2020 (baseline), with follow-up in December 2020. We developed a qualitative hospital services questionnaire modeled on the World Health Organization COVID-19 assessment tool and converted answers into quantitative ordinal variables. At baseline we found all 12 domains had areas demonstrating preparedness and weakness. Key baseline gaps within infection prevention and control were lack of a dedicated team, and insufficient personal protective equipment and space for donning and doffing. Substantial limitations were noted in hypoxemia diagnosis and treatment; information management and care coordination pathways were also suboptimal. Our baseline findings may reflect uneven early pandemic care quality. Targeted follow-up after five months revealed marked improvement in the availability of pulse oximetry, oxygen capacity, and heated high flow nasal cannula devices.
U.S. Regional Differences in Physical Distancing: Evaluating Racial and Socioeconomic Divides During the COVID-19 Pandemic
Authors: Zang Emma , West Jessica , Kim Nathan , Pao Christina
Published: April 2021

Health varies by U.S. region of residence. Despite regional heterogeneity in the outbreak of COVID-19, regional differences in physical distancing behaviors over time are relatively unknown. This study examines regional variation in physical distancing trends during the COVID-19 pandemic and investigates variation by race and socioeconomic status (SES) within regions.

Data from the 2015-2019 five-year American Community Survey were matched with anonymized location pings data from over 20 million mobile devices (SafeGraph, Inc.) at the Census block group level. We visually present trends in the stay-at-home proportion by Census region, race, and SES throughout 2020 and conduct regression analyses to statistically examine these patterns.

From March to December, the stay-at-home proportion was highest in the Northeast (0.25 in March to 0.35 in December) and lowest in the South (0.24 to 0.30). Across all regions, the stay-at-home proportion was higher in block groups with a higher percentage of Blacks, as Blacks disproportionately live in urban areas where stay-at-home rates were higher (0.009 [CI: 0.008, 0.009]). In the South, West, and Midwest, higher-SES block groups stayed home at the lowest rates pre-pandemic; however, this trend reversed throughout March before converging in the months following. In the Northeast, lower-SES block groups stayed home at comparable rates to higher-SES block groups during the height of the pandemic but diverged in the months following.

Differences in physical distancing behaviors exist across U.S. regions, with a pronounced Southern and rural disadvantage. Results can be used to guide reopening and COVID-19 mitigation plans.
Exposure to landscape fire smoke extremely reduced birthweight in low- and middle-income countries
Authors: Li Jiajianghui , Guan Tianjia , Guo Qian , Geng Guannan , Wang Huiyu , Guo Fuyu , Li Jiwei , Xue Tao
Published: April 2021

Landscape fire smoke (LFS) has been associated with reduced birthweight, but evidence from low- and middle-income countries (LMICs) is rare. Here, we present a sibling-matched case– control study of 227,948 newborns to identify an association between fire-sourced fine particulate matter (PM2.5) and birthweight in 54 LMICs from 2000 to 2014.

We selected mothers from the geocoded Demographic and Health Survey with at least two children and valid birthweight records. Newborns affiliated with the same mother were defined as a family group. Gestational exposure to LFS was assessed in each newborn using the concentration of fire-sourced PM2.5. We determined the associations of the within-group variations in LFS exposure with birthweight differences between matched siblings using a fixed-effects regression model. Additionally, we analyzed the binary outcomes of low birthweight (LBW) or very low birthweight (VLBW).

According to fully adjusted models, a 1 µg/m3 increase in the concentration of fire-sourced PM2.5 was significantly associated with a 2.17 g (95% confidence interval [CI]: 0.56–3.77) reduction in birthweight, a 2.80% (95% CI: 0.97–4.66) increase in LBW risk, and an 11.68% (95% CI: 3.59–20.40) increase in VLBW risk.

Our findings indicate that gestational exposure to LFS harms maternal health.
Defining the KRAS-regulated kinome in KRAS-mutant pancreatic cancer
Authors: Diehl J. Nathaniel , Klomp Jennifer E. , Snare Kayla R. , Blake Devon R. , Hibshman Priya S. , Kaiser Zane D. , Gilbert Thomas S.K. , Baldelli Elisa , Pierobon Mariaelena , Papke Björn , Yang Runying , Hodge Richard G. , Rashid Naim U. , Petricoin Emanuel F. , Herring Laura E. , Graves Lee M. , Cox Adrienne D. , Der Channing J.
Published: April 2021

Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines, and then applied Multiplexed Inhibitor Bead/Mass Spectrometry (MIB/MS) chemical proteomics to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transforming activities, and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGFBR1, ILK), and pharmacologic inhibition of the upregulated kinase, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacologic inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death than WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.
Artificial Intelligence System Reduces False-Positive Findings in the Interpretation of Breast Ultrasound Exams
Authors: Shen Yiqiu , Shamout Farah E. , Oliver Jamie R. , Witowski Jan , Kannan Kawshik , Park Jungkyu , Wu Nan , Huddleston Connor , Wolfson Stacey , Millet Alexandra , Ehrenpreis Robin , Awal Divya , Tyma Cathy , Samreen Naziya , Gao Yiming , Chhor Chloe , Gandhi Stacey , Lee Cindy , Kumari-Subaiya Sheila , Leonard Cindy , Mohammed Reyhan , Moczulski Christopher , Altabet Jaime , Babb James , Lewin Alana , Reig Beatriu , Moy Linda , Heacock Laura , Geras Krzysztof J.
Published: April 2021

Ultrasound is an important imaging modality for the detection and characterization of breast cancer. Though consistently shown to detect mammographically occult cancers, especially in women with dense breasts, breast ultrasound has been noted to have high false-positive rates. In this work, we present an artificial intelligence (AI) system that achieves radiologist-level accuracy in identifying breast cancer in ultrasound images. To develop and validate this system, we curated a dataset consisting of 288,767 ultrasound exams from 143,203 patients examined at NYU Langone Health, between 2012 and 2019. On a test set consisting of 44,755 exams, the AI system achieved an area under the receiver operating characteristic curve (AUROC) of 0.976. In a reader study, the AI system achieved a higher AUROC than the average of ten board-certified breast radiologists (AUROC: 0.962 AI, 0.924±0.02 radiologists). With the help of the AI, radiologists decreased their false positive rates by 37.4% and reduced the number of requested biopsies by 27.8%, while maintaining the same level of sensitivity. To confirm its generalizability, we evaluated our system on an independent external test dataset where it achieved an AUROC of 0.911. This highlights the potential of AI in improving the accuracy, consistency, and efficiency of breast ultrasound diagnosis worldwide.