bluuebunny/crossref_metadata_2025 huggingface dataset:
Year-round dynamics of amplicon sequence variant communities differ among eukaryotes,Imiterviralesand prokaryotes in a coastal ecosystem
Authors: Prodinger Florian , Endo Hisashi , Takano Yoshihito , Li Yanze , Tominaga Kento , Isozaki Tatsuhiro , Blanc-Mathieu Romain , Gotoh Yasuhiro , Hayashi Tetsuya , Taniguchi Etsunori , Nagasaki Keizo , Yoshida Takashi , Ogata Hiroyuki
Published: December 2021

Coastal microbial communities are affected by seasonal environmental change, biotic interactions and fluctuating nutrient availability. We investigated the seasonal dynamics of communities of eukaryotes, a major group of double-stranded DNA viruses that infect eukaryotes (order Imitervirales; phylum Nucleocytoviricota), and prokaryotes in the Uranouchi Inlet, Kochi, Japan. We performed metabarcoding using ribosomal RNA genes and viral polB genes as markers in 43 seawater samples collected over 20 months. Eukaryotes, prokaryotes and Imitervirales communities characterized by the compositions of amplicon sequence variants (ASVs) showed synchronic seasonal cycles. However, the community dynamics showed intriguing differences in several aspects, such as the recovery rate after a year. We also showed that the differences in community dynamics were at least partially explained by differences in recurrence/persistence levels of individual ASVs among eukaryotes, prokaryotes and Imitervirales. Prokaryotic ASVs were the most persistent, followed by eukaryotic ASVs and Imitervirales ASVs, which were the least persistent. We argue that the differences in the specificity of interactions (virus–eukaryote vs prokaryote–eukaryote) as well as the niche breadth of community members were at the origin of the distinct community dynamics among eukaryotes, their viruses and prokaryotes.
Global Emergence and Dissemination of Neisseria gonorrhoeae ST-9363 Isolates with Reduced Susceptibility to Azithromycin
Authors: Joseph Sandeep J , Thomas Jesse C , Schmerer Matthew W , Cartee John C , St Cyr Sancta , Schlanger Karen , Kersh Ellen N , Raphael Brian H , Gernert Kim M ,   Antimicrobial Resistant Neisseria gonorrhoeae Working Group, Hun Sopheay , Hua Chi , Ruiz Ryan , Soge Olusegun O , Dominguez Catherine , Loomis Jillian , Patel Ami , Zhang Jenny , Baldwin Tamara , Wang Chun , Leavitt John , Moore Christina , Whelen Christian , O'Brien Pamela
Published: December 2021

Neisseria gonorrhoeae multilocus sequence type (ST) 9363 core-genogroup isolates have been associated with reduced azithromycin susceptibility (AZMrs) and show evidence of clonal expansion in the United States. Here, we analyze a global collection of ST-9363 core-genogroup genomes to shed light on the emergence and dissemination of this strain. The global population structure of ST-9363 core-genogroup falls into three lineages: Basal, European, and North American; with 32 clades within all lineages. Although, ST-9363 core-genogroup is inferred to have originated from Asia in the mid-19th century; we estimate the three modern lineages emerged from Europe in the late 1970s to early 1980s. The European lineage appears to have emerged and expanded from around 1986 to 1998, spreading into North America and Oceania in the mid-2000s with multiple introductions, along with multiple secondary reintroductions into Europe. Our results suggest two separate acquisition events of mosaic mtrR and mtrR promoter alleles: first during 2009–2011 and again during the 2012–2013 time, facilitating the clonal expansion of this core-genogroup with AZMrs in the United States. By tracking phylodynamic evolutionary trajectories of clades that share distinct demography as well as population-based genomic statistics, we demonstrate how recombination and selective pressures in the mtrCDE efflux operon granted a fitness advantage to establish ST-9363 as a successful gonococcal lineage in the United States and elsewhere. Although it is difficult to pinpoint the exact timing and emergence of this young core-genogroup, it remains critically important to continue monitoring it, as it could acquire additional resistance markers.
Pediatric data from the All of Us research program: demonstration of pediatric obesity over time
Authors: Giangreco Nicholas P , Lina Sulieman , Qian Jun , Kouame Aymone , Subbian Vignesh , Boerwinkle Eric , Cicek Mine , Clark Cheryl R , Cohen Elizabeth , Gebo Kelly A , Loperena-Cortes Roxana , Mayo Kelsey , Mockrin Stephen , Ohno-Machado Lucila , Schully Sheri D , Tatonetti Nicholas P , Ramirez Andrea H
Published: December 2021

Objective

To describe and demonstrate use of pediatric data collected by the All of Us Research Program.

Materials and Methods

All of Us participant physical measurements and electronic health record (EHR) data were analyzed including investigation of trends in childhood obesity and correlation with adult body mass index (BMI).

Results

We identified 19 729 participants with legacy pediatric EHR data including diagnoses, prescriptions, visits, procedures, and measurements gathered since 1980. We found an increase in pediatric obesity diagnosis over time that correlates with BMI measurements recorded in participants’ adult EHRs and those physical measurements taken at enrollment in the research program.

Discussion

We highlight the availability of retrospective pediatric EHR data for nearly 20 000 All of Us participants. These data are relevant to current issues such as the rise in pediatric obesity.

Conclusion

All of Us contains a rich resource of retrospective pediatric EHR data to accelerate pediatric research studies.
Expanding Virtual Health Capabilities Into Trainee Health
Authors: Poindexter Elizabeth A , Rodriguez Amanda , Switaj Timothy
Published: December 2021

Virtual health and secure messaging gained newfound relevance in medicine during the coronavirus disease (COVID)-19 pandemic. For a military trainee health care clinic located on Joint Base San Antonio, the McWethy Troop Medical Clinic (TMC), implementation of virtual health and secure messaging services meant decreased risk of COVID-19 exposure for trainees and clinical staff. Through ongoing utilization, these services also made impacts to reduce loss of instruction time and improve access to care for the McWethy TMC trainee population. In defining the challenges, successes, and future implications for virtual health and secure messaging at the McWethy TMC, key lessons emerge for other military trainee clinics. The key concepts explored in this article are virtual health and secure messaging.
Evolution of Olfactory Receptors Tuned to Mustard Oils in Herbivorous Drosophilidae
Authors: Matsunaga Teruyuki , Reisenman Carolina E , Goldman-Huertas Benjamin , Brand Philipp , Miao Kevin , Suzuki Hiromu C , Verster Kirsten I , Ramírez Santiago R , Whiteman Noah K
Published: December 2021

The diversity of herbivorous insects is attributed to their propensity to specialize on toxic plants. In an evolutionary twist, toxins betray the identity of their bearers when herbivores coopt them as cues for host-plant finding, but the evolutionary mechanisms underlying this phenomenon are poorly understood. We focused on Scaptomyza flava, an herbivorous drosophilid specialized on isothiocyanate (ITC)-producing (Brassicales) plants, and identified Or67b paralogs that were triplicated as mustard-specific herbivory evolved. Using in vivo heterologous systems for the expression of olfactory receptors, we found that S. flava Or67bs, but not the homologs from microbe-feeding relatives, responded selectively to ITCs, each paralog detecting different ITC subsets. Consistent with this, S. flava was attracted to ITCs, as was Drosophila melanogaster expressing S. flava Or67b3 in the homologous Or67b olfactory circuit. ITCs were likely coopted as olfactory attractants through gene duplication and functional specialization (neofunctionalization and subfunctionalization) in S. flava, a recently derived herbivore.
Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma
Authors: Duchatel Ryan J , Mannan Abdul , Woldu Ameha S , Hawtrey Tom , Hindley Phoebe A , Douglas Alicia M , Jackson Evangeline R , Findlay Izac J , Germon Zacary P , Staudt Dilana , Kearney Padraic S , Smith Nathan D , Hindley Kate E , Cain Jason E , André Nicolas , La Madrid Andres Morales , Nixon Brett , De Iuliis Geoffry N , Nazarian Javad , Irish Kathleen , Alvaro Frank , Eisenstat David D , Beck Alexander , Vitanza Nicholas A , Mueller Sabine , Morris Jonathan C , Dun Matthew D
Published: December 2021

Background

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound—ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc.

Methods

Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017–2020) was analyzed.

Results

GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months (P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not (P = .012).

Conclusions

This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy.
Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients
Authors: Novak Alison R , Krsak Martin , Kiser Tyree H , Neumann Robert T , Cava Prado Luis , Molina Kyle C , Mueller Scott W
Published: December 2021

Background

The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin into the CSF in noninfected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVDs) in neurologically injured adults.

Methods

Blood and CSF were collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule–based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000 mg intravenously every 8 hours or the renal dose equivalent for EVD prophylaxis.

Results

A median (range) of 3 (2–4) blood and 3 (2–5) CSF samples were collected for each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). The median calculated cefazolin CSF Cmax and Cmin values (interquartile range [IQR]) were 2.97 (1.76–8.56) mg/L and 1.59 (0.77–2.17) mg/L, respectively. The median (IQR) CSF to serum area under the curve ratio was 6.7% (3.7%–10.6%), with time-matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration ≥4 hours following administration were 1.87 and 0.78 mg/L, respectively.

Conclusions

Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic–pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.
Moderate to Intense Physical Activity Is Associated With Improved Clinical, CD4/CD8 Ratio, and Immune Activation Status in HIV-Infected Patients on ART
Authors: Bernal Enrique , Martinez Monica , Campillo José Antonio , Puche Gabriel , Baguena Carlos , Tomás Cristina , Jimeno Amaya , Alcaraz Maria Jose , Alcaraz Antonia , Muñoz Angeles , Oliver Eva , de la Torre Alejandro , Marín Irene , Cano Alfredo , Minguela Alfredo
Published: December 2021

Background

Physical activity has anti-inflammatory effects and reduces morbidity and mortality in the general population, but its role in the clinical, CD4/CD8 ratio, and immune activation status of HIV-infected patients has been poorly studied.

Methods

A cross-sectional study was carried out in a cohort of 155 HIV-infected patients on stable antiretroviral therapy (ART) to compare clinical, biochemical, CD4/CD8 ratio, and immune activation status according to their physical activity in the last 2 years (sedentary/low vs moderate/intense) assessed by the iPAQ. A binary logistic regression and mixed analysis of variance were performed to evaluate the impact of levels of physical activity on CD4/CD8 ratio.

Results

In our series, 77 (49.7%) out of 155 patients were sedentary, and 78 (50.3%) practiced moderate/intense physical activity. Moderate/intense physical activity was associated with better metabolic control (lower body mass index, P = .024; glucose, P = .024; and triglyceride, P = .002) and CDC HIV stage (P = .046), lower CD8+ (P =  .018), CD4+CD8+ (P = .026), CD4+CD86+ (P = .045), CD4+HLA-DR+ (P = .011), CD8+HLA-DR+ (P = .048) T lymphocytes and CD16+HLA-DR+ natural killer cells (P = .026), and higher CD3+CD4+ T lymphocytes (P = .016) and CD4/CD8 ratio (P = .001). Sedentary lifestyle (odds ratio [OR], 2.12; P = .042), CD4 nadir (OR, 1.005; P < .001), and CD8+CD38+ T cells (OR, 1.27; P = .006) were independently associated with low CD4/CD8 ratio (<0.8). Earlier and more intense CD4/CD8 ratio recovery was observed in patients with higher physical activity in the 2-year follow-up with a significant interaction between these variables: F(2, 124) = 3.31; P = .049; partial η2 = 0.042.

Conclusions

Moderate to high physical activity is associated with beneficial health effects, improvement in metabolic profile, and reduction of chronic inflammation in patients with HIV. Although more studies and clinical trials are needed to confirm these findings, a healthy lifestyle including at least moderate physical activity should be recommended to HIV patients on stable ART.
Multiple endocrine neoplasia 2A presenting in a family with a history of Hirschprung’s disease
Authors: Johns Allison M , Vuong Angela H , Hassan Omer A , Randle Reese W , Gorris Matthew A
Published: December 2021

Hirschprung’s disease co-occurs with multiple endocrine neoplasia type 2A infrequently but at a higher rate with certain RET mutations. We present a case of a patient evaluated for an adrenal incidentaloma with a history of familial Hirschprung’s. Our patient was found to have synchronous pheochromocytoma and medullary thyroid carcinoma illustrating the importance of genetic testing in these patients to determine appropriate screening for endocrine tumors.
Mind the Gap: An Analysis of Physical Therapist Earnings in the United States by Male/Female Sex
Authors: Chevan Julia , Chevan Albert
Published: December 2021

Objective

Earnings discrepancies between male and female health and medical professionals are well documented. The purpose of this study was to examine the distribution of physical therapist earnings using a quartile regression approach to determine the nature of the gender-based differences in earnings between male and female physical therapists in the United States, with “gender” as defined by the dataset as being male or female.

Methods

This observational study used data from the 2014 to 2018 American Community Survey 5-year public use microdata file. The file contained 12,123 physical therapist cases weighted to an estimate of the physical therapist active workforce of 238,221 (95% CI = 232,587 to 243,855). To analyze the influence of gender on earnings, a multivariable quantile regression approach was used in which physical therapist earnings were the dependent variable and the variables representing the geographic distribution, social characteristics, and employment characteristics were the independent variables.

Results

In 2018 dollars, the average annual earnings of a physical therapist were $73,444.98 (95% CI = $72,498.19 to $74,391.11), with a median value of $71,735.09. Differences in male and female earnings were evident in both the unadjusted bivariable and in the adjusted values produced by the quartile regression. The ratios of female-to-male earnings at each quartile were 0.89, 0.90, and 0.89. When age of the earner is accounted for, male physical therapists earned more than female therapists in both the 30-to-54-year age group and the ≥55-year age group. In the youngest age group of earners under 30 years of age, the differences were substantially smaller.

Conclusions

Gender differences in income persist across the distribution of earnings, resulting in female physical therapists earning approximately 10% less than their male counterparts. The differences are most distinct as physical therapists advance in their careers.

Impact

The etiology of the earnings gap is unknown, but gender equity has not been achieved yet for physical therapy.
Efficacy and safety of belimumab during maintenance therapy in patients with systemic lupus erythematosus
Authors: Miyazaki Yusuke , Nakayamada Shingo , Sonomoto Koshiro , Kawabe Akio , Inoue Yoshino , Okubo Naoaki , Iwata Shigeru , Hanami Kentaro , Tanaka Yoshiya
Published: December 2021

Objectives

The efficacy of belimumab (BEL) during maintenance therapy in patients with SLE remains unclear in the real-life clinical setting. This study investigated the efficacy and safety of BEL in patients with SLE during maintenance therapy.

Methods

In this retrospective observational study, maintenance therapy was defined as low-dose glucocorticoid (GC) therapy (prednisolone equivalent dose of ≤0.2 mg/kg/day) in patients with a Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score <10. Participants comprised patients with SLE on HCQ or MMF [standard-of-care (SoC) group: n = 103] and those on BEL plus SoC (BEL+SoC group: n = 100). Selection bias was minimized using propensity score-based inverse probability of treatment weighting (IPTW). GC dose trajectories were modelled using growth mixture modelling (GMM). The primary end point was GC dose at 52 weeks.

Results

No significant difference was observed in patient characteristics between the two groups after IPTW adjustment. The BEL+SoC group exhibited a significant decrease in GC dose. GC dose at 52 weeks and relapse rate were significantly lower in the BEL+SoC group than in the SoC group. The proportion of patients in one of four groups defined by GMM for which GC dose was tapered to 0 mg within 52 weeks (GC tapering-discontinuation group) was significantly higher in the BEL+SoC group than in the SoC group. In the BEL+SoC group, low SELENA-SLEDAI score and low GC dose at baseline were associated with being GC dose-tapering discontinuation.

Conclusion

The present study suggests that BEL is suitable for patients with SLE during maintenance therapy.
Objective sleep profile in LGI1/CASPR2 autoimmunity
Authors: Devine Michelle F , Feemster John C , Lieske Elizabeth A , McCarter Stuart J , Sandness David J , Steele Tyler , Timm Paul C , Mandrekar Jay , Boeve Bradley F , Silber Michael H , Dubey Divyanshu , McKeon Andrew , St. Louis Erik K
Published: December 2021

Study Objectives

Rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients.

Methods

We retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM + AT) RSWA was the primary outcome.

Results

Among 11 (LGI1+, n = 9; CASPR2+, n = 2) patients, Morvan syndrome sleep features were present in seven (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and dream enactment behavior (DEB) in three (27.3%), and the most common presenting sleep disturbances were DEB (n = 5), insomnia (n = 5), and sleep apnea (n = 8; median apnea-hypopnea index = 15/hour). Median Epworth Sleepiness Scale was nine (range 3–24; n = 10), with hypersomnia in four (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p = .02), decreased REM sleep (p = .001), and higher levels of SM + AT any RSWA (p < .001). Eight of nine (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n = 5; isolated RSWA, n = 3). RSWA was greater in AT than SM. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances.

Conclusions

LGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.
Tox-GAN: An Artificial Intelligence Approach Alternative to Animal Studies—A Case Study With Toxicogenomics
Authors: Chen Xi , Roberts Ruth , Tong Weida , Liu Zhichao
Published: December 2021

Animal studies are a critical component in biomedical research, pharmaceutical product development, and regulatory submissions. There is a worldwide effort in toxicology toward “reducing, refining, and replacing” animal use. Here, we proposed a deep generative adversarial network (GAN)-based framework capable of deriving new animal results from existing animal studies without additional experiments. To prove the concept, we employed this Tox-GAN framework to generate both gene activities and expression profiles for multiple doses and treatment durations in toxicogenomics (TGx). Using the pre-existing rat liver TGx data from the Open Toxicogenomics Project-Genomics-Assisted Toxicity Evaluation System (Open TG-GATES), we generated Tox-GAN transcriptomic profiles with high similarity (0.997 ± 0.002 in intensity and 0.740 ± 0.082 in fold change) to the corresponding real gene expression profiles. Consequently, Tox-GAN showed an outstanding performance in 2 critical TGx applications, gaining a molecular understanding of underlying toxicological mechanisms and gene expression-based biomarker development. For the former, over 87% agreement in Gene Ontology was found between Tox-GAN results and real gene expression data. For the latter, the concordance of biomarkers between real and generated data was high in both predictive performance and biomarker genes. We also demonstrated that the Tox-GAN models constructed with the Open TG-GATES data were capable of generating transcriptomic profiles reported in DrugMatrix. Finally, we demonstrated potential utility for Tox-GAN in aiding chemical-based read-across. To the best of our knowledge, the proposed Tox-GAN model is novel in its ability to generate in vivo transcriptomic profiles at different treatment conditions from chemical structures. Overall, Tox-GAN holds great promise for generating high-quality toxicogenomic profiles without animal experimentation.
Leech anticoagulants are ancestral and likely to be multifunctional
Authors: Iwama Rafael Eiji , Tessler Michael , Kvist Sebastian
Published: December 2021

Bloodfeeding leeches have powerful anticoagulants that allow them to feed for extended periods. However, many leech species are predatory rather than bloodfeeding. It is not known whether they express these proteins and whether the proteins are co-opted for other purposes. Little is known about salivary secretions of the sister groups of leeches, where blood is not part of the diet. We screened the transcriptomes of four non-bloodfeeding leeches and four leech relatives to identify major lineages of anticoagulant genes, helping to determine their evolutionary origin and maintenance. We estimated selection regimes that are expected after a change in feeding behaviour. We found widespread presence of putative anticoagulants, although our results also indicate that several of these are members of multicopy gene families. Our analyses suggest that homologues to leech anticoagulants were already present before the origin of bloodfeeding in leeches and that negative selection is the major driver of evolutionary rates even in non-bloodfeeding taxa. These results point to the retention of the original function by these molecules in non-bloodfeeding species. Ultimately, the proteins might not be involved in bloodfeeding or it seems likely that their putative pleiotropic effects are of great importance.
Outcomes of Patients With Large Versus Small Bone Defects in Open Tibia Fractures Treated With an Intramedullary Nail: A Descriptive Analysis of a Multicenter Retrospective Study
Authors: Obremskey William T. , Tornetta Paul , Luly Jason , Morshed Saam , O'Toole Robert V. , Hsu Joseph R. , Mitchell Stuart L. , Mackenzie Ellen J. , Frey Katherine P. , Castillo Renan C. , Bosse Michael J. , Scharfstein Daniel O. ,   on behalf of METRC
Published: December 2021

Objectives:

To compare outcomes in patients with open tibia shaft fractures based on defect size.

Design:

Retrospective review.

Setting:

Eighteen trauma centers.

Population:

The study included 132 patients with diaphyseal tibia bone defects >1 cm and ≥50% cortical loss treated with intramedullary nail.

Outcomes:

The primary outcome was number of secondary surgeries to promote healing (bone graft, revision fixation, or bone transport). Additional outcomes included occurrence of secondary surgeries (bone graft, infection, amputation, and flap failure) and proportion healed at one year. Results are compared by “radiographic apparent bone gap” of <2.5 or ≥2.5 cm.

Results:

The estimated conditional probability of bone grafting within one year given graft-free at 90 days was 44% and 47% in the <2.5 cm and ≥2.5 cm groups, respectively. An estimated infection risk of 14% was observed in both groups [adjusted hazard ratio (HR) 0.98, 95% confidence interval (CI): 0.33–2.92], estimated amputation risk was 9% (<2.5 cm) and 4% (≥2.5 cm) (unadjusted HR 0.66, 95% CI: 0.13–3.29), and estimated flap failure risk (among those with flaps) was 10% and 13%, respectively (unadjusted HR 1.71, 95% CI: 0.24–12.25). There was no appreciable difference in the proportion healed at one year between defect sizes [adjusted HR: 1.07 (95% CI, 0.63–1.82)].

Conclusions:

Larger size bone defects were not associated with higher number of secondary procedures to promote healing or a lower overall one-year healing rate.

Level of Evidence:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Reported COVID-19 Incidence in Indoor Winter Sports Among US High-School Athletes
Authors: Watson Andrew M. , Haraldsdottir Kristin , Biese Kevin , Goodavish Leslie , Stevens Bethany , McGuine Timothy
Published: December 2021

Objective:

To evaluate the association between COVID-19 incidence among high-school athletes participating in different indoor winter sports and attending schools with in-person versus virtual instructional delivery.

Design:

Cross-sectional survey.

Setting:

US high schools.

Participants:

High-school athletic directors.

Independent Variables:

Indoor winter sports, school instructional delivery method, and state COVID-19 incidence.

Main Outcome Measures:

Surveys were distributed to high-school athletic directors throughout the United States regarding sport reinitiation and COVID-19 cases in winter 2020 to 2021. Separate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and (1) different sports and (2) school instructional delivery method, while adjusting for the background, state COVID-19 incidence.

Results:

Four hundred thirty schools had restarted fall sports, representing 31 274 athletes on 1404 teams from 14 states. One thousand four hundred sixty cases of COVID-19 were reported, representing a case rate of 4668 cases per 100 000 athletes and an incidence rate of 58.7 cases per 100 000 player-days. Reported COVID-19 incidence was greatest among girls' hockey (82.1 cases per 100 000 player-days (95% CI, 56.8-115) and boys' hockey [76.7 (61.8-94.2)] and lowest among swimming [39.0 (31.1-48.2)] and gymnastics [28.5 (13.1-54.2)]. No difference in reported COVID-19 incidence was identified among athletes attending schools with virtual versus in-person instruction [incidence rate ratio = 0.86 (0.52-1.4)].

Conclusions:

In this nationwide survey of US high-school athletic directors regarding indoor winter sports, reported COVID-19 incidence was lower in noncontact sports but unrelated to school instructional delivery method. This information may help guide decision-making regarding high-school sport participation during the COVID-19 pandemic.
Incarceration and Sexual Risk Behavior and Incident Sexually Transmitted Infection/HIV in HIV Prevention Trials Network 061: Differences by Study City and Among Black Sexual Minority Men Who Have Sex With Men, Black Sexual Minority Men Who Have Sex With Men and Women, and Black Transgender Women
Authors: Khan Maria Rabia , Brewer Russell , Abrams Jasmyn , Mazumdar Medha , Scheidell Joy D. , Feelemyer Jonathan , Dyer Typhanye V. , Turpin Rodman E. , Hucks-Ortiz Christopher , Gaydos Charlotte A. , Severe MacRegga , Irvine Natalia M. , Kaufman Jay S. , Cleland Charles M. , Mayer Kenneth H.
Published: December 2021

Background

Black sexual minority men (BSMM) and Black transgender women face a disproportionate risk of incarceration and sexually transmitted infection (STI)/HIV, yet research on the longitudinal association between incarceration and STI/HIV risk in these groups is limited.

Methods

We used data from the HIV Prevention Trials Network (HPTN) 061 study conducted among BSMM and Black transgender women in Atlanta, Boston, Los Angeles, New York City, San Francisco, and Washington, DC, restricting analyses to those who returned for the 6-month follow-up visit when recent incarceration was measured (n = 1169). Using inverse probability of treatment weighting, we measured associations between incarceration and next 6-month multiple partnerships; selling or buying sex; condomless anal intercourse; and incident chlamydia, gonorrhea, syphilis, and HIV. We explored differences by study city, and among BSMM who had sex with men only, BSMM who had sex with men and women, and Black transgender women.

Results

Approximately 14% reported past 6-month incarceration. Incarceration was associated with next 6-month selling sex (adjusted risk ratio [ARR], 1.80; 95% confidence interval [CI], 1.12–2.87) in the overall sample and multiple partnerships among BSMM who had sex with men and women (ARR, 1.34; 95% CI, 1.10–1.63) and transgender women (ARR, 1.77; 95% CI, 1.22–2.57). There is evidence suggesting that incarceration may predict gonorrhea (ARR, 2.35; 95% CI, 0.95–5.77), with particularly strong associations observed in Los Angeles (ARR, 6.48; 95% CI, 1.48–28.38).

Conclusions

Incarceration may increase STI/HIV risk among BSMM and Black transgender women. Additional mixed-methods research is needed to validate associations and understand pathways.
Transcriptome deregulation of peripheral monocytes in GBA-related Parkinson’s disease
Authors: Riboldi Giulietta Maria , Vialle Ricardo A , Navarro Elisa , Udine Evan , de Paiva Lopes Katia , Allan Amanda , Parks Madison , Henderson Brooklyn , Astudillo Kelly , Argyrou Charalambos , Zhuang Maojuan , Sikder Tamjeed , Narcis Oriol J. , Kumar Shilpa Dilip , Janssen William , Sowa Allison , Comi Giacomo P , Di Fonzo Alessio , Crary John F. , Frucht Steven J , Raj Towfique
Published: December 2021

Background

Genetic mutations in the beta-glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinson’s disease (PD). The function of the GBA gene is at the crossroads between the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated.

Methods

we characterized the transcriptomic profiles of circulating monocytes and whole blood in a population of patients with PD and healthy controls (CTRL) with (PD/GBA and CTRL/GBA) and without GBA variants (iPD and CTRL) (monocytes: n = 56 iPD, 66 CTRL, 23 PD/GBA, 13 CTRL/GBA; whole blood: n = 616 iPD, 362 CTRLs, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathways enrichment analysis, and outliers detections were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy.

Results

We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, GBA-PD showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing (i.e. SNCA, LMNA). Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels.

Conclusions

Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.
Predicting risk of pancreatic cancer in individuals with new-onset type-2 diabetes in primary care: protocol for the development and validation of a clinical prediction model (QPancreasD)
Authors: Tan Pui San , Clift Ashley Kieran , Liao Weiqi , Patone Martina , Coupland Carol , Bashford-Rogers Rachael , Sivakumar Shivan , Clifton David , Pereira Stephen P , Hippisley-Cox Julia
Published: December 2021

Background

Pancreatic cancer continues to have an extremely poor prognosis in part due to late diagnosis. 25% of pancreatic cancer patients have a prior diagnosis of diabetes, and hence identifying individuals at risk of pancreatic cancer in those with recently diagnosed type 2 diabetes may be a useful opportunity to identify candidates for screening and early detection. In this study, we will comparatively evaluate regression and machine learning-based clinical prediction models for estimating individual risk of developing pancreatic cancer two years after type 2 diabetes diagnosis.

Methods

In the development dataset, we will include adults aged 30-84 years with incident type-2 diabetes registered with QResearch primary care database. Patients will be followed up from type-2 diabetes diagnosis to first diagnosis of pancreatic cancer as recorded in any one of primary care records, hospital episode statistics, cancer registry data, or death records. Cox-proportional hazards models will be used to develop a risk prediction model for estimating individual risk of developing pancreatic cancer during up to 2 years of follow-up. We will perform variable selection using a combination of clinical and statistical significance approach i.e. HR <0.9 or >1.1 and p<0.01. Linear predictors and baseline survivor function at 2 years will be used to compute absolute risk predictions.

Internal-external cross-validation (IECV) framework across geographical regions within England will be used to assess performance and pooled using random effects meta-analysis using: (i) model fit in terms of variation explained by the model Royston & Sauerbrei’s R2D, (ii) calibration slope and calibration-in-the-large, and (iii) discrimination measured in terms of Harrell’s C and Royston & Sauerbrei’s D-statistic.

Further, we will evaluate machine learning (ML) approaches for the clinical prediction model using neural networks (NN) and XGBoost. The model predictors and performance of these will be compared with the results of those derived from the regression-based strategy.

Discussion

The proposed study will develop and validate a novel risk prediction model to aid early diagnosis of pancreatic cancer in patients with new-onset diabetes in primary care. With an enhanced decision-risk tool for use at point-of care by general practitioners to assess pancreatic cancer risk, it may improve decision-making so that at-risk patients are rapidly prioritised to aid early diagnosis of pancreatic cancer in patients with newly diagnosed diabetes.
COVID-19 vaccination effectiveness rates by week and sources of bias
Authors: Ostropolets Anna , Hripcsak George
Published: December 2021

Importance

Randomized clinical trials and observational studies have demonstrated high overall effectiveness for the three US-authorized COVID-19 vaccines against symptomatic COVID-19 infection. Nevertheless, the challenges associated with the use of observational data can undermine the results of the studies.

Objective

To assess the feasibility of using observational data for vaccine effectiveness studies by examining granular weekly effectiveness.

Design, Settings and Participants

In this retrospective cohort study, we used Columbia University Medical Center data linked to State and City Immunization Registries to assess the weekly effectiveness of mRNA COVID-19 vaccines. We conducted manual chart review of cases in week one in both groups along with a set of sensitivity analyses for Pfizer-BioNTech, Moderna and Janssen vaccines.

Main Outcomes and Measures

We used propensity score matching with up to 54,987 covariates and fitted Cox proportional hazards models to estimate hazard ratios and constructed Kaplan-Meier plots for two main outcomes (COVID-19 infection and COVID-19-associated hospitalization).

Results

The study included 179,666 patients. We observed increasing effectiveness after the first dose of mRNA vaccines with week 6 effectiveness approximating 84% (95% CI 72-91%) for COVID-19 infection and 86% (95% CI 69-95) for COVID-19-associated hospitalization. When analyzing unexpectedly high effectiveness in week one, chart review revealed that vaccinated patients are less likely to seek care after vaccination and are more likely to be diagnosed with COVID-19 during the encounters for other conditions. Sensitivity analyses showed potential outcome misclassification for COVID-19 ICD10-CM diagnosis and the influence of excluding patients with prior COVID-19 infection and anchoring in the unexposed group. Overall vaccine effectiveness analysis in fully vaccinated patients matched the results of the randomized trials.

Conclusions and Relevance

Observational data can be used to ascertain vaccine effectiveness if potential biases are accounted for. The data need to be scrutinized to ensure that compared groups exhibit similar health seeking behavior and are equally likely to be captured in the data. Given the difference in temporal trends of vaccine exposure and baseline characteristics, indirect comparison of vaccines may produce biased results.

KEY POINTS

Question

When accounted for all potential biases, what is the weekly effectiveness of COVID-19 vaccines?

Findings

In this cohort study we replicated the results of randomized clinical trials, discovered plausible increase in effectiveness after week one following the first dose of mRNA COVID-19 vaccines and found differences in temporal trends of vaccine exposure and baseline characteristics in vaccinated groups.

Meaning

Observational data can be used to reliably estimate vaccine effectiveness if the biases are accounted for. Vaccines need to be directly compared.
CMV seropositivity is a potential novel risk factor for severe COVID-19 in non-geriatric patients
Authors: Weber Simone , Kehl Victoria , Erber Johanna , Wagner Karolin I. , Jetzlsperger Ana-Marija , Burrell Theresa , Schober Kilian , Schommers Philipp , Augustin Max , Crowell Claudia S. , Gerhard Markus , Winter Christof , Spinner Christoph D. , Protzer Ulrike , Hoffmann Dieter , D’Ippolito Elvira , Busch Dirk H
Published: December 2021

Background

COVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19.

Methods

National German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV serostatus of patients who experienced mild (n=101), moderate (n=130) or severe to critical (n=80) disease by CMV IgG serology. We then investigated the relationship between disease severity and CMV serostatus via statistical models.

Results

Non-geriatric patients (< 70 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19.

Conclusions

We identified ‘CMV-seropositivity’ as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.
Research themes of family and community physicians in Brazil
Authors: Fontenelle Leonardo Ferreira , Rossi Stephani Vogt , de Oliveira Miguel Henrique Moraes , Brandão Diego José , Sarti Thiago Dias
Published: December 2021

Family and community medicine is a specialty dedicated to primary care, the cornerstone of effective health systems. Research capacity in primary care varies worldwide, and bibliographic databases such as MEDLINE, Scopus and Web of Science do not index most primary care research coming from Latin America. Our objective was to investigate the research themes of family and community physicians in Brazil, and to correlate the articles’ research themes with their authors’ trajectories in postgraduate education. For that, we compiled a national list of family and community physicians, retrieved their curricula from the Lattes Platform, compiled a list of journal articles, and obtained their keywords from LILACS and MEDLINE. Treating journal articles and their keywords as the two node types in a bipartite network, we derived research themes using the dual-projection algorithm, combining the Leiden algorithm with hierarchical clustering. We found two research themes to be the largest, most developed, and most central ones: human health and primary care. Authors with a master’s or PhD in collective health (public health, epidemiology, and social sciences and humanities in health) were as likely as those with no postgraduate degree to publish articles on primary care. On the other hand, authors with a postgraduate degree in medicine were more likely to publish articles on human health. After discussing the findings in light of previous research and methodological aspects, we conclude there’s a relative divide between primary care and clinical research, and the highlight policy implications.
Neutralizing antibodies to SARS-CoV-2 Omicron variant after 3rdmRNA vaccination in health care workers and elderly subjects and response to a single dose in previously infected adults
Authors: Haveri Anu , Solastie Anna , Ekström Nina , Österlund Pamela , Nohynek Hanna , Nieminen Tuomo , Palmu Arto A. , Melin Merit
Published: December 2021

The emergence of SARS-CoV-2 Omicron variant (B.1.1.529) with major spike protein mutations has raised concern over potential neutralization escape and breakthrough infections among vaccinated and previously SARS-CoV-2 infected subjects. We measured cross-protective antibodies against variants in health care workers (HCW, n=20) and nursing home residents (n=9) from samples collected 1-2 months following the booster (3rd) dose. We also assessed the antibody responses in prior to Omicron era infected subjects (n=38) with subsequent administration of a single mRNA vaccine dose. Following booster vaccination HCWs had high IgG antibody concentrations to the spike protein and neutralizing antibodies (NAb) were detectable against all variants. IgG concentrations among the elderly remained lower, and some lacked NAbs against the Beta and Omicron variants. NAb titers were significantly reduced against Delta, Beta and Omicron compared to wild-type virus regardless of age. Vaccination induced high IgG concentrations and variable titers of cross-reactive NAbs in previously infected subjects, whereas NAb titers against Omicron were barely detectable 1-month post-infection. High IgG concentrations with cross-protective neutralizing activity were detected after three COVID-19 vaccine doses in HCWs. However, lower NAb titers seen in the frail elderly suggest inadequate protection against Omicron breakthrough infections, yet protection against severe COVID-19 is expected.

Clinical trial registration

EudraCT 2021-004788-29
Decreased diastolic hydraulic forces incrementally associate with survival beyond conventional measures of diastolic dysfunction
Authors: Soundappan Dhnanjay , Fung Angus SY , Loewenstein Daniel E , Playford David , Strange Geoffrey , Kozor Rebecca , Otton James , Ugander Martin
Published: December 2021

Decreased hydraulic forces during diastole contribute to reduced left ventricular (LV) filling and heart failure with preserved ejection fraction. However, their association with diastolic function and patient outcomes are unknown. The aim of this study was to determine the association between diastolic hydraulic forces, estimated by echocardiography as the atrioventricular area difference (AVAD), and both diastolic function and survival. Patients (n=5,176, median [interquartile range] 5.0 [5.0–5.0] years follow-up, 1,213 events) were selected from the National Echo Database Australia based on the presence of relevant transthoracic echocardiographic measures, LV ejection fraction (LVEF) ≥50%, heart rate 50-100 beats/minute, the absence of moderate or severe valvular disease, and no prior cardiac surgery. AVAD was calculated as the cross-sectional area difference between the LV and left atrium. LV diastolic dysfunction was graded according to 2016 guidelines. AVAD was weakly associated with E/e’, left atrial volume index, and LVEF (multivariable global R2=0.15, p<0.001), and not associated with e’ and peak tricuspid regurgitation velocity. Decreased AVAD was independently associated with poorer survival, and demonstrated improved model discrimination after adjustment for diastolic function grading (C-statistic [95% confidence interval] 0.644 [0.629–0.660] vs 0.606 [0.592–0.621], p<0.001) and E/e’ (0.649 [0.635–0.664] vs 0.634 [0.618–0.649], p<0.001), respectively. Therefore, decreased hydraulic forces, estimated by AVAD, are weakly associated with diastolic dysfunction and demonstrate an incremental prognostic association with survival beyond conventional measures used to grade diastolic dysfunction.