bluuebunny/crossref_metadata_2025 huggingface dataset:
Inflammatory biomarkers and soft tissue changes among patients commencing second-line antiretroviral therapy after first-line virological failure
Authors: Mwasakifwa Gwamaka Eliudi , Amin Janaki , Kelleher Anthony , Boyd Mark A.
Published: July 2021

Introduction:

We explored associations of inflammatory and immune activation biomarkers at baseline and percentage gain in peripheral and trunk fat and lean mass over 96 weeks in patients with confirmed virological failure initiating lopinavir-anchored second-line antiretroviral therapy (ART) regimens.

Method:

We measured baseline plasma concentration of interleukin (IL)-6, tumour necrosis factor (TNF), neopterin, IL-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, soluble cluster of differentiation 14 (sCD14), and soluble CD163 in 123 participants of the SECOND-LINE body composition substudy. Linear regression assessed the association between biomarkers and percentage gain in limb/trunk fat and lean mass, adjusting for age, nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) use, body mass index, ethnicity, smoking, viral load, CD4+ T-cell counts, smoking, duration of ART use, and cholesterol.

Results:

Mean (standard deviation) age was 38 (7.3) years, CD4+ T-cell count was 252 (185.9) cells/μl, human immunodeficiency virus viral load was 4.2 (0.9) log10 copies/ml, 47% (58/123) were in the N(t)RTI arm (vs. raltegravir [RAL] arm in 53%); 56.1% (69/123) were females. In adjusted analyses, for every log10 increase in baseline levels of IL-6, neopterin, and D-dimer, the percentage gain in peripheral fat over 96 weeks was 11.8% (95% confidence interval [CI]: 0.9–22.6, P = 0.033); neopterin, 11.2% (95% CI: 3.2–19.2, P = 0.007); D-dimer 9.6% (95% CI: 3.1–15.9, P = 0.004), respectively. The associations remained significant when analysis was stratified by N(t)RTI vs. RAL and included only patients with viral suppression at week 48. A significant gradient in lean mass gain was seen across quartiles of IL-6, TNF, neopterin, hsCRP, D-dimer, and sCD14.

Conclusion:

Inflammatory biomarkers provide important mechanistic insights into the pathogenesis of limb fat and lean mass changes independently of ART.
Evaluating Treatment Preferences and Perceptions of a Prosthetic Versus a Transplanted Hand
Authors: Shammas Ronnie L. , Huh Ji , Huber Joel , Mithani Suhail K.
Published: July 2021

Introduction

This study used a conjoint analysis–based survey to assess which factors are most influential when considering treatment with a prosthesis or transplant after a unilateral hand amputation.

Methods

Overall, 469 respondents were recruited using Amazon Mechanical Turk and asked to assume that they experienced a hand amputation. To determine preferences for a prosthetic, respondents chose among 11 pairs of alternatives with variations in the following attributes: appearance, function, maintenance, and learning time. Respondents were then presented with descriptions of the risks and outcomes of hand transplantation. The most compelling reasons for and against a transplant were determined and characteristics predictive of support for a transplant were identified.

Results

The most important attributes for a prosthesis were “lifelike appearance” and “myolectric function.” For hand transplantation, respondents were most concerned about immunosuppression side effects (n = 323, 69%) and the intense nature of surgery (n = 275, 59%), whereas the most positive benefit was the concept of the transplant being “natural” (n = 339, 72%). When faced with the choice of a hand transplant or a prosthetic, approximately 50% of respondents chose a transplantation. Younger age, previous medical experiences, a perceived “familiarity with medical issues,” and the regular attendance of religious services were associated with strong support for a hand transplantation (P < 0.01).

Conclusions

When considering a hand prosthesis, respondents are motivated most by appearance and function. Meanwhile, with hand transplantation, the risks of immunosuppression and the intense nature of surgery and recovery are predominant concerns. These findings may help inform patient-physician discussions when considering treatment after unilateral hand amputation.
Rarely Seen Intradiploic Skull Hematoma in Infants
Authors: Malçok Ümit Ali , Akar Ali
Published: July 2021

Although the first intradiploic hematoma (IH) case was reported in 1934, only 7 infant cases were reported in the literature. The authors present 2 IH cases, without birth trauma or bleeding disorder, which were treated surgically. IH is also included in the differential diagnosis of babies with a skull deformity. Computed tomography and magnetic resonance imaging modalities should be used together in diagnosis and treatment. The authors believe that the surgery to treat skull deformity because of IH in babies should be planned in the early period.
3D-Printed Custom Cutting Guides Facilitate Frontal Cranioplasty in Gender Affirmation Surgery
Authors: Hohman Marc H. , Jastrzembski Meghan E. , Choe Nicholas , Nuara Michael J. , Teixeira Jeffrey C. , Vincent Aurora G.
Published: July 2021

Frontal cranioplasty in gender affirmation surgery requires precise identification of the borders of the frontal sinus in order to reduce brow prominence effectively and avoid complications. Several approaches to this have been described in the literature, but many techniques are imprecise or logistically cumbersome. Custom 3D-printing of cutting guides is an emerging modality that offers a method of identifying the frontal sinus accurately and rapidly. We herein present the results of 5 transgender woman who underwent type 3 frontal cranioplasty with the assistance of 3D-printed custom cutting guides. Our preliminary analysis suggests that the use of custom 3D-printed cutting guides is safe and would likely be cost-effective for many surgeons.
Enhanced Recovery After Surgery Patients Are Prescribed Fewer Opioids at Discharge
Authors: Maurer Lydia R. , El Moheb Mohamad , Cavallo Elena , Antonelli Donna M. , Linov Pamela , Bird Sarah , Faulkner Heather R. , del Carmen Marcela , Qadan Motaz , Ferrone Cristina R. , Kaafarani Haytham M. A. , Sisodia Rachel , Ellis Dan B.
Published: July 2021

Objective:

We aimed to compare discharge opioid prescriptions pre- and post-ERAS implementation.

Summary of Background Data:

ERAS programs decrease inpatient opioid use, but their relationship with postdischarge opioids remains unclear.

Methods:

All patients undergoing hysterectomy between October 2016 and November 2020 and pancreatectomy or hepatectomy between April 2017 and November 2020 at 1 tertiary care center were included. For each procedure, ERAS was implemented during the study period. PSM was performed to compare pre - versus post-ERAS patients on discharge opioids (number of pills and oral morphine equivalents). Patients were matched on age, sex, race, payor, American Society of Anesthesiologists score, prior opioid use, and procedure. Sensitivity analyses in open versus minimally invasive surgery cohorts were performed.

Results:

A total of 3983 patients were included (1929 pre-ERAS; 2054 post-ERAS). Post-ERAS patients were younger (56.0 vs 58.4 years;P <0.001), more often female (95.8% vs 78.1%;P <0.001), less often white (77.2% vs 82.0%;P <0.001), less often had prior opioid use (20.1% vs 28.1%;P <0.001), and more often underwent hysterectomy (91.1% vs 55.7%;P <0.001). After PSM, there were no significant differences between cohorts in baseline characteristics. Matched post-ERAS patients were prescribed fewer opioid pills (17.4 pills vs 22.0 pills;P <0.001) and lower oral morphine equivalents (129.4 mg vs 167.6 mg;P <0.001) than pre-ERAS patients. Sensitivity analyses confirmed these findings [open (18.8 pills vs 25.4 pills;P <0.001 \ 138.9 mg vs 198.7 mg;P <0.001); minimally invasive surgery (17.2 pills vs 21.1 pills;P <0.001 \ 127.1 mg vs 160.1 mg;P <0.001).

Conclusions:

Post-ERAS patients were prescribed significantly fewer opioids at discharge compared to matched pre-ERAS patients.
Conservative management of occult pneumothorax in mechanically ventilated patients: A systematic review and meta-analysis
Authors: Smith Jeremy Adam , Secombe Paul , Aromataris Edoardo
Published: July 2021

BACKGROUND

The aim of this systematic review was to investigate the safety and effectiveness of conservative management versus prophylactic intercostal catheter (ICC) insertion for the management of occult pneumothoraces in mechanically ventilated patients.

METHODS

PubMed, Embase, CINAHL, Web of Science, Cochrane Central, and other trial registries were searched. Eligible studies were critically appraised using standardized instruments. Meta-analysis was performed with mixed-methods logistic regression where appropriate and sensitivity analyses were performed with alternative statistical methods (Stata™ 15 or RevMan 5.3) or summarized in narrative. Randomized controlled trials (RCTs) and cohort studies were analyzed separately.

RESULTS

Twelve studies with a total of 354 participants were included; three RCTs (178 participants) and nine cohort studies (176 participants). The majority of the included studies, particularly the cohort studies, were well conducted. Two of the RCTs were rated as low quality. Statistically significant differences were observed in the RCT analysis: ICC insertion (any reason) (odds ratio, 2.86; 95% confidence interval, 1.26–6.43, 2 RCTs) in favor of prophylactic ICC; ICC complications (odds ratio, 0.12; 95% confidence interval, 0.02–0.62, 2 RCTs) in favor of conservative management. Nonstatistically significant differences were observed for progression of pneumothorax, ICC insertion (progression to simple pneumothorax), and ICC insertion (nonpneumothorax reasons). Results of analyses showed high imprecision (wide confidence limits). Conservative management showed a low rate of tension pneumothorax (2.8%). Complications were higher in the ICC group (19.5% vs. 5.8%).

CONCLUSION

Available evidence suggests that conservative management is safe for the management of occult pneumothoraces in mechanically ventilated patients, especially when undergoing short-term (<4 days) ventilation. We recommend that patients undergoing mechanical ventilation for a procedure alone and patients suspected to be ventilated less than 4 days can be conservatively managed.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, level III.
Platelet to erythrocyte transfusion ratio and mortality in massively transfused trauma patients. A systematic review and meta-analysis
Authors: Rijnhout Tim W.H. , Duijst Jeanette , Noorman Femke , Zoodsma Margreet , van Waes Oscar J.F. , Verhofstad Michael H.J. , Hoencamp Rigo
Published: July 2021

BACKGROUND

Platelet transfusion during major hemorrhage is important and often embedded in massive transfusion protocols. However, the optimal ratio of platelets to erythrocytes (platelet-rich plasma [PLT]/red blood cell [RBC] ratio) remains unclear. We hypothesized that high PLT/RBC ratios, as compared with low PLT/RBC ratios, are associated with improved survival in patients requiring massive transfusion.

METHODS

Four databases (Pubmed, CINAHL, EMBASE, and Cochrane) were systematically screened for literatures published until January 21, 2021, to determine the effect of PLT/RBC ratio on the primary outcome measure mortality at 1 hour to 6 hours and 24 hours and at 28 days to 30 days. Studies comparing various PLT/RBC ratios were included in the meta-analysis. Secondary outcomes included intensive care unit length of stay and in-hospital length of stay and total blood component use. The study protocol was registered in PROSPERO under number CRD42020165648.

RESULTS

The search identified a total of 8903 records. After removing the duplicates and second screening of title, abstract, and full text, a total of 59 articles were included in the analysis. Of these articles, 12 were included in the meta-analysis. Mortality at 1 hour to 6 hours, 24 hours, and 28 days to 30 days was significantly lower for high PLT/RBC ratios as compared with low PLT/RBC ratios.

CONCLUSION

Higher PLT/RBC ratios are associated with significantly lower 1-hour to 6-hour, 24-hour, 28-day to 30-day mortalities as compared with lower PLT/RBC ratios. The optimal PLT/RBC ratio for massive transfusion in trauma patients is approximately 1:1.

LEVEL OF EVIDENCE

Systematic review and meta-analysis, therapeutic Level III.
The hidden burden of unplanned readmission after emergency general surgery
Authors: Urrechaga Eva M. , Cioci Alessia C. , Parreco Joshua P. , Gilna Gareth P. , Saberi Rebecca A. , Yeh D. Dante , Zakrison Tanya L. , Namias Nicholas , Rattan Rishi
Published: July 2021

BACKGROUND

There are no national studies of nonelective readmissions after emergency general surgery (EGS) diagnoses that track nonindex hospital readmission. We sought to determine the rate of overall and nonindex hospital readmissions at 30 and 90 days after discharge for EGS diagnoses, hypothesizing a significant portion would be to nonindex hospitals.

METHODS

The 2013 to 2014 Nationwide Readmissions Database was queried for all patients 16 years or older admitted with an EGS primary diagnosis and survived index hospitalization. Multivariable logistic regression identified risk factors for nonelective 30- and 90-day readmission to index and nonindex hospitals.

RESULTS

Of 4,171,983 patients, 13% experienced unplanned readmission at 30 days. Of these, 21% were admitted to a nonindex hospital. By 90 days, 22% experienced an unplanned readmission, of which 23% were to a nonindex hospital. The most common reason for readmission was infection. Publicly insured or uninsured patients accounted for 67% of admissions and 77% of readmissions. Readmission predictors at 30 days included leaving against medical advice (odds ratio [OR], 2.51 [2.47–2.56]), increased length of stay (4–7 days: OR, 1.42 [1.41–1.43]; >7 days: OR, 2.04 [2.02–2.06]), Charlson Comorbidity Index ≥2 (OR, 1.72 [1.71–1.73]), public insurance (Medicare: OR, 1.45 [1.44–1.46]; Medicaid: OR, 1.38 [1.37–1.40]), EGS patients who fell into the “Other” surgical category (OR, 1.42 [1.38–1.48]), and nonroutine discharge. Risk factors for readmission remained consistent at 90 days.

CONCLUSION

Given that nonindex hospital EGS readmission accounts for nearly a quarter of readmissions and often related to important benchmarks such as infection, current EGS quality metrics are inaccurate. This has implications for policy, benchmarking, and readmission reduction programs.

LEVEL OF EVIDENCE

Epidemiological study, level III.
Extracellular vesicle–associated procoagulant activity is highest the first 3 hours after trauma and thereafter declines substantially: A prospective observational pilot study
Authors: Rognes Ingrid Nygren , Hellum Marit , Ottestad William , Bache Kristi Grønvold , Eken Torsten , Henriksson Carola Elisabeth
Published: July 2021

BACKGROUND

Trauma patients have high concentrations of circulating extracellular vesicles (EVs) following injury, but the functional role of EVs in this setting is only partly deciphered. We aimed to describe in detail EV-associated procoagulant activity in individual trauma patients during the first 12 hours after injury to explore their putative function and relate findings to relevant trauma characteristics and outcome.

METHODS

In a prospective observational study of 33 convenience recruited trauma patients, citrated plasma samples were obtained at trauma center admission and 2, 4, 6, and 8 hours thereafter. We measured thrombin generation from isolated EVs and the procoagulant activity of phosphatidylserine (PS)-exposing EVs. Correlation and multivariable linear regression analyses were used to explore associations between EV-associated procoagulant activity and trauma characteristics as well as outcome measures.

RESULTS

EV–associated procoagulant activity was highest in the first 3 hours after injury. EV–associated thrombin generation normalized within 7 to 12 hours of injury, whereas the procoagulant activity of PS-exposing EVs declined to a level right above that of healthy volunteers. Increased EV-associated procoagulant activity at admission was associated with higher New Injury Severity Score, lower admission base excess, higher admission international normalized ratio, prolonged admission activated partial thromboplastin time, higher Sequential Organ Failure Assessment score at day 0, and fewer ventilator-free days.

CONCLUSION

Our data suggest that EVs have a transient hypercoagulable function and may play a role in the early phase of hemostasis after injury. The role of EVs in trauma-induced coagulopathy and posttraumatic thrombosis should be studied bearing in mind this novel temporal pattern.

LEVEL OF EVIDENCE

Prognostic/epidemiologic, level V.
A pilot study of stored low titer group O whole blood + component therapy versus component therapy only for civilian trauma patients
Authors: Siletz Anaar E. , Blair Kevin J. , Cooper Richelle J. , Nguyen N. Charity , Lewis Scott J. , Fang Amy , Ward Dawn C. , Jackson Nicholas J. , Rodriguez Tyler , Grotts Jonathan , Hwang Jonathan , Ziman Alyssa , Cryer Henry Magill
Published: July 2021

BACKGROUND

This pilot assessed transfusion requirements during resuscitation with whole blood followed by standard component therapy (CT) versus CT alone, during a change in practice at a large urban Level I trauma center.

METHODS

This was a single-center prospective cohort pilot study. Male trauma patients received up to 4 units of cold-stored low anti-A, anti-B group O whole blood (LTOWB) as initial resuscitation followed by CT as needed (LTOWB + CT). A control group consisting of women and men who presented when LTOWB was unavailable, received CT only (CT group). Exclusion criteria included antiplatelet or anticoagulant medication and death within 24 hours. The primary outcome was total transfusion volume at 24 hours. Secondary outcomes were mortality, morbidity, and intensive care unit- and hospital-free days.

RESULTS

Thirty-eight patients received LTOWB, with a median of 2.0 (interquartile range [IQR] 1.0-3.0) units of LTOWB transfused. Thirty-two patients received CT only. At 24 hours after presentation, the LTOWB +CT group had received a median of 2,138 mL (IQR, 1,275–3,325 mL) of all blood products. The median for the CT group was 4,225 mL (IQR, 1,900–5,425 mL; p = 0.06) in unadjusted analysis. When adjusted for Injury Severity Score, sex, and positive Focused Assessment with Sonography for Trauma, LTOWB +CT group patients received 3307 mL of blood products, and CT group patients received 3,260 mL in the first 24 hours (p = 0.95). The adjusted median ratio of plasma to red cells transfused was higher in the LTOWB + CT group (0.85 vs. 0.63 at 24 hours after admission; p = 0.043. Adjusted mortality was 4.4% in the LTOWB + CT group, and 11.7% in the CT group (p = 0.19), with similar complications, intensive care unit-, and hospital-free days in both groups.

CONCLUSION

Beginning resuscitation with LTOWB results in equivalent outcomes compared with resuscitation with CT only.

LEVEL OF EVIDENCE

Therapeutic (Prospective study with 1 negative criterion, limited control of confounding factors), level III.
Reliable and valid assessment of procedural skills in resuscitative endovascular balloon occlusion of the aorta
Authors: Engberg Morten , Lönn Lars , Konge Lars , Mikkelsen Søren , Hörer Tal , Lindgren Hans , Søvik Edmund , Svendsen Morten Bo , Frendø Martin , Taudorf Mikkel , Russell Lene
Published: July 2021

BACKGROUND

Valid and reliable assessment of skills is essential for improved and evidence-based training concepts. In a recent study, we presented a novel tool to assess procedural skills in resuscitative endovascular balloon occlusion of the aorta (REBOA), REBOA-RATE, based on international expert consensus. Although expert consensus is a strong foundation, the performance of REBOA-RATE has not been explored. The study aimed to examine the reliability and validity of REBOA-RATE.

METHODS

This was an experimental simulation-based study. We enrolled doctors with three levels of expertise to perform two REBOA procedures in a simulated scenario of out-of-hospital cardiac arrest. Procedures were video-recorded, and videos were blinded and randomized. Three clinical experts independently rated all procedures using REBOA-RATE. Data were analyzed using Messick’s framework for validity evidence, including generalizability analysis of reliability and determination of a pass/fail standard.

RESULTS

Forty-two doctors were enrolled: 16 novices, 13 anesthesiologists, and 13 endovascular experts. They all performed two procedures, yielding 84 procedures and 252 ratings. The REBOA-RATE assessment tool showed high internal consistency (Cronbach’s α = 0.95) and excellent interrater reliability (intraclass correlation coefficient, 0.97). Assessment using one rater and three procedures could ensure overall reliability suitable for high-stakes testing (G-coefficient >0.80). Mean scores (SD) for the three groups in the second procedure were as follows: novices, 32% (24%); anesthesiologists, 55% (29%); endovascular experts, 93% (4%) (p < 0.001). The pass/fail standard was set at 81%, which all experts but no novices passed.

CONCLUSION

Data strongly support the reliability and validity of REBOA-RATE, which successfully discriminated between all experience levels. The REBOA-RATE assessment tool requires minimal instruction, and one rater is sufficient for reliable assessment. Together, these are strong arguments for the use of REBOA-RATE to assess REBOA skills, allowing for competency-based training and certification concepts.

LEVEL OF EVIDENCE

Diagnostic test, no or poor gold standard, level V.
KRP-203 Is a Desirable Immunomodulator for Islet Allotransplantation
Authors: Fathi Ibrahim , Nishimura Ryuichi , Imura Takehiro , Inagaki Akiko , Kanai Norifumi , Ushiyama Akira , Kikuchi Masafumi , Maekawa Masamitsu , Yamaguchi Hiroaki , Goto Masafumi
Published: July 2021

Background.

The current standard immunosuppressive regimens, calcineurin inhibitors, have diabetogenic and anti-vascularization effects on islet grafts. KRP-203, a sphingosine-1-phosphate functional antagonist, exerts its immunomodulatory function through lymphocyte sequestration. However, the effect of this antagonist on islets is unclear. We examined the effect of KRP-203 on the islet function and vascularization and sought a calcineurin-free regimen for islet allotransplantation.

Methods.

KRP-203 was administered for 14 d to mice, then diabetogenic effect was evaluated by blood glucose levels and a glucose tolerance test. Static glucose stimulation, the breathing index, and insulin/DNA were examined using isolated islets. Islet neovascularization was evaluated using a multiphoton laser scanning microscope. After islet allotransplantation with either KRP-203 alone, sirolimus alone, or both in combination, the graft survival was evaluated by blood glucose levels and immunohistochemical analyses. A mixed lymphocyte reaction was also performed to investigate the immunologic characteristics of KRP-203 and sirolimus.

Results.

No significant differences in the blood glucose levels or glucose tolerance were observed between the control and KRP-203 groups. Functional assays after islet isolation were also comparable. The multiphoton laser scanning microscope showed no inhibitory effect of KRP-203 on islet neovascularization. Although allogeneic rejection was effectively inhibited by KRP-203 monotherapy (44%), combination therapy prevented rejection in most transplanted mice (83%).

Conclusions.

KRP-203 is a desirable immunomodulator for islet transplantation because of the preservation of the endocrine function and lack of interference with islet neovascularization. The combination of KRP-203 with low-dose sirolimus may be promising as a calcineurin-free regimen for islet allotransplantation.
Synergistic multi-spectral CT reconstruction with directional total variation
Authors: Cueva Evelyn , Meaney Alexander , Siltanen Samuli , Ehrhardt Matthias J.
Published: July 2021

This work considers synergistic multi-spectral CT reconstruction where information from all available energy channels is combined to improve the reconstruction of each individual channel. We propose to fuse these available data (represented by a single sinogram) to obtain a polyenergetic image which keeps structural information shared by the energy channels with increased signal-to-noise ratio. This new image is used as prior information during a channel-by-channel minimization process through the directional total variation. We analyse the use of directional total variation within variational regularization and iterative regularization. Our numerical results on simulated and experimental data show improvements in terms of image quality and in computational speed.

This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.
Aureimonas mangrovi sp. nov., a marine alphaproteobacterium isolated from mangrove sediment in Thailand
Authors: Huang Hao , Punnarak Porntep , Zhang Qinghua , Piumsomboon Ajcharaporn , Wang Lei , Li Weiwen , Chen Shunyang , Chen Guangcheng , Ou Danyun
Published: July 2021

Two bacterial strains, designated as 1-4-3T and 1-4-4, were isolated from a mangrove sediment cultured with coastal seawater. The cells were Gram-stain-negative, motile, short, rod-shaped bacteria with flagella. Growth occurred at 4–37 °C, pH 7.0–9.0, and 0–7% NaCl. The predominant fatty acids of the novel strains were C18 : 1
 ω7c, C19 : 0 cyclo ω8c, C18 : 0, and C16 : 0. A phylogenetic analysis based on 16S rRNA gene sequences and whole genome phylogeny analysis based on distance matrix revealed an affiliation between the two strains and the genus

Aureimonas

, with closest sequence similarity to

A. populi

4M3-2T (96.41 and 96.64% similarity, respectively) and

A. glaciistagni

(96.01 and 96.23% similarity, respectively). The DNA G+C content of strain 1-4-3T was 66.80 mol%. Strain 1-4-3T displayed low DNA–DNA relatedness to

A. populi

4M3-2T, with an average nucleotide identity value of 77.47 % and digital DNA–DNA hybridization value of 22.83 %. Genotypic, chemotaxonomic, and phenotypic data indicate that strains 1-4-3T and 1-4-4 represent a novel species of the genus

Aureimonas

, for which we propose the name Aureimonas mangrovi sp. nov. The type strain is 1-4-3T (=LMG 31693T=CGMCC 1.18507T).
Phase-variable bacteria simultaneously express multiple capsules
Authors: Hsieh Samantha A. , Donermeyer David L. , Horvath Stephen C. , Allen Paul M.
Published: July 2021

Capsular polysaccharides (CPSs) protect bacteria from host and environmental factors. Many bacteria can express different CPSs and these CPSs are phase variable. For example, Bacteroides thetaiotaomicron (B. theta) is a prominent member of the human gut microbiome and expresses eight different capsular polysaccharides. Bacteria, including B. theta, have been shown to change their CPSs to adapt to various niches such as immune, bacteriophage, and antibiotic perturbations. However, there are limited tools to study CPSs and fundamental questions regarding phase variance, including if gut bacteria can express more than one capsule at the same time, remain unanswered. To better understand the roles of different CPSs, we generated a B. theta CPS1-specific antibody and a flow cytometry assay to detect CPS expression in individual bacteria in the gut microbiota. Using these novel tools, we report for the first time that bacteria can simultaneously express multiple CPSs. We also observed that nutrients such as glucose and salts had no effect on CPS expression. The ability to express multiple CPSs at the same time may provide bacteria with an adaptive advantage to thrive amid changing host and environmental conditions, especially in the intestine.
Reduced COVID-19 Hospitalizations among New York City Residents Following Age-Based SARS-CoV-2 Vaccine Eligibility: Evidence from a Regression Discontinuity Design
Authors: Greene Sharon K. , Levin-Rector Alison , McGibbon Emily , Baumgartner Jennifer , Devinney Katelynn , Ternier Alexandra , Sell Jessica , Kahn Rebecca , Kishore Nishant
Published: July 2021

Background

In clinical trials, several SARS-CoV-2 vaccines were shown to reduce risk of severe COVID-19 illness. Local, population-level, real-world evidence of vaccine effectiveness is accumulating. We assessed vaccine effectiveness for community-dwelling New York City (NYC) residents using a quasi-experimental, regression discontinuity design, leveraging a period (January 12–March 9, 2021) when ≥65-year-olds were vaccine-eligible but younger persons, excluding essential workers, were not.

Methods

We constructed segmented, negative binomial regression models of age-specific COVID-19 hospitalization rates among 45–84-year-old NYC residents during a post-vaccination program implementation period (February 21–April 17, 2021), with a discontinuity at age 65 years. The relationship between age and hospitalization rates in an unvaccinated population was incorporated using a pre-implementation period (December 20, 2020–February 13, 2021). We calculated the rate ratio (RR) and 95% confidence interval (CI) for the interaction between implementation period (pre or post) and age-based eligibility (45–64 or 65–84 years). Analyses were stratified by race/ethnicity and borough of residence. Similar analyses were conducted for COVID-19 deaths.

Results

Hospitalization rates among 65–84-year-olds decreased from pre- to post-implementation periods (RR 0.85, 95% CI: 0.74–0.97), controlling for trends among 45–64-year-olds. Accordingly, an estimated 721 (95% CI: 126–1,241) hospitalizations were averted. Residents just above the eligibility threshold (65–66-year-olds) had lower hospitalization rates than those below (63–64-year-olds). Racial/ethnic groups and boroughs with higher vaccine coverage generally experienced greater reductions in RR point estimates. Uncertainty was greater for the decrease in COVID-19 death rates (RR 0.85, 95% CI: 0.66–1.10).

Conclusion

The vaccination program in NYC reduced COVID-19 hospitalizations among the initially age-eligible ≥65-year-old population by approximately 15%. The real-world evidence of vaccine effectiveness makes it more imperative to improve vaccine access and uptake to reduce inequities in COVID-19 outcomes.
Dynamic, stage-course protein interaction network using high power CpG sites in Head and Neck Squamous Cell Carcinoma
Authors: Riaz Arsalan , Shah Maryam , Zaheer Saad , Salam Abdus , Khan Faisal F
Published: July 2021

Head and neck cancer is the sixth leading cause of cancer across the globe and is significantly more prevalent in South Asian countries, including Pakistan. Prediction of pathological stages of cancer can play a pivotal role in early diagnosis and personalized medicine. This project ventures into the prediction of different stages of head and neck squamous cell carcinoma (HNSCC) using prioritized DNA methylation patterns. DNA methylation profiles for each HNSCC stage (stage-I-IV) were used to extensively analyze 485,577 methylation CpG sites and prioritize them on the basis of the highest predictive power using a wrapper-based feature selection method, along with different classification models. We identified 68 high-power methylation sites which predicted the pathological stage of HNSCC samples with 90.62 % accuracy using a Random Forest classifier. We set out to construct a protein-protein interaction network for the proteins encoded by the 67 genes associated with these sites to study its network topology and also undertook enrichment analysis of nodes in their immediate neighborhood for GO and KEGG Pathway annotations which revealed their role in cancer-related pathways, cell differentiation, signal transduction, metabolic and biosynthetic processes. With information on the predictive power of each of the 67 genes in each HNSCC stage, we unveil a dynamic stage-course network for HNSCC. We also intend to further study these genes in light of functional datasets from CRISPR, RNAi, drug screens for their putative role in HNSCC initiation and progression.
Considerations for using multiple imputation in propensity score-weighted analysis
Authors: Eiset Andreas Halgreen , Frydenberg Morten
Published: July 2021

We present our considerations for using multiple imputation to account for missing data in propensity score-weighted analysis with bootstrap percentile confidence interval. We outline the assumptions underlying each of the methods and discuss the methodological and practical implications of our choices and briefly point to alternatives. We made a number of choicesa priorifor example to use logistic regression-based propensity scores to produce “standardized mortality ratio”-weights and Substantive Model Compatible-Full Conditional Specification to multiply impute missing data (given no violation of underlying assumptions). We present a methodology to combine these methods by choosing the propensity score model based on covariate balance, using this model as the substantive model in the multiple imputation, producing and averaging the point estimates from each multiple imputed data set to give the estimate of association and computing the percentile confidence interval by bootstrapping. The described methodology is demanding in both work-load and in computational time, however, we do not consider the prior a draw-back: it makes some of the underlying assumptions explicit and the latter may be a nuisance that will diminish with faster computers and better implementations.
Crowd Annotations Can Approximate Clinical Autism Impressions from Short Home Videos with Privacy Protections
Authors: Washington Peter , Leblanc Emilie , Dunlap Kaitlyn , Kline Aaron , Mutlu Cezmi , Chrisman Brianna , Stockham Nate , Paskov Kelley , Wall Dennis P.
Published: July 2021

Artificial Intelligence (A.I.) solutions are increasingly considered for telemedicine. For these methods to adapt to the field of behavioral pediatrics, serving children and their families in home settings, it will be crucial to ensure the privacy of the child and parent subjects in the videos. To address this challenge in A.I. for healthcare, we explore the potential for global image transformations to provide privacy while preserving behavioral annotation quality. Crowd workers have previously been shown to reliably annotate behavioral features in unstructured home videos, allowing machine learning classifiers to detect autism using the annotations as input. We evaluate this method with videos altered via pixelation, dense optical flow, and Gaussian blurring. On a balanced test set of 30 videos of children with autism and 30 neurotypical controls, we find that the visual privacy alterations do not drastically alter any individual behavioral annotation at the item level. The AUROC on the evaluation set was 90.0% +/- 7.5% for the unaltered condition, 85.0% +/- 9.0% for pixelation, 85.0% +/- 9.0% for optical flow, and 83.3% +/- 9.3% for blurring, demonstrating that an aggregation of small changes across multiple behavioral questions can collectively result in increased misdiagnosis rates. We also compare crowd answers against clinicians who provided the same annotations on the same videos and find that clinicians are more sensitive to autism-related symptoms. We also find that there is a linear correlation (r=0.75, p<0.0001) between the mean Clinical Global Impression (CGI) score provided by professional clinicians and the corresponding classifier score emitted by the logistic regression classifier with crowd inputs, indicating that the classifier’s output probability is a reliable estimate of clinical impression of autism from home videos. A significant correlation is maintained with privacy alterations, indicating that crowd annotations can approximate clinician-provided autism impression from home videos in a privacy-preserved manner.
Fragmented QRS is independently predictive of long-term adverse clinical outcomes in Asian patients hospitalized for heart failure: a retrospective cohort study
Authors: Kai Chan Jeffrey Shi , Zhou Jiandong , Lee Sharen , Li Andrew , Tan Martin , Leung Keith S K , Jeevaratnam Kamalan , Liu Tong , Roever Leonardo , Liu Ying , Tse Gary , Zhang Qingpeng
Published: July 2021

Background

Fragmented QRS (fQRS) results from myocardial scarring and predicts cardiovascular mortality and ventricular arrhythmia (VA). We evaluated the prevalence and prognostic value of fQRS in Asian patients hospitalized for heart failure.

Methods and results

This was a retrospective cohort study of adult patients hospitalized for heart failure between 1st January 2010 and 31st December 2016 at a tertiary center in Hong Kong. The baseline ECG was analysed. QRS complexes (<120 ms) with fragmented morphology in ≥2 contiguous leads were defined as fQRS. The primary outcome was a composite of cardiovascular mortality, VA, and sudden cardiac death (SCD). The secondary outcomes were the components of the primary outcome, myocardial infarction, and new-onset atrial fibrillation. In total, 2192 patients were included, of whom 179 (8.20%) exhibited fQRS. The follow-up duration was 5.63±4.09 years. fQRS in any leads was associated with a higher risk of the primary outcome (adjusted hazard ratio (HR) 1.541 [1.185, 2.004], p=0.001), but not myocardial infarction or new-onset atrial fibrillation. fQRS in >2 contiguous leads was an independent predictor of SCD (HR 2.679 [1.252, 5.729], p=0.011). In patients without ischaemic heart disease (N=1396), fQRS in any leads remained predictive of VA and SCD (adjusted HR 3.336 [1.343, 8.282], p=0.009, and 1.928 [1.135, 3.278], p=0.015, respectively), but not cardiovascular mortality (adjusted HR 1.049 [0.662, 1.662], p=0.839).

Conclusion

fQRS is an independent predictor of cardiovascular mortality, VA, and SCD. Higher fQRS burden increased SCD risk. The implications of fQRS in heart failure patients without ischaemic heart disease require further studies.
Pre-exposure prophylaxis adherence with real-time adherence feedback and partner HIV self-testing: A pilot trial among postpartum women
Authors: Davey Dvora Leah Joseph , Dovel Kathryn , Mvududu Rufaro , Nyemba Dorothy , Mashele Nyiko , Bekker Linda-Gail , Gorbach Pamina M. , Coates Thomas J. , Myer Landon
Published: July 2021

Background

Pre-exposure prophylaxis (PrEP) is safe and effective in postpartum women. HIV self-testing (HIVST) for partners combined with biofeedback counselling through real-time adherence measures may improve daily PrEP use among postpartum women.

Methods

Between August 2020 and April 2021 we conducted a pilot study in one primary care clinic in Cape Town, South Africa. We randomized postpartum women who initiated PrEP in pregnancy 1:1 to the intervention group (HIVST + biofeedback counselling following urine tenofovir test) or to standard of care (facility-based HIV tests and routine counselling without biofeedback). The outcomes of interest were PrEP adherence in the past 48-72hours via urine tenofovir tests and partner HIV testing, measured 1-month after randomisation. Secondary outcomes included proportion of partners who tested for HIV and discrepancy between self-reported PrEP adherence and urine tenofovir result.

Findings

We enrolled 106 women (median age=26 years; median months postpartum=2). Almost half of women reported having sex since giving birth (48%); 76% of those reported condomless sex at last sex. At enrolment most women (72%) reported missing <2 doses in the past 7-days; 36% of women had tenofovir present in her urine (no significant differences by arm). One month after enrolment, 62% (n=33) of women in the intervention arm had tenofovir present in their urine compared to 34% (n=18) in the standard of care arm (RR=1.83; 95% CI=1.19, 2.82). Two-thirds of women in the intervention arm reported that her partner tested for HIV (66%; n=35); compared to 17% (n=9) in the standard of care arm (RR=3.89; 95% CI=2.08, 7.27). The proportion of women with a discrepant adherence result (self-reported good recent adherence with no tenofovir in urine test) was significantly lower in the intervention group (n=8; 17%) compared to the standard of care group (n=24; 46%) (RR=0.33; 95% CI=0.17, 0.67). No social or clinical adverse events were reported in the intervention arm.

Interpretation

In this pilot study, HIVST for partners and biofeedback counseling increased levels of recent PrEP adherence, pointing to the importance of these interventions to support PrEP use in this population.

Funding

Our study is funded by Fogarty International Center (K01TW011187) with additional support from NIMH (R01MH116771). Trial registration:Clinicaltrials.gov(NCT04897737). Funders had no role in data collection or analysis.
GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans
Authors: Saidas Nair K. , Srivastava Chitrangda , Brown Robert V. , Koli Swanand , Choquet Hélène , Kang Hong Soon , Kuo Yien-Ming , Grimm Sara A. , Sutherland Caleb , Badea Alexandra , Allan Johnson G. , Zhao Yin , Yin Jie , Okamoto Kyoko , Clark Graham , Borras Teresa , Zode Gulab , Kizhatil Krishnakumar , Chakrabarti Subhabrata , John Simon W.M. , Jorgenson Eric , Jetten Anton M.
Published: July 2021

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open- angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel- like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P=4.73x10-6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.
Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection
Authors: Laise Pasquale , Stanifer Megan L. , Bosker Gideon , Sun Xiaoyun , Triana Sergio , Doldan Patricio , Manna Federico La , De Menna Marta , Realubit Ronald B. , Pampou Sergey , Karan Charles , Alexandrov Theodore , Kruithof-de Julio Marianna , Califano Andrea , Boulant Steeve , Alvarez Mariano J.
Published: July 2021

Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, with-out adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.
Gene drive that results in addiction to a temperature sensitive version of an essential gene triggers population collapse in Drosophila
Authors: Oberhofer Georg , Ivy Tobin , Hay Bruce A.
Published: July 2021

One strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, such as a change in temperature. Cleave and Rescue (ClvR) selfish genetic elements use Cas9 and gRNAs to disrupt endogenous versions of an essential gene, while also including a Rescue version of the essential gene resistant to disruption. ClvR spreads by creating loss-of-function alleles of the essential gene that select against those lacking it, resulting in populations in which the Rescue provides the only source of essential gene function. In consequence, if function of the Rescue, a kind of Trojan horse now omnipresent in a population, is condition-dependent, so too will be the survival of that population. To test this idea we created a ClvR in Drosophila in which Rescue activity of an essential gene, dribble, requires splicing of a temperature-sensitive intein (TS-ClvRdbe). This element spreads to transgene fixation at 23°C, but when populations now dependent on Ts-ClvRdbe are shifted to 29°C death and sterility result in a rapid population crash. These results show that conditional population elimination can be achieved. A similar logic, in which Rescue activity is conditional, could also be used in HEG-based drive, and to bring about suppression and/or killing of specific individuals in response to other stimuli..

SIGNIFICANCE STATEMENT

Gene drive can be used to spread traits of interest through wild populations. In some contexts the goal is to suppress or eliminate the population. In principle, one way to achieve this goal is if the trait being spread confers on carriers conditional lethality in response to an environmental stimulus that is either introduced by humans into the target area at a specific time (a virus, otherwise benign chemical; a kind of species-specific insecticide), or that occurs naturally on a seasonal basis, such as a change in temperature. Here we show that ClvR selfish elements can be used to spread a gene that confers lethality and sterility in response to increased temperature, demonstrating that conditional population elimination can be achieved.
Enzymatic and structural characterization of HAD5, an essential phosphomannomutase of malaria parasites
Authors: Frasse Philip M , Miller Justin J , Soleimani Ebrahim , Zhu Jian-She , Jakeman David L , Jez Joseph M , Goldberg Daniel E , Odom John Audrey R
Published: July 2021

The malaria parasite Plasmodium falciparum is responsible for over 200 million infections and 400,000 deaths per year. At multiple stages during its complex life cycle, P. falciparum expresses several essential proteins tethered to its surface by glycosylphosphatidylinositol (GPI) anchors, which are critical for biological processes such as parasite egress and reinvasion of host red blood cells. Targeting this pathway therapeutically has the potential to broadly impact parasite development across several life stages. Here, we characterize an upstream component of GPI anchor biosynthesis, the putative phosphomannomutase (EC 5.4.2.8) of the parasites, HAD5 (PF3D7_1017400). We confirm the phosphomannomutase and phosphoglucomutase activity of purified recombinant HAD5. By regulating expression of HAD5 in transgenic parasites, we demonstrate that HAD5 is required for malaria parasite egress and erythrocyte reinvasion. Finally, we determine the three-dimensional crystal structure of HAD5 and identify a substrate analog that specifically inhibits HAD5, compared to orthologous human phosphomannomutases. These findings demonstrate that the GPI anchor biosynthesis pathway is exceptionally sensitive to inhibition, and that HAD5 has potential as a multi-stage antimalarial target.