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BackgroundThe lack of race/ethnic and gender diversity in grants funded by the National Institutes of Health (NIH) is a persistent challenge related to career advancement and the quality and relevance of health research. We describe pilot programs at nine institutions supported by the NIH-sponsored Building Infrastructure Leading to Diversity (BUILD) program aimed at increasing diversity in biomedical research.MethodsWe collected data from the 2016-2017 Higher Education Research Institute survey of faculty and NIH progress reports for the first four years of the program (2015-2018). We then conducted descriptive analyses of data from the nine BUILD institutions that had collected data and evaluated which activities were associated with research productivity. We used Poisson regression and rate ratios of the numbers of BUILD pilots funded, students included, abstracts, presentations, publications, and submitted and funded grant proposals.ResultsTeaching workshops were associated with more abstracts (RR 4.04, 95% CI 2.21-8.09). Workshops on grant writing were associated with more publications (RR 2.64, 95% CI 1.64-4.34) and marginally with marginally more presentations. Incentives to develop courses were associated with more abstracts published (RR 4.33, 95% CI 2.56-7.75). Workshops on research skills and other incentives were not associated with any positive effects.ConclusionsPilot interventions show promise in supporting diversity in NIH-level research. Longitudinal modeling that considers time lags in career development in moving from project development to grants submissions can provide more direction for future diversity pilot interventions. more...

OBJECTIVE: To better understand the impact of USMLE scores and interview scores on the National Resident Matching Program (NRMP) rank of applicants to the residency program at The Children's Hospital of Philadelphia. METHODOLOGY: We evaluated 935 applicants' files from 2000, 2001, and 2002. For each candidate, one interviewer had access to the full application, while the other interviewer was blinded to USMLE scores and grades. Interview scores were generated by both interviewers. Statistical analysis was performed to evaluate relationships between USMLE scores, interview scores, and NRMP rank list number. RESULTS: There were a wide range of USMLE scores among candidates who interviewed (range 181 to 269, 227.7 +/- 17.1, M +/- standard deviation). USMLE scores were weakly correlated to nonblinded interview scores (r = -0.17), final committee scores (r = -0.26), and NRMP ranking (r = -0.21): P < .0005. Blinded interviews did not correlate with USMLE scores. Both nonblinded and blinded interviews had stronger correlations with NRMP rank list number (r = 0.49, P < .0005 and r = 0.36, P < .0005, respectively). The nonblinded interview accounted for 20.6% of variance in the NRMP rank list order. CONCLUSIONS: Interview scores were the most important variable for candidate ranking on the NRMP list. Furthermore, when interviewers had access to board scores, there was a modest correlation to performance on the USMLE. While interviews may reflect a candidate's personality, they may not effectively measure desired characteristics when access to academic markers is unrestricted. We suggest incorporating blinded interviews into the selection process to give candidates a better opportunity to display communication skills, emotional stability, and 'fit' for the program. [ABSTRACT FROM AUTHOR] more...

In utero surgery may provide benefit to a compromised fetus. The possibility of fetal surgery in a twin pregnancy extends the risk-benefit calculus beyond that of the fetus and mother to include the companion fetus and raises the issue of when, if ever, may fetus B be placed at substantial risk to benefit fetus A. Insight into the ethical dimensions of this issue is provided by the norms that govern the use of children in nontherapeutic research and the justifications used in twin-to-twin transplant cases. [ABSTRACT FROM AUTHOR] more...

Objective. In recent years, the increased prevalence of breastfeeding in conjunction with early discharge practices has increased the risk for marked hyperbilirubinemia in neonates. This has resulted in the potential for bilirubin brain injury in affected infants. The purpose of this study was to identify all infants >/=36 weeks' gestational age with bilirubin levels >25 mg/dL and evaluate them for early and late evidence of bilirubin brain injury. Methods. We reviewed the charts of all infants (from 1993-1996) >/=36 weeks' gestational age who were readmitted to the hospital during the first week of life with bilirubin levels >25 mg/dL. Readmission records were reviewed for early signs of bilirubin encephalopathy. Magnetic resonance imaging (MRIs) and Brainstem auditory-evoked responses (BAERs) were reviewed for evidence of bilirubin toxicity. At follow-up, study infants had a complete neurodevelopmental examination, repeat MRIs, and behavioral hearing evaluations. Results. From 1993 to 1996, we identified 6 term and near-term infants readmitted to the hospital within the first week of life with peak bilirubin values ranging from 26.4 mg/dL (451 ?mol/L) to 36.9 mg/dL (631 ?mol/L). Five of 6 infants had bilirubin values >30 mg/dL (513 ?mol/L). All were exclusively breastfed or fed a combination of breast and bottle feedings. Five of 6 infants presented with abnormal neurologic signs. Four infants had initial MRIs, 3 of whom had increased signal intensity in the basal ganglia consistent with kernicterus. Two infants had abnormal BAERs; both also had abnormal MRIs. Five of 6 infants received exchange transfusions and all were treated with phototherapy and intravenous fluids. Follow-up examinations between 3 months and 2 years showed resolution of clinical signs in all but 1 infant. Four infants had a subsequent normal MRI and 1 had residual hearing impairment. One infant demonstrated severely abnormal developmental evaluations, as well as both an abnormal initial MRI and BAERs. Follow-up MRI showed evidence of encephalomalacia with changes not characteristic of kernicterus. Conclusions. We observed transient neurologic abnormalities in 5 of 6 infants readmitted to the hospital during the first week of life with marked hyperbilirubinemia. The abnormalities resolved following aggressive management using hydration, phototherapy, and exchange transfusion and may not correlate with long-term prognosis. Less aggressive therapy may be associated with residual neurologic abnormalities. We speculate that inadequate establishment of breastfeeding coupled with early discharge practices may play a role in the development of marked hyperbilirubinemia in these infants. [ABSTRACT FROM AUTHOR] more...

The association of B7-1/CD28 between antigen presenting cells (APCs) and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide. more...

Bacterial meningitis causes significant morbidity and mortality in infants. Lumbar punctures are often deferred until the results of blood cultures are known and sometimes not considered, making this population susceptible to a missed diagnosis. There are few studies describing the epidemiology of neonatal meningitis in quaternary neonatal intensive care unit settings. We describe the epidemiology of meningitis in a level IV neonatal intensive care unit; compare pathogens and rates of concordant bacteremia between infants with and without neurosurgical (NS) devices. Retrospective review of infants < 1 year of age in the Children's Hospital of Philadelphia neonatal intensive care unit with bacterial meningitis (June 2007-October 2021). Analysis included summary statistics, Wilcoxon rank sum, Chi square, and Fisher exact tests. We identified 101 episodes of bacterial meningitis (95 infants). 9 infants died. At diagnosis, 26 infants (27%) had NS devices. Group B streptococcus (GBS) and Escherichia coli (E coli) were most common pathogens, however, coagulase-negative staphylococci and Staphylococcus aureus (S aureus) predominated among infants with NS devices. While 86% had positive blood cultures in the absence of a NS device, only 14% of episodes with NS devices had concomitant bacteremia (P < .0001). Although Group B streptococcus and E coli remain most prevalent overall, coagulase-negative staphylococci and S aureus were common pathogens in NS patients. Infants with NS devices rarely had concomitant bacteremia. Meningitis was diagnosed in the absence of a positive blood culture in 36% of episodes, underscoring the importance of developing guidance for lumbar punctures in infants evaluated for sepsis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.) more...

CD1 is an antigen-presenting glycoprotein homologous to MHC I; however, CD1 proteins present lipid rather than peptide antigens. CD1 proteins are well established to present lipid antigens of Mycobacterium tuberculosis (Mtb) to T cells, but understanding the role of CD1-restricted immunity in vivo in response to Mtb infection has been limited by the availability of animal models naturally expressing the CD1 proteins implicated in human response: CD1a, CD1b, and CD1c. Guinea pigs, in contrast to other rodent models, express four CD1b orthologs, and here we utilize the guinea pig to establish the kinetics of gene and protein expression of CD1b orthologs, as well as the Mtb lipid-antigen and CD1b-restricted immune response at the tissue level over the course of Mtb infection. Our results indicate transient upregulation of CD1b expression during the effector phase of adaptive immunity that wanes with disease chronicity. Gene expression indicates that the upregulation of CD1b is the result of transcriptional induction across all CD1b orthologs. We show high CD1b3 expression on B cells, and identify CD1b3 as the predominant CD1b ortholog in pulmonary granuloma lesions. We identify ex vivo cytotoxic activity directed against CD1b that parallels the kinetic changes in CD1b expression in Mtb-infected lungs and spleen. This study confirms that CD1b expression is modulated by Mtb infection in lung and spleen, leading to pulmonary and extrapulmonary CD1b-restricted immunity as a component of the antigen-specific response to Mtb infection., Competing Interests: D.B.M. consults for Pfizer and has CD1-related intellectual property through the Brigham and Women's Hospital. more...

Objective: To analyze relationships between provider-documented signs prompting sepsis evaluations, assessments of illness severity, and late-onset infection (LOI)., Study Design: Retrospective cohort study of all infants receiving a sepsis huddle in conjunction with a LOI evaluation. Participants were ≥3 days old and admitted to a level IV neonatal intensive care unit (NICU) from September 2018 through May 2021. Data were extracted from standardized sepsis huddle notes in the electronic health record, including clinical signs prompting LOI evaluations, illness severity assessments (from least to most severe: green, yellow, and red), and management plans. To analyze relationships of sepsis huddle characteristics with the detection of culture-confirmed LOI (bacteremia, urinary tract infection, or meningitis), we utilized diagnostic test statistics, area under the receiver-operator characteristic analyses, and multivariable logistic regression., Results: We identified 1209 eligible sepsis huddles among 604 infants. There were 111 culture-confirmed LOI episodes (9% of all huddles). Twelve clinical signs of infection poorly distinguished infants with and without LOI, with sensitivity for each ranging from 2% to 36% and area under the receiver-operator characteristic ranging 0.49-0.53. Multivariable logistic regression identified increasing odds of infection with higher perceived illness severity at the time of sepsis huddle, adjusted for gestational age and receipt of intensive care supports., Conclusions: Clinical signs prompting sepsis huddles were nonspecific and not predictive of concurrent LOI. Higher perceived illness severity was associated with presence of infection, despite some misclassification based on objective criteria. In level IV NICUs, antimicrobial stewardship through development of criteria for antibiotic noninitiation may be challenging, as presenting signs of LOI are similar among infants with and without confirmed infection., Competing Interests: Declaration of Competing Interest LHC is partial owner of 2minutemedicine.com, a medical news and educational website. The authors have no conflicts of interest or financial disclosures relevant to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.) more...

Purpose: Osteoporotic patients are at risk of peri-implant fractures after distal radius fixation. A unicortical screw in the proximal hole of the plate can theoretically decrease stress riser formation by eliminating the hole in the far bone cortex. This construct has been proposed in orthopedic literature to prevent peri-implant fractures but has not been tested in an osteoporotic distal radius model., Methods: Eleven paired cadaver radii were harvested and plated with four-hole titanium volar distal radius plates. No osteotomies were created. The fixation constructs were identical except that group A used a bicortical proximal locking screw and group B used a unicortical proximal locking screw. Bone mineral density was estimated using radiographic measurements. The samples were potted and tested for four-point bending stiffness, torsion stiffness, and load to failure., Results: Between the bicortical and unicortical screw groups, there was no significant difference in four-point bending stiffness (110.8 vs 106.2 N/mm, apex volar bending; 105.4 vs 107.1 N/mm, apex dorsal bending) or torsional stiffness (430.6 vs 427.6 N-mm/degree, internal rotation; 430.8 vs 429.7 N-mm/degree, external rotation). There was also no significant difference in load to failure with apex dorsal four-point bending (795.3 vs 770.0 N)., Conclusions: This study shows that a healed osteoporotic distal radius volar plate construct with a proximal unicortical locking screw is not statistically different from a bicortical screw in stiffness or load to failure in apex dorsal bending. Although a unicortical locking screw has been proposed as a mechanism to prevent stress risers at the proximal aspect of the distal radius plate, this study suggests no significant difference when compared with a bicortical locking screw., Clinical Relevance: There is no significant biomechanical advantage to unicortical over bicortical locking screws in the proximal hole of a distal radius plate to prevent diaphyseal peri-implant fractures in osteoporotic patients., Competing Interests: No benefits in any form have been received or will be received related directly to this article. more...

Introduction: Pancreatic cancer recurrence following surgery is a significant challenge, and personalized surgical care is crucial. Topographical variations in pancreatic duct anatomy are frequent but often underestimated. This study aimed to investigate the potential importance of these variations in outcomes and patient survival after Whipple's procedures., Methods: Data were collected from 105 patients with confirmed pancreatic head neoplasms who underwent surgery between 2008 and 2020. Radiological measurements of pancreatic duct location were performed, and statistical analysis was carried out using IBM SPSS., Results: Inferior pancreatic duct topography was associated with an increased rate of metastatic spread and tumour recurrence. Additionally, inferior duct topography was associated with reduced overall and recurrence-free survival. Posterior pancreatic duct topography was associated with decreased incidence of perineural sheet infiltration and improved overall survival., Discussion: These findings suggest that topographical diversity of pancreatic duct location can impact outcomes in Whipple's procedures. Intraoperative review of pancreatic duct location could help surgeons define areas of risk or safety and deliver a personalized surgical approach for patients with beneficial or deleterious anatomical profiles. This study provides valuable information to improve surgical management by identifying high-risk patients and delivering a personalized surgical approach with prognosis stratification., (© 2024 Royal Australasian College of Surgeons.) more...

Autism and gender diversity often intersect. Many transgender youth seeking gender-related medical interventions are autistic. Clinicians serving these youth lack an autism-specific evidence base to guide gender care decisions. At present, care decisions are based on extrapolation of care models from transgender youth samples, generally. At this point, there is no evidence to suggest that autistic youth are likely to experience shifts in gender or gender-related medical requests, although this has been insufficiently studied. In this article, cowritten by expert clinicians and autistic gender-diverse collaborators, an overview of clinical care considerations and the current evidence base is provided., (Copyright © 2023 Elsevier Inc. All rights reserved.) more...

Background: Autistic transgender people face unique risks in society, including inequities in accessing needed care and related mental health disparities. Given the need for specific and culturally responsive accommodations/supports, the characterization of key experiences, challenges, needs, and resilience factors within this population is imperative. This study developed a structured self-report tool for autistic transgender young adults to communicate their experiences and needs in a report format attuned to common autistic thinking and communication styles., Methods: This cross-nation project developed and refined the Gender-Diversity and Autism Questionnaire through an iterative community-based approach using Delphi panel methodology. This proof-of-principle project defined "expertise" broadly, employing a multi-input expert search approach to balance academic-, community-, and lived experience-based expertise., Results: The expert collaborators ( N  = 24 respondents) completed a two-round Delphi study, which developed 85 mostly closed-ended items based on 90% consensus. Final item content falls within six topic areas: the experience of identities; the impact of experienced or anticipated discrimination, bias, and violence toward autistic people and transgender people; tasks and experiences of everyday life; gender diversity- or autism-related care needs and history; the experience of others doubting an individual's gender identity and/or autism; and the experience of community and connectedness. The majority of retained items relate to tasks and experiences of everyday life or the impact of experienced or anticipated discrimination, bias, and violence., Conclusions: This study employed a multipronged multimodal search approach to maximize equity in representation of the expert measure development team. The resulting instrument, designed for clinical, research, and self-advocacy applications, has parallel Dutch and English versions and is available for immediate use. Future cross-cultural research with this instrument could help identify contextual risk and resilience factors to better understand and address inequities faced by this large intersectional population., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.) more...

CD1 is an antigen presenting glycoprotein homologous to MHC I; however, CD1 proteins present lipid rather than peptide antigen. CD1 proteins are well established to present lipid antigens of Mycobacterium tuberculosis (Mtb) to T cells, but understanding the role of CD1-restricted immunity in vivo in response to Mtb infection has been limited by availability of animal models naturally expressing the CD1 proteins implicated in human response: CD1a, CD1b and CD1c. Guinea pigs, in contrast to other rodent models, express four CD1b orthologs, and here we utilize the guinea pig to establish the kinetics of gene and protein expression of CD1b orthologs, as well as the Mtb lipid-antigen and CD1b-restricted immune response at the tissue level over the course of Mtb infection. Our results indicate transient upregulation of CD1b expression during the effector phase of adaptive immunity that wanes with disease chronicity. Gene expression indicates that upregulation of CD1b is the result of transcriptional induction across all CD1b orthologs. We show high CD1b3 expression on B cells, and identify CD1b3 as the predominant CD1b ortholog in pulmonary granuloma lesions. We identify ex vivo cytotoxic activity directed against CD1b that closely paralleled the kinetic changes in CD1b expression in Mtb infected lung and spleen. This study confirms that CD1b expression is modulated by Mtb infection in lung and spleen, leading to pulmonary and extrapulmonary CD1b-restricted immunity as a component of the antigen-specific response to Mtb infection. more...

Background: Although previous studies have shown that vitamin A deficiency is associated with incident tuberculosis (TB) disease, the direction of the association has not been established. We investigated the impact of vitamin A deficiency on TB disease progression., Methods: We conducted a longitudinal cohort study nested within a randomized clinical trial among HIV-infected patients in Haiti. We compared serial vitamin A levels in individuals who developed TB disease to controls matched on age, gender, follow-up time, and time to antiretroviral therapy initiation. We also evaluated histopathology, bacterial load, and immune outcomes in TB infection in a guinea pig model of dietary vitamin A deficiency., Results: Among 773 participants, 96 developed incident TB during follow-up, 62.5% (60) of whom had stored serum samples obtained 90-365 days before TB diagnosis. In age- and sex- adjusted and multivariate analyses, respectively, incident TB cases were 3.99 times (95% confidence interval [CI], 2.41 to 6.60) and 3.59 times (95% CI, 2.05 to 6.29) more likely to have been vitamin A deficient than matched controls. Vitamin A-deficient guinea pigs manifested more extensive pulmonary pathology, atypical granuloma morphology, and increased bacterial growth after experimental TB infection. Reintroduction of dietary vitamin A to deficient guinea pigs after established TB disease successfully abrogated severe disease manifestations and altered cellular immune profiles., Conclusions: Human and animal studies support the role of baseline vitamin A deficiency as a determinant of future TB disease progression., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.) more...

Objective: To determine whether culture yield and time to positivity (TTP) differ between peripheral and central vascular catheter-derived blood cultures (BCx) in neonatal intensive care unit (NICU) patients evaluated for late-onset sepsis., Design: Single-centre, retrospective, observational study., Setting: Level IV NICU., Participants: The study included infants >72 hours old admitted to NICU in 2007-2019 with culture-confirmed bacteraemia. All episodes had simultaneous BCx drawn from a peripheral site and a vascular catheter ('catheter culture')., Main Outcome Measures: Dual-site culture yield and TTP., Results: Among 179 episodes of late-onset bacteraemia (among 167 infants) with concurrently drawn peripheral and catheter BCx, the majority (67%, 120 of 179) were positive from both sites, compared with 17% (30 of 179) with positive catheter cultures only and 16% (29 of 179) with positive peripheral cultures only. 66% (19 of 29) of episodes with only positive peripheral BCx grew coagulase-negative Staphylococcus , while 34% (10 of 29) were recognised bacterial pathogens. Among 120 episodes with both peripheral and catheter BCx growth, catheter cultures demonstrated bacterial growth prior to paired peripheral cultures in 78% of episodes (93 of 120, p<0.001). The median TTP was significantly shorter in catheter compared with peripheral cultures (15.0 hours vs 16.8 hours, p<0.001). The median elapsed time between paired catheter and peripheral culture growth was 1.3 hours., Conclusion: Concurrently drawn peripheral and catheter BCx had similar yield. While a majority of episodes demonstrated dual-site BCx growth, a small but important minority of episodes grew virulent pathogens from either culture site alone. While dual-site culture practices may be useful, clinicians should balance the gain in sensitivity of bacteraemia detection against additive contamination risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Background: Malreduction after syndesmotic stabilization occurs in as many as 52% of cases and has been shown to detrimentally affect clinical outcomes. We propose that the modified Glide Path technique reduces the occurrence of syndesmotic malreduction., Methods: This study is a prospective series comparing 16 patients reduced with the modified Glide Path technique with a retrospectively reviewed series of 25 patients reduced with a traditional technique using fluoroscopy and a clamp. The modified Glide Path technique consists of manual reduction of the fibula and placement of a Kirschner wire through the fibula and tibia along the transmalleolar axis. The syndesmosis can then be reduced along the glide path created by the Kirschner wire to prevent posterior or anterior malreduction. Computed tomographic scans of the repaired and contralateral ankles were obtained postoperatively to assess reduction., Results: We found a statistically significant decrease of syndesmotic malreductions using the modified Glide Path technique when compared with technique that did not use a glide path. In our study, 2 of 16 patients (12.5%) had syndesmotic malreductions using the modified Glide Path technique, compared with 11 of 25 patients (44%) with syndesmotic malreductions in the historical cohort., Conclusion: The modified Glide Path technique is a simple method for ankle syndesmotic reduction. The technique has lower rates of malreduction compared with historical methods and may be useful for most operative syndesmotic injuries., Level of Evidence: Level II, prospective cohort study. more...

Purpose: Excellent metabolic improvement following one anastomosis gastric bypass (OAGB) remains compromised by the risk of esophageal bile reflux and theoretical carcinogenic potential. No 'gold standard' investigation exists for esophageal bile reflux, with diverse methods employed in the few studies evaluating it post-obesity surgery. As such, data on the incidence and severity of esophageal bile reflux is limited, with comparative studies lacking. This study aims to use specifically tailored biliary scintigraphy and upper gastrointestinal endoscopy protocols to evaluate esophageal bile reflux after OAGB, sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB)., Methods: Fifty-eight participants underwent OAGB (20), SG (15) or RYGB (23) between November 2018 and July 2020. Pre-operative reflux symptom assessment and gastroscopy were performed and repeated post-operatively at 6 months along with biliary scintigraphy., Results: Gastric reflux of bile was identified by biliary scintigraphy in 14 OAGB (70%), one RYGB (5%) and four SG participants (31%), with a mean of 2.9% (SD 1.5) reflux (% of total radioactivity). One participant (OAGB) demonstrated esophageal bile reflux. De novo macro- or microscopic gastroesophagitis occurred in 11 OAGB (58%), 8 SG (57%) and 7 RYGB (30%) participants. Thirteen participants had worsened reflux symptoms post-operatively (OAGB, 4; SG, 7; RYGB, 2). Scintigraphic esophageal bile reflux bore no statistical association with de novo gastroesophagitis or reflux symptoms., Conclusion: Despite high incidence of gastric bile reflux post-OAGB, esophageal bile reflux is rare. With scarce literature of tumour development post-OAGB, frequent low-volume gastric bile reflux likely bears little clinical consequence; however, longer-term studies are needed., Clinical Trial Registry: Australian New Zealand Clinical Trials Registry number ACTRN12618000806268., (© 2022. Crown.) more...

Background: Although lengthening of the lateral column through a calcaneal neck osteotomy is an integral component of flatfoot reconstruction in younger patients with flexible planovalgus deformities, concern exists as to the effect of this intra-articular osteotomy on subtalar motion. The purpose of this study was to quantify the alterations in subtalar motion following lateral column lengthening (LCL)., Methods: The subtalar motion of 14 fresh-frozen cadaveric feet was assessed using a 3-dimensional motion capture system and materials testing system (MTS). Following potting of the tibia and calcaneus, optic markers were placed into the tibia, calcaneus, and talus. The MTS was used to apply a rotational force across the subtalar joint to a torque of 5 Nm. Abduction/adduction, supination/pronation, and plantarflexion/dorsiflexion about the talus were recorded. Specimens then underwent LCL via a calcaneal neck osteotomy, which was maintained with a 12-mm porous titanium wedge. Repeat subtalar motion analysis was performed and compared to pre-LCL motion using a paired t test., Results: No statistically significant differences in subtalar abduction/adduction (10.9 vs 11.8 degrees, P = .48), supination/pronation (3.5 vs 2.7 degrees, P = .31), or plantarflexion/dorsiflexion (1.6 vs 1.0 degrees, P = .10) were identified following LCL., Conclusion: No significant changes in subtalar motion were observed following lateral column lengthening in this biomechanical cadaveric study., Clinical Relevance: Although these findings do not obviate concerns of clinical subtalar stiffness following lateral column lengthening for planovalgus deformity correction, they suggest that diminished postoperative subtalar motion, when it occurs, may be due to soft tissue scarring rather than alterations of joint anatomy. more...

Objectives: To determine incidence and severity of acute kidney injury (AKI) within 7 days of sepsis evaluation and to assess AKI duration and the association between AKI and 30-day mortality., Study Design: Retrospective, matched cohort study in a single-center level IV neonatal intensive care unit. Eligible infants underwent sepsis evaluations at ≥72 hours of age during calendar years 2013-2018. Exposed infants (cases) were those with culture-proven sepsis and antimicrobial duration ≥5 days. Nonexposed infants (controls) were matched 1:1 to exposed infants based on gestational and corrected gestational age, and had negative sepsis evaluations with antibiotic durations <48 hours. AKI was defined by modified neonatal Kidney Disease Improving Global Outcomes criteria. Statistical analysis included Mann-Whitney and χ 2 tests, multivariable logistic regression, and Kaplan-Meier time-to-event analysis., Results: Among 203 episodes of late-onset sepsis, 40 (20%) developed AKI within 7 days after evaluation, and among 193 episodes with negative cultures, 16 (8%) resulted in AKI (P = .001). Episodes of sepsis also led to greater AKI severity, compared with nonseptic episodes (P = .007). The timing of AKI onset and AKI duration did not differ between groups. Sepsis was associated with increased odds of developing AKI (aOR, 3.0; 95% CI, 1.5-6.2; P = .002). AKI was associated with increased 30-day mortality (aOR, 4.5; 95% CI, 1.3-15.6; P = .017)., Conclusions: Infants with late-onset sepsis had increased odds of AKI and greater AKI severity within 7 days of sepsis evaluation, compared with age-matched infants without sepsis. AKI was independently associated with increased 30-day mortality. Strategies to mitigate AKI in critically ill neonates with sepsis may improve outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.) more...

Background: Although lengthening of the lateral column through an osteotomy of the anterior calcaneus is an integral component of flatfoot reconstruction in younger patients with flexible planovalgus deformities, the procedure has been implicated in iatrogenic calcaneocuboid (CC) subluxation and subsequent degenerative changes at the CC articulation. The purpose of this study is to characterize alterations at the CC joint after lateral column lengthening (LCL) and determine if Steinmann pin stabilization of the CC joint before distraction maintains a normal relationship., Methods: Seven matched pairs of fresh-frozen cadaveric feet underwent preprocedure plain radiography and cross-sectional computed tomography (CT) imaging. LCL by osteotomy through the anterior calcaneus was then performed. One foot of each matched pair had a single smooth Steinmann pin placed centrally across the CC joint before osteotomy distraction. Distraction across each osteotomy was then performed and maintained with a 12-mm porous titanium wedge. Repeat imaging was obtained and compared with preprocedure studies to quantify sagittal and rotational differences at the CC articulation., Results: Following LCL, plain radiography demonstrated statistically significant increases in the percentage of the calcaneal articular surface dorsal to the superior aspect of the cuboid in both the pinned (8.2% vs. 17.6%, P=0.02) and unpinned (12.5% vs. 16.3%, P=0.04) specimens. No difference in the percentage of subluxation was found between the 2 groups after LCL. CT imaging demonstrated statistically significant increases in rotation between the calcaneus and cuboid after LCL in both the pinned (7.6±5.6 degrees, P=0.01) and unpinned (17±12.3 degrees, P=0.01) specimens. The degree of rotation was greater in unpinned specimens after LCL (P=0.043)., Conclusions: Both sagittal and rotatory subluxation seem to occur at the CC joint after LCL regardless of pin stabilization. As a single pin would be expected to limit pure translation while having little effect on rotation, it is possible that the rotational changes identified on 3-dimensional imaging are interpreted as dorsal translation when viewed 2 dimensionally using plain radiography. Consideration should therefore be given to CC stabilization with 2 pins during LCL to prevent this rotatory subluxation., Level of Evidence: Level V-cadaver study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Diagnosis of bacterial meningitis (BM) is challenging in newborn infants. Presently, biomarkers of BM have limited diagnostic accuracy. Analysis of cerebrospinal fluid (CSF) metabolites may be a useful diagnostic tool in BM., Methods: In a nested case-control study, we examined >400 metabolites in CSF of uninfected infants and infants with culture-confirmed BM using gas and liquid chromatography mass spectrometry. Preterm and full-term infants in a Level III or IV Neonatal Intensive Care Unit were prospectively enrolled when evaluated for serious bacterial infection., Results: Over 200 CSF metabolites significantly differed in uninfected infants and infants with BM. Using machine learning, we found that as few as 6 metabolites distinguished infants with BM from uninfected infants in this pilot cohort. Further analysis demonstrated three metabolites associated with Group B Streptococcal meningitis., Conclusions: We report the first comprehensive metabolic analysis of CSF in infants with BM. In our pilot cohort, we derived a metabolic signature that predicted the presence or absence of BM, irrespective of gestational age, postnatal age, sex, race and ethnicity, presence of neurosurgical hardware, white blood cell count in CSF, and red blood cell contamination in CSF. Metabolic analysis may aid diagnosis of BM and facilitate clinical decision-making in infants., Impact: In a pilot cohort, metabolites in cerebrospinal fluid distinguished infants with bacterial meningitis from uninfected infants.We report the first comprehensive metabolic analysis of cerebrospinal fluid in infants with bacterial meningitis.Our findings may be used to improve diagnosis of bacterial meningitis and to offer mechanistic insights into the pathophysiology of bacterial meningitis in infants. more...

Background: Primary spontaneous pneumothorax occurs in otherwise healthy young patients. Optimal management is not defined and often results in prolonged hospitalisation. Data on efficacy of ambulatory options are poor. We aimed to describe the duration of hospitalisation and safety of ambulatory management compared with standard care., Methods: In this open-label, randomised controlled trial, adults (aged 16-55 years) with symptomatic primary spontaneous pneumothorax were recruited from 24 UK hospitals during a period of 3 years. Patients were randomly assigned (1:1) to treatment with either an ambulatory device or standard guideline-based management (aspiration, standard chest tube insertion, or both). The primary outcome was total length of hospital stay including re-admission up to 30 days after randomisation. Patients with available data were included in the primary analysis and all assigned patients were included in the safety analysis. The trial was prospectively registered with the International Standard Randomised Clinical Trials Number, ISRCTN79151659., Findings: Of 776 patients screened between July, 2015, and March, 2019, 236 (30%) were randomly assigned to ambulatory care (n=117) and standard care (n=119). At day 30, the median hospitalisation was significantly shorter in the 114 patients with available data who received ambulatory treatment (0 days [IQR 0-3]) than in the 113 with available data who received standard care (4 days [IQR 0-8]; p<0·0001; median difference 2 days [95% CI 1-3]). 110 (47%) of 236 patients had adverse events, including 64 (55%) of 117 patients in the ambulatory care arm and 46 (39%) of 119 in the standard care arm. All 14 serious adverse events occurred in patients who received ambulatory care, eight (57%) of which were related to the intervention, including an enlarging pneumothorax, asymptomatic pulmonary oedema, and the device malfunctioning, leaking, or dislodging., Interpretation: Ambulatory management of primary spontaneous pneumothorax significantly reduced the duration of hospitalisation including re-admissions in the first 30 days, but at the expense of increased adverse events. This data suggests that primary spontaneous pneumothorax can be managed for outpatients, using ambulatory devices in those who require intervention., Funding: UK National Institute for Health Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.) more...

Objectives: To evaluate accuracy of systemic inflammatory response syndrome (SIRS) criteria in identifying culture-proven late-onset neonatal sepsis and to assess prevalence of organ dysfunction and its relationship with SIRS criteria., Study Design: This was a retrospective case-control study of patients in the Children's Hospital of Philadelphia level IV neonatal intensive care unit undergoing sepsis evaluations (concurrent blood culture and antibiotics). During calendar years 2016-2017, 77 case and 77 control sepsis evaluations were identified. Cases included infants who had sepsis evaluations with positive blood cultures and antibiotic duration ≥7 days. Controls were matched by gestational and postmenstrual age, and had sepsis evaluations with negative blood cultures and antibiotic duration ≤48 hours. SIRS criteria were determined at time of sepsis evaluation, and organ dysfunction evaluated in the 72 hours following sepsis evaluation. Statistical analysis included descriptive statistics, Mann-Whitney tests, and χ 2 (Fisher exact) tests., Results: At time of sepsis evaluation, 42% of cases and 26% of controls met SIRS criteria. Among infants of ≤37 weeks postmenstrual age, SIRS criteria were met in only 17% of sepsis evaluations (4 of 23 in both cases and controls). Test characteristics for SIRS at diagnosis of culture-proven sepsis included sensitivity 42% and specificity 74%. Cases had higher rates of new organ dysfunction within 72 hours (40% vs 21%); however, 58% of cases developing organ dysfunction did not meet SIRS criteria at time of sepsis evaluation. Of 6 deaths (all cases with organ dysfunction), 2 did not meet SIRS criteria at sepsis evaluation., Conclusions: SIRS criteria did not accurately identify culture-proven late-onset sepsis, with poorest accuracy in preterm infants. SIRS criteria did not predict later organ dysfunction or mortality., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events. more...

Unlike in the production of most goods, changes in capacity for labor-intensive services only affect outcomes of interest insofar as service providers change the way they allocate their time in response to those capacity changes. In this paper, we examine how public sector service providers respond to unexpected capacity constraints in the specific context of public health clinics. We exploit an exogenous reduction in public health clinic capacity to quantify the trade-off between patients treated and time spent with each patient, which we treat as a proxy for a quality versus quantity decision. We provide evidence that these small and generally insignificant effects on nurse time favor public sector employees prioritizing quality of each interaction over clearing the patient queue., (© 2020 John Wiley & Sons, Ltd.) more...

Objective: To determine if time to antibiotic administration is associated with mortality and in-hospital outcomes in a neonatal intensive care unit (NICU) population., Study Design: We conducted a prospective evaluation of infants with suspected sepsis between September 2014 and February 2018; sepsis was defined as clinical concern prompting blood culture collection and antibiotic administration. Time to antibiotic administration was calculated from time of sepsis identification, defined as the order time of either blood culture or an antibiotic, to time of first antibiotic administration. We used linear models with generalized estimating equations to determine the association between time to antibiotic administration and mortality, ventilator-free and inotrope-free days, and NICU length of stay in patients with culture-proven sepsis., Results: Among 1946 sepsis evaluations, we identified 128 episodes of culture-proven sepsis in 113 infants. Among them, prolonged time to antibiotic administration was associated with significantly increased risk of mortality at 14 days (OR, 1.47; 95% CI, 1.15-1.87) and 30 days (OR, 1.47; 95% CI, 1.11-1.94) as well as fewer inotrope-free days (incidence rate ratio, 0.91; 95% CI, 0.84-0.98). No significant associations with ventilator-free days or NICU length of stay were demonstrated., Conclusions: Among infants with sepsis, delayed time to antibiotic administration was an independent risk factor for death and prolonged cardiovascular dysfunction. Further study is needed to define optimal timing of antimicrobial administration in high-risk NICU populations., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

Background: Physician diversity is linked to improved quality of care of diverse patient populations. The transition from medical school to residency is an opportunity to improve and increase workforce diversity in all specialties. However, there is limited published literature on the factors contributing to the ranking of residency programs on women and underrepresented minorities (URMs)., Objective: To characterize factors medical students used to rank residency programs and describe any differences based on race/ethnicity or gender., Methods: A mixed-methods study consisting of a web-based survey and semi-structured interviews with National Resident Matching Program (NRMP) participating graduates over a two-year period. The survey assessed demographics and a 6-point Likert scale rating of various factors used to rank residency programs. Unpaired student t-tests were used to compare means. A subset of students was interviewed and a modified grounded theory approach identified decision-making themes as well as the role of gender and URM status., Results: Out of a total of 316 invitations sent, 148 completed the survey (46.8% response rate), of which 21% of respondents self-identified as URMs. The majority of respondents graduated in 2014 (53%), and were male (51%). Participants ranked program atmosphere, reputation, location, and proximity to family the highest. URM students ranked patient population (p < 0.01), revisit opportunities (p = 0.04), gender diversity (p < 0.01), and ethnic diversity (p < 0.01) significantly higher than non-URM students. Female students ranked patient population (p < 0.01) and gender diversity (p < 0.01) significantly higher than males. Qualitative findings revealed differences in perceptions by URMs and non-URMs of patient population, revisit opportunities, gender diversity, and ethnic diversity., Conclusions: While all students prioritized pragmatic factors, women and URM students assess and weigh additional factors related to culture, inclusion, and diversity more than others. By tailoring recruitment strategies to meet the expectations of women and URMs, residency programs can better meet goals in becoming more diverse and inclusive., (Copyright © 2019 National Medical Association. Published by Elsevier Inc. All rights reserved.) more...

Objective: Research addressing the co-occurrence of autism (and/or neurodiversity) and gender-diversity (A/ND-GD) has been conducted largely without the perspectives and voices of the A/ND-GD community. Including A/ND-GD community advocates as research partners may be a critical next step for advancing research initiatives on the co-occurrence given the apparent complexity and alterity of the A/ND-GD experience., Method: Consistent with the community-based participatory research (CBPR) model we propose herein, our authorship team includes a partnership between clinician researchers and diverse A/ND-GD community collaborators. Multiple facets of the A/ND-GD lived experience are examined, including through narratives provided by our A/ND-GD community partners., Results: Based on our experience conducting A/ND-GD-related research and our lived experience as A/ND-GD self-advocates, we highlight challenges in this line of research, including risks of conducting studies without the involvement of the A/ND-GD community. And given that many A/ND-GD youth present with gender-related urgency during the teen years, we provide a developmental framework for how CBPR-informed methods may enrich our understanding of the care needs of these young people and provide context for the apparent heterogeneity in their gender needs and trajectories over time., Conclusions: Integrating CBPR methodologies in A/ND-GD research initiatives has the potential to optimize the relevance of the research questions asked and the interpretation and contextualization of study findings., Competing Interests: Conflicts of Interest: The authors declare that they have no conflicts of interest. more...

This article describes the process of extracting electronic health record (EHR) data into a format that supports analyses related to the timeliness of antibiotic administration. The de-identified data that accompanies this article were collected from a cohort of infants who were evaluated for possible sepsis in the Neonatal Intensive Care Unit (NICU) at the Children's Hospital of Philadelphia (CHOP). The interpretation of findings from these data are reported in a separate manuscript [1]. For purposes of illustration for interested readers, scripts written in the R programming language related to the creation and use of the dataset have also been provided. Interested researchers are encouraged to contact the research team to discuss opportunities for collaboration., (© 2019 The Author(s).) more...

Background: Optimal timing of anterior cruciate ligament (ACL) reconstruction has been a topic of controversy. Reconstruction has historically been delayed for at least 3 weeks, given previous studies reporting a high risk of postoperative arthrofibrosis and suboptimal clinical results., Purpose: To prospectively evaluate postoperative range of motion following acutely reconstructed ACLs with patellar tendon autograft., Study Design: Case series; Level of evidence, 4., Methods: Patients (age >18 years) who had ACL reconstruction as soon as possible after injury, regardless of the condition or preoperative range of motion of the injured knee, underwent reconstruction with patellar tendon autograft. An identical standard surgical technique and postoperative rehabilitation were employed for all patients. Postoperative assessment included active range of motion measurements with a goniometer. Subjective outcomes were assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS)., Results: A total of 25 consecutive patients who met the inclusion criteria were enrolled. The mean age was 27.9 years (range, 20-48 years), and 19 were men. The time from injury to surgery was a mean 4.5 days (range, 1-9 days). The mean objective follow-up was 10.9 months (range, 3 days-19.4 months), and range of motion was regained at a mean 4.4 months (range, 1-9 months). Three meniscal repairs and 3 microfractures were performed concomitantly. There was 1 graft failure at 3 years postoperatively, noted at 50 months of subjective follow-up. There was no loss of extension >3° as compared with the contralateral knee in any patient. There was no loss of flexion >5° as compared with the contralateral knee in any patient who completed objective follow-up. The mean KOOS at final subjective follow-up was 82.8 (range, 57.7-98.8) at a mean 56.6 months postoperative (n = 14/24; range, 48-58 months)., Conclusion: Excellent clinical results can be achieved following ACL reconstruction performed ≤9 days after injury with patellar tendon autograft. The authors found that early ACL reconstructions do not result in loss of motion or suboptimal clinical results as long as a rehabilitation protocol emphasizing extension and early range of motion is employed., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: M.C.H. has received educational support from Stryker. A.C.H. has received educational support from Titan Surgical Group. D.J.R. has received educational support and hospitality payments from Arthrex, the Musculoskeletal Transplant Foundation, Pylant Medical, and Sportstek Medical. J.M.T. has received speaking fees from Arthrex; consulting fees from Arthrex; educational support from Arthrex, DePuy Orthopaedics, Elite Orthopaedics, Medical Device Business Solution, Peerless Surgical, Stryker, and Zimmer Biomet; grant support from Arthrex; and hospitality payments from Arthrex, DePuy Orthopaedics, Elite Orthopaedics, Medical Device Business Solutions, Peerless Surgical, Stryker, and Zimmer Biomet. C.R.B. has received speaking fees from Arthrex and the Musculoskeletal Transplant Foundation; grant support from Arthrex; educational support from Arthrex, Sanofi Aventis, and Sportstek Medical; consulting fees from the Musculoskeletal Transplant Foundation; honoraria from the Musculoskeletal Transplant Foundation; and hospitality payments from Arthrex, the Musculoskeletal Transplant Foundation, Sanofi Aventis, and Sportstek Medical. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2019.) more...

Brodie's abscess is a subacute form of osteomyelitis which generally occurs in the metaphysis of the femur and tibia in the pediatric population. Pathogens are most commonly Gram-positive bacteria, notably Staphylococcus and Streptococcus. In this article, we describe a young pediatric patient presenting with subacute ankle pain with a subsequent diagnosis of Brodie's abscess of the talus secondary to Morganella morganii. We review the presentation, diagnosis, and treatment of this unique patient. To our knowledge, this is the first report of Morganella morganii as a cause of Brodie's abscess. more...

Background: Rapid antibiotic administration is known to improve sepsis outcomes, however early diagnosis remains challenging due to complex presentation. Our objective was to develop a model using readily available electronic health record (EHR) data capable of recognizing infant sepsis at least 4 hours prior to clinical recognition., Methods and Findings: We performed a retrospective case control study of infants hospitalized ≥48 hours in the Neonatal Intensive Care Unit (NICU) at the Children's Hospital of Philadelphia between September 2014 and November 2017 who received at least one sepsis evaluation before 12 months of age. We considered two evaluation outcomes as cases: culture positive-positive blood culture for a known pathogen (110 evaluations); and clinically positive-negative cultures but antibiotics administered for ≥120 hours (265 evaluations). Case data was taken from the 44-hour window ending 4 hours prior to evaluation. We randomly sampled 1,100 44-hour windows of control data from all times ≥10 days removed from any evaluation. Model inputs consisted of up to 36 features derived from routine EHR data. Using 10-fold nested cross-validation, 8 machine learning models were trained to classify inputs as sepsis positive or negative. When tasked with discriminating culture positive cases from controls, 6 models achieved a mean area under the receiver operating characteristic (AUC) between 0.80-0.82 with no significant differences between them. Including both culture and clinically positive cases, the same 6 models achieved an AUC between 0.85-0.87, again with no significant differences., Conclusions: Machine learning models can identify infants with sepsis in the NICU hours prior to clinical recognition. Learning curves indicate model improvement may be achieved with additional training examples. Additional input features may also improve performance. Further research is warranted to assess potential performance improvements and clinical efficacy in a prospective trial., Competing Interests: The authors have declared that no competing interests exist. more...

Background: Bacterial meningitis is challenging to diagnose in infants, especially in the common setting of antibiotic pre-treatment, which diminishes yield of cerebrospinal fluid (CSF) cultures. Prior studies of diagnostic markers have not demonstrated sufficient accuracy. Interleukin-23 (IL-23), interleukin-18 (IL-18) and soluble receptor for advanced glycation end products (sRAGE) possess biologic plausibility, and may be useful as diagnostic markers in bacterial meningitis., Methods: In a prospective cohort study, we measured IL-23, IL-18 and sRAGE levels in CSF. We compared differences between infected and non-infected infants, and conducted receiver operating characteristic (ROC) analyses to identify individual markers and combinations of markers with the best diagnostic accuracy., Results: 189 infants <6 months, including 8 with bacterial meningitis, 30 without meningitis, and 151 with indeterminate diagnosis (due to antibiotic pretreatment) were included. CSF IL-23, IL-18 and sRAGE levels were significantly elevated in infants with culture proven meningitis. Among individual markers, IL-23 possessed the greatest accuracy for diagnosis of bacterial meningitis (area under the curve (AUC) 0.9698). The combination of all three markers had an AUC of 1., Conclusions: IL-23, alone and in combination with IL-18 and sRAGE, identified bacterial meningitis with excellent accuracy. Following validation, these markers could aid clinicians in diagnosis of bacterial meningitis and decision-making regarding prolongation of antibiotic therapy. more...

Using the National Health and Nutrition Examination Survey Data, I find that individuals who overestimate their activity level by one standard deviation consume 40-60 extra calories per day, or enough to gain five pounds per year. These extra calories are composed mainly of sugar and carbohydrate, and are concentrated among individuals in the 75th and 90th percentiles of caloric intake. The link between overeating and inaccurate estimation of physical activity is strongest among less educated individuals and individuals with high variance in their physical activity, suggesting that imperfect recall or information gaps explain at least part of the relationship of interest. These results imply the existence of a necessary condition for physical activity-based information treatments to be effective in changing health behaviors and obesity rates., (Copyright © 2017 Elsevier B.V. All rights reserved.) more...

Neonatal meningitis is a devastating condition. Prognosis has not improved in decades, despite the advent of improved antimicrobial therapy and heightened index of suspicion among clinicians caring for affected infants. One in ten infants die from meningitis, and up to half of survivors develop significant lifelong complications, including seizures, impaired hearing and vision, and delayed or arrested development of such basic skills as talking and walking. At present, it is not possible to predict which infants will suffer poor outcomes. Early treatment is critical to promote more favorable outcomes, though diagnosis of meningitis in infants is technically challenging, time-intensive, and invasive. Profound neuronal injury has long been described in the setting of neonatal meningitis, as has elevated levels of many pro- and anti-inflammatory cytokines. Mechanisms of the host immune response that drive clearance of the offending organism and underlie brain injury due to meningitis are not well understood, however. In this review, we will discuss challenges in diagnosis, prognosis, and treatment of neonatal meningitis. We will highlight transcriptomic, proteomic, and metabolomic data that contribute to suggested mechanisms of inflammation and brain injury in this setting with a view toward fruitful areas for future investigation. more...

Although several proteins have been implicated in secretory vesicle tethering, the identity and mechanical properties of the components forming the physical vesicle-plasma membrane link remain unknown. Here we present the first experimental measurements of nanomechanical properties of secretory vesicle-plasma membrane tethers using combined AFM force clamp and TIRF microscopy on membrane sheets from PC12 cells expressing the vesicle marker ANF-eGFP. Application of pulling forces generated tether extensions composed of multiple steps with variable length. The frequency of short (<10 nm) tether extension events was markedly higher when a fluorescent vesicle was present at the cantilever tip and increased in the presence of GTPγS, indicating that these events reflect specifically the properties of vesicle-plasma membrane tethers. The magnitude of the short tether extension events is consistent with extension lengths expected from progressive unfolding of individual helices of the exocyst complex, supporting its direct role in forming the physical vesicle-plasma membrane link. more...

Exudative age-related macular degeneration (AMD) is the most common cause of moderate and severe vision loss in developed countries. Intraocular injections of vascular endothelial growth factor (VEGF or VEGF-A)-neutralizing proteins provide substantial benefit, but frequent, long-term injections are needed. In addition, many patients experience initial visual gains that are ultimately lost due to subretinal fibrosis. Preclinical studies and early phase clinical trials suggest that combined suppression of VEGF and platelet-derived growth factor-BB (PDGF-BB) provides better outcomes than suppression of VEGF alone, due to more frequent regression of neovascularization (NV) and suppression of subretinal fibrosis. We generated a dual variable domain immunoglobulin molecule, ABBV642 that specifically and potently binds and neutralizes VEGF and PDGF-BB. ABBV642 has been optimized for treatment of exudative AMD based on the following design characteristics: 1) high affinity binding to all VEGF-A isoforms and both soluble and extracellular matrix (ECM)-associated PDGF-BB; 2) potential for extended residence time in the vitreous cavity to decrease the frequency of intraocular injections; 3) rapid clearance from systemic circulation compared with molecules with wild type Fc region for normal FcRn binding, which may reduce the risk of systemic complications; and 4) low risk of potential effector function. The bispecificity of ABBV642 allows for a single injection of a single therapeutic agent, and thus a more streamlined development and regulatory path compared with combination products. In a mouse model of exudative AMD, ABBV642 was observed to be more effective than aflibercept. ABBV642 has potential to improve efficacy with reduced injection frequency in patients with exudative AMD, thereby reducing the enormous disease burden for patients and society. more...

This paper examines how a single female's investment in healthy body weight is affected by the quality of single males in her marriage market. A principle concern in estimation is the presence of market-level unobserved heterogeneity that may be correlated with changes in single male quality, measured as earning potential. To address this concern, we employ a differencing strategy that normalizes the exercise behaviors of single women to those of their married counterparts. Our main results suggest that when potential mate quality in a marriage market decreases, single black women invest less in healthy body weight. For example, we find that a 10 percentage point increase in the proportion of low quality single black males leads to a 5-10% decrease in vigorous exercise taken by single black females. Results for single white women are qualitatively similar, but not consistent across specifications. These results highlight the relationship between male and female human capital acquisition that is driven by participation in the marriage market. Our results suggest that programs designed to improve the economic prospects of single males may yield positive externalities in the form of improved health behaviors, such as more exercise, particularly for single black females., (Copyright © 2016 Elsevier B.V. All rights reserved.) more...

We have developed a workflow to extract, separate, and semi-quantify bioactive oxysterols from mouse colon tissues and fecal matters using solid- and liquid-phase extractions, enzymatic and chemical modifications, and stable-isotope dilution LC/MS/MS. The method was applied to a dextran sodium sulphate (DSS)-induced mouse colitis model, which revealed that one particular dihydroxycholesterol (diOHC), 7α,25-diOHC, was significantly elevated in both colon tissue and fecal matters of mice with colitis compared to that in naïve mice. The extent of 7α,25-diOHC elevation was positively correlated with colitis severity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.) more...

Enterococcal spondylitis (ES) is a disease of commercial broiler chickens, with a worldwide distribution. Symmetrical hind limb paralysis typical of ES results from infection of the free thoracic vertebra (FTV) by pathogenic strains of Enterococcus cecorum . To determine the pathogenesis of ES, birds with natural and experimental ES were studied over time. In natural disease, case birds (n = 150) from an affected farm and control birds (n = 100) from an unaffected farm were evaluated at weeks 1-6. In control birds, intestinal colonization by E. cecorum began at week 3. In case birds, E. cecorum was detected in intestine and spleen at week 1, followed by infection of the FTV beginning at week 3. E. cecorum isolates recovered from intestine, spleen, and FTV of case birds had matching genotypes, confirming that intestinal colonization with pathogenic strains precedes bacteremia and infection of the FTV. Clinical intestinal disease was not required for E. cecorum bacteremia. In 1- to 3-week-old case birds, pathogenic E. cecorum was observed within osteochondrosis dissecans (OCD) lesions in the FTV. To determine whether OCD of the FTV was a risk factor for ES, 214 birds were orally infected with E. cecorum, and the FTV was evaluated histologically at weeks 1-7. Birds without cartilage clefts of OCD in the FTV did not develop ES; while birds with OCD scores ≥3 were susceptible to lesion development. These findings suggest that intestinal colonization, bacteremia, and OCD of the FTV in early life are crucial to the pathogenesis of ES. more...