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BackgroundRecent reports of the utilisation of pyrvinium pamoate (PP), an FDA-approved anti-helminth, have shown that it inhibits pancreatic ductal adenocarcinoma (PDAC) cell growth and proliferation in-vitro and in-vivo in preclinical models. Here, we report about an ongoing phase I open-label, single-arm, dose escalation clinical trial to determine the safety and tolerability of PP in PDAC surgical candidates.Methods and analysisIn a 3+3 dose design, PP is initiated 3 days prior to surgery. The first three patients will be treated with the initial dose of PP at 5 mg/kg orally for 3 days prior to surgery. Dose doubling will be continued to a reach a maximum of 20 mg/kg orally for 3 days, if the previous two dosages (5 mg/kg and 10 mg/kg) were tolerated. Dose-limiting toxicity grade≥3 is used as the primary endpoint. The pharmacokinetic and pharmacodynamic (PK/PD) profile of PP and bioavailability in humans will be used as the secondary objective. Each participant will be monitored weekly for a total of 30 days from the final dose of PP for any side effects. The purpose of this clinical trial is to examine whether PP is safe and tolerable in patients with pancreatic cancer, as well as assess the drug’s PK/PD profile in plasma and fatty tissue. Potential implications include the utilisation of PP in a synergistic manner with chemotherapeutics for the treatment of pancreatic cancer.Ethics and disseminationThis study was approved by the Thomas Jefferson Institutional Review Board. The protocol number for this study is 20F.041 (Version 3.1 as of 27 October 2021). The data collected and analysed from this study will be used to present at local and national conferences, as well as, written into peer-reviewed manuscript publications.Trial registration numberClinicalTrials.gov: NCT05055323.

Background Facilitating placental transfusion—the transfer of blood from the placenta to the newborn—via delayed cord clamping (DCC) or umbilical cord milking (UCM) at birth has been shown to improve iron stores in healthy term infants and may positively impact long-term neurodevelopmental outcomes. Infants who are non-vigorous at birth and at risk of developing hypoxic-ischemic encephalopathy (HIE) are particularly likely to benefit from placental transfusion. This process may offer neuroprotection by enhancing cardiopulmonary transition, supporting cardiac preload, improving systemic and cerebral perfusion, delivering stem cells and neurotrophic factors, and preventing iron deficiency. While DCC is not currently recommended for non-vigorous term infants requiring immediate resuscitation, UCM offers a viable alternative, as it can be performed quickly. Methods This study is a multicenter, cluster-randomized, crossover-controlled trial comparing UCM with early cord clamping (ECC) in term and late preterm infants who are non-vigorous at birth. The trial will be conducted across seven centers in India. Before the trial begins, each site will be assigned to an initial study arm using a computer-generated randomization scheme. Once 50% of the enrollment is complete, sites will switch to the alternate study arm after a 2-month washout period. The study is designed with sufficient power to assess the composite outcome of death or moderate-to-severe HIE during birth hospitalization and survival without moderate-to-severe neurodevelopmental impairment at 2 years of age. Secondary outcomes include survival without moderate-to-severe neurodevelopmental impairment at 1 year of age and survival without evidence of brain injury on MRI during the birth hospitalization. Discussion The CORDMILK trial aims to generate critical evidence on whether UCM can improve survival without moderate-to-severe HIE during birth hospitalization and survival without significant neurodevelopmental impairment at 2 years of age in late preterm and term neonates who are non-vigorous at birth. Trial registration Clinical Trial Registry–India CTRI/2021/09/036759. Registered on 22/09/2021. ClinicalTrials.Gov number NCT03657394 and NCT03682042.

Zika virus (ZIKV) can cause devastating effects in the unborn fetus of pregnant women. To develop a candidate vaccine that can protect human fetuses, we generated a panel of live measles vaccine (MV) vectors expressing ZIKV-E and -NS1. Our MV-based ZIKV-E vaccine, MV-E2, protected mice from the non-lethal Zika Asian strain (PRVABC59) and the lethal African strain (MR766) challenge. Despite 100% survival of the MV-E2 mice, however, complete viral clearance was not achieved in the brain and reproductive tract of the lethally challenged mice. We then tested MV-based vaccines that expressed E and NS1 together or separately in two different vaccines. We observed complete clearance of ZIKV from the female reproductive tract and complete fetal protection in the lethal African challenge model in animals that received the dual antigen vaccines. Additionally, MV-E2 and MV-NS1, when administered together, induced durable plasma cell responses. Our findings suggest that NS1 antibodies are required to enhance the protection of ZIKV-E antibodies in the female reproductive tract.

Background Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India’s National Family Health Survey (NFHS-5) for 2019–2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019–21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. Methods This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. Discussion This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. Trial registration ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry – India CTRI/2022/05/042933 . Registered on 31 May 2022.

Objectives Pancreaticoduodenectomy (PD) remains a procedure that carries considerable morbidity. Numerous studies have evaluated factors to predict patients at risk. The aim of this study was to determine whether the surgical Apgar score (SAS) predicts perioperative morbidity and mortality. Methods We examined 553 patients undergoing successful PD between January 2000 and December 2010. Postoperative complications were graded using the Clavien scale, and the SAS (range, 0–10) was determined. The Cochran–Armitage test for trend was used to determine the association between grouped SAS scores (0–2, 3–4, 5–6, 7–8, and 9–10) and each of the outcomes. Results The average patient age was 64 years, and there was an even distribution of males and females. There were 11 perioperative deaths (2%), 186 grade 2 or higher complications (34%), and 86 major complications (grades 3–5, 16%). Additionally, 61 patients developed pancreatic fistulae (11%). Statistical analysis determined that SAS was a significant predictor of grade 2 or higher complications ( p  < 0.0001), major morbidity ( p  = 0.01), and pancreatic fistula ( p  = 0.04) but not mortality ( p  = 0.20). Conclusions We demonstrate that the SAS is a significant predictor of perioperative morbidity for patients undergoing PD. This score should be used to identify patients at higher risk in order to prioritize use of postoperative critical care beds and hospital resources.

OBJECTIVES Internal medicine clerkship grades are important for residency selection, but inconsistencies between evaluator ratings threaten their ability to accurately represent student performance and perceived fairness. Clerkship grading committees are recommended as best practice, but the mechanisms by which they promote accuracy and fairness are not certain. The ability of a committee to reliably assess and account for grading stringency of individual evaluators has not been previously studied. METHODS This is a retrospective analysis of evaluations completed by faculty considered to be stringent, lenient, or neutral graders by members of a grading committee of a single medical college. Faculty evaluations were assessed for differences in ratings on individual skills and recommendations for final grade between perceived stringency categories. Logistic regression was used to determine if actual assigned ratings varied based on perceived faculty's grading stringency category. RESULTS “Easy graders” consistently had the highest probability of awarding an above-average rating, and “hard graders” consistently had the lowest probability of awarding an above-average rating, though this finding only reached statistical significance only for 2 of 8 questions on the evaluation form (P = .033 and P = .001). Odds ratios of assigning a higher final suggested grade followed the expected pattern (higher for “easy” and “neutral” compared to “hard,” higher for “easy” compared to “neutral”) but did not reach statistical significance. CONCLUSIONS Perceived differences in faculty grading stringency have basis in reality for clerkship evaluation elements. However, final grades recommended by faculty perceived as “stringent” or “lenient” did not differ. Perceptions of “hawks” and “doves” are not just lore but may not have implications for students’ final grades. Continued research to describe the “hawk and dove effect” will be crucial to enable assessment of local grading variation and empower local educational leadership to correct, but not overcorrect, for this effect to maintain fairness in student evaluations.

The Capabilities of Upper Extremity Test (CUE-T) and the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) were both developed to detect change in upper extremity (UE) function in persons with tetraplegia. To compare the responsiveness and minimal clinically important difference (MCID) of the CUE-T and the quantitative prehension (QtP) scale of the GRASSP. Subjects included 69 persons with tetraplegia: 60 with acute and 9 with chronic injuries. Subjects were assessed twice 3 months apart using the CUE-T, QtP-GRASSP, and upper extremity motor scores (UEMS). Subjects rated their impression of change in overall and right/left UE function from -7 to +7. The standardized response mean (SRM) was determined for acute subjects. MCID was estimated using a small subjective change (2-3 points) and change in UEMS. Subjects were 41.9 ± 18.1 years old, neurological levels C1-C7; 25 were motor complete. For acute subjects, the SRMs for total/side CUE-T scores were 1.07/0.96, and for the QtP-GRASSP they were 0.88/0.78. MCIDs based on subjective change for total/side CUE-T scores were 11.7/6.1 points and for QtP-GRASSP were 6.4/3.0 points. Based on change in UEMS, MCIDs for total/side were 11.9/6.3 points for CUE-T and 6.0/3.3 points for QtP-GRASSP. Some subjects had changes in the CUE-T due to its arm items that were not seen with the QtP-GRASSP. Both the CUE-T and QtP-GRASSP are responsive to change in persons with acute cervical spinal cord injury with large SRMs. The CUE-T detects some changes in UE function not seen with the QtP-GRASSP.

Background Diagnostic uncertainty occurs frequently in emergency medical care, with more than one-third of patients leaving the emergency department (ED) without a clear diagnosis. Despite this frequency, ED providers are not adequately trained on how to discuss diagnostic uncertainty with these patients, who often leave the ED confused and concerned. To address this training need, we developed the Uncertainty Communication Education Module (UCEM) to teach physicians how to discuss diagnostic uncertainty. The purpose of the study is to evaluate the effectiveness of the UCEM in improving physician communications. Methods The trial is a multicenter, two-arm randomized controlled trial designed to teach communication skills using simulation-based mastery learning (SBML). Resident emergency physicians from two training programs will be randomly assigned to immediate or delayed receipt of the two-part UCEM intervention after completing a baseline standardized patient encounter. The two UCEM components are: 1) a web-based interactive module, and 2) a smart-phone-based game. Both formats teach and reinforce communication skills for patient cases involving diagnostic uncertainty. Following baseline testing, participants in the immediate intervention arm will complete a remote deliberate practice session via a video platform and subsequently return for a second study visit to assess if they have achieved mastery. Participants in the delayed intervention arm will receive access to UCEM and remote deliberate practice after the second study visit. The primary outcome of interest is the proportion of residents in the immediate intervention arm who achieve mastery at the second study visit. Discussion Patients’ understanding of the care they received has implications for care quality, safety, and patient satisfaction, especially when they are discharged without a definitive diagnosis. Developing a patient-centered diagnostic uncertainty communication strategy will improve safety of acute care discharges. Although use of SBML is a resource intensive educational approach, this trial has been deliberately designed to have a low-resource, scalable intervention that would allow for widespread dissemination and uptake. Trial registration The trial was registered at clinicaltrials.gov ( NCT04021771 ). Registration date: July 16, 2019.

Purpose: The Philadelphia Eagle Eye Mobile (EEM) provides optometric vision care to children who fail a vision screening performed by nurses at schools in low-income areas. Methods: Data for children seen on the EEM between 2006 and 2008 for whom school nurse feedback was available regarding glasses wear at 1-, 4-, and 12-month intervals served as the study population. Optometric findings and glasses prescriptions at initial examination were recorded in the EEM database. The ophthalmic records for children referred for pediatric ophthalmology consultation at our institution were reviewed and those who did not attend were counted. Results: A random subset of 689 students at 28 different schools at which follow-up forms were distributed to the school nurses regarding glasses wear was studied. This represents 10.8% of 6,365 children screened at 131 public schools visited by the EEM during that period. False-positive rates of school nurse screening averaged 16.11% (0% to 44%) for 689 children from 28 schools. Glasses compliance was 71% at 12 months and correlated to higher prescriptions. Only 53% of children attended their pediatric ophthalmology referral. Conclusions: Nurse training to reduce false-positive screening and strategies to improve attendance at arranged pediatric ophthalmologist consultations are recommended. The EEM effectively gets glasses to students where needed and use rates are satisfactory. [[ J Pediatr Ophthalmol Strabismus. 2015;52(2):98–105.]

This study tests the hypothesis that an Onchocerca volvulus vaccine, consisting of two recombinant antigens (Ov-103 and Ov-RAL-2) formulated with the combination-adjuvant Advax-2, can induce protective immunity in genetically diverse Collaborative Cross recombinant inbred intercross mice (CC-RIX). CC-RIX lines were immunized with the O. volvulus vaccine and challenged with third-stage larvae. Equal and significant reductions in parasite survival were observed in 7 of 8 CC-RIX lines. Innate protective immunity was seen in the single CC-RIX line that did not demonstrate protective adaptive immunity. Analysis of a wide array of immune factors showed that each line of mice have a unique set of immune responses to vaccination and challenge suggesting that the vaccine is polyfunctional, inducing different equally-protective sets of immune responses based on the genetic background of the immunized host. Vaccine efficacy in genetically diverse mice suggests that it will also be effective in genetically complex human populations.