From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease.

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.

Einkorn genomics sheds light on history of the oldest domesticated wheat.

Einkorn (Triticum monococcum) was the first domesticated wheat species, and was central to the birth of agriculture and the Neolithic Revolution in the Fertile Crescent around 10,000 years ago1,2. Here we generate and analyse 5.2-Gb genome assemblies for wild and domesticated einkorn, including completely assembled centromeres. Einkorn centromeres are highly dynamic, showing evidence of ancient and recent centromere shifts caused by structural rearrangements. Whole-genome sequencing analysis of a diversity panel uncovered the population structure and evolutionary history of einkorn, revealing complex patterns of hybridizations and introgressions after the dispersal of domesticated einkorn from the Fertile Crescent. We also show that around 1% of the modern bread wheat (Triticum aestivum) A subgenome originates from einkorn. These resources and findings highlight the history of einkorn evolution and provide a basis to accelerate the genomics-assisted improvement of einkorn and bread wheat.

Reduced Long-Term Bowel Obstruction Risk With Minimally Invasive Diaphragmatic Hernia Repair.

INTRODUCTION: The introduction of minimally invasive surgery (MIS) for repair of congenital diaphragmatic hernias (CDH) has reduced postoperative length of stay, postoperative opioid consumption, and provided a more esthetic repair. In adult abdominal surgery, minimally invasive techniques have been associated with decreased long-term rates of small bowel obstruction (SBO), although it is unclear if this benefit carries over into the pediatric population. Our objective was to evaluate the rates of SBO following open versus MIS CDH repair. MATERIAL AND METHODS: Infants who underwent CDH repair between 2010 and 2021 were identified using the PearlDiver Mariner database. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate time to SBO by surgical approach (MIS versus open) while adjusting for mesh use, patient sex, and length of stay. RESULTS: Of 1033 patients that underwent CDH repair, 258 (25.0%) underwent a minimally invasive approach. The overall rate of SBO was 7.5% (n = 77). Rate of SBO following MIS repair was lower than open repair at 1 y (0.8% versus 5.1%), 3 y, (2.3% versus 9.0%), and 5 y (4.4% versus 10.1%, P = 0.004). Following adjustment, the rate of SBO following MIS repair remained significantly lower than open repair (adjusted hazard ratio: 0.37, 95% confidence interval: 0.18, 0.79). CONCLUSIONS: Following CDH repair, long-term rates of SBO are lower among patients treated with MIS approaches. Long-term risk of SBO should be considered when selecting surgical approach for CDH patients.

When a test is more than just a test: Findings from patient interviews and survey in the trial of a technology to measure antidepressant medication response (the PReDicT Trial).

BACKGROUND: A RCT of a novel intervention to detect antidepressant medication response (the PReDicT Test) took place in five European countries, accompanied by a nested study of its acceptability and implementation presented here. The RCT results indicated no effect of the intervention on depression at 8 weeks (primary outcome), although effects on anxiety at 8 weeks and functioning at 24 weeks were found. METHODS: The nested study used mixed methods. The aim was to explore patient experiences of the Test including acceptability and implementation, to inform its use within care. A bespoke survey was completed by trial participants in five countries (n = 778) at week 8. Semi-structured interviews were carried out in two countries soon after week 8 (UK n = 22, Germany n = 20). Quantitative data was analysed descriptively; for qualitative data, thematic analysis was carried out using a framework approach. Results of the two datasets were interrogated together. OUTCOMES: Survey results showed the intervention was well received, with a majority of participants indicating they would use it again, and it gave them helpful extra information; a small minority indicated the Test made them feel worse. Qualitative data showed the Test had unexpected properties, including: instigating a process of reflection, giving participants feedback on progress and new understanding about their illness, and making participants feel supported and more engaged in treatment. INTERPRETATION: The qualitative and quantitative results are generally consistent. The Test's unexpected properties may explain why the RCT showed little effect, as properties were experienced across both trial arms. Beyond the RCT, the qualitative data sheds light on measurement reactivity, i.e., how measurements of depression can impact patients.

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds.

Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald = 4.83x10-9) and 19 (Pwald = 2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

MEG abnormalities and mechanisms of surgical failure in neocortical epilepsy.

OBJECTIVE: Epilepsy surgery fails to achieve seizure freedom in 30%-40% of cases. It is not fully understood why some surgeries are unsuccessful. By comparing interictal magnetoencephalography (MEG) band power from patient data to normative maps, which describe healthy spatial and population variability, we identify patient-specific abnormalities relating to surgical failure. We propose three mechanisms contributing to poor surgical outcome: (1) not resecting the epileptogenic abnormalities (mislocalization), (2) failing to remove all epileptogenic abnormalities (partial resection), and (3) insufficiently impacting the overall cortical abnormality. Herein we develop markers of these mechanisms, validating them against patient outcomes. METHODS: Resting-state MEG recordings were acquired for 70 healthy controls and 32 patients with refractory neocortical epilepsy. Relative band-power spatial maps were computed using source-localized recordings. Patient and region-specific band-power abnormalities were estimated as the maximum absolute z-score across five frequency bands using healthy data as a baseline. Resected regions were identified using postoperative magnetic resonance imaging (MRI). We hypothesized that our mechanistically interpretable markers would discriminate patients with and without postoperative seizure freedom. RESULTS: Our markers discriminated surgical outcome groups (abnormalities not targeted: area under the curve [AUC] = 0.80, p = .003; partial resection of epileptogenic zone: AUC = 0.68, p = .053; and insufficient cortical abnormality impact: AUC = 0.64, p = .096). Furthermore, 95% of those patients who were not seizure-free had markers of surgical failure for at least one of the three proposed mechanisms. In contrast, of those patients without markers for any mechanism, 80% were ultimately seizure-free. SIGNIFICANCE: The mapping of abnormalities across the brain is important for a wide range of neurological conditions. Here we have demonstrated that interictal MEG band-power mapping has merit for the localization of pathology and improving our mechanistic understanding of epilepsy. Our markers for mechanisms of surgical failure could be used in the future to construct predictive models of surgical outcome, aiding clinical teams during patient pre-surgical evaluations.

Effect of Material Properties and Variability of Mannitol on Tablet Formulation Development.

PURPOSE: Using a high level of mannitol as a diluent in oral formulations can potentially result in tablet defects (e.g., chipping, cracking) during compression. This work aims to scrutinize the linkage between the mechanical properties and material attributes of mannitol and also uncover how variations between vendors and lots can lead to significant changes in the compaction performance of tablet formulations containing mannitol. METHODS: The mechanical properties (Poisson's ratio, fracture energy) and mechanical performance (ejection force, pressure transmission ratio, residual radial die-wall stress, and tensile strength) of mannitol compacts were assessed on a compaction simulator for four lots of mannitol from two different vendors. The variation of material attributes of each lot, including particle size distribution (PSD), crystal form, primary crystal size and morphology, specific surface area (SSA), powder flow, and moisture absorption were investigated. RESULTS: The variability of material attributes in mannitol lots, especially primary crystal size and SSA, can result in significant changes in mechanical properties and mechanical performance such as ejection force and residual radial die-wall stresses, which potentially led to chipping during compression. CONCLUSION: The study elucidated the linkage between fundamental material attributes and mechanical properties of mannitol, highlighting their impact on tablet defects and compaction performance in compression. A comprehensive understanding of the variability in mannitol properties between vendors and lots is crucial for successful formulation development, particularly when high percentages of mannitol are included as a brittle excipient.

Associations of water, sanitation, and hygiene with typhoid fever in case-control studies: a systematic review and meta-analysis.

BACKGROUND: Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. METHODS: We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. RESULTS: We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. CONCLUSIONS: The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH. TRIAL REGISTRATION: PROSPERO 2021 CRD42021271881.

Elective and non-elective endomyocardial biopsy in heart transplant patients and procedural outcomes: An IMPACT registry analysis.

BACKGROUND: Endomyocardial biopsies are standard of care for transplant surveillance, however the procedural risks are not well established, especially in children. The purpose of the study was therefore to assess procedural risks and outcomes associated with elective (surveillance) biopsies and non-elective (clinically indicated) biopsies. METHODS: We used the NCDR IMPACT registry database for this retrospective analysis. Patients undergoing an endomyocardial biopsy were identified using the procedural code, with a diagnosis of heart transplantation required. Data regarding indication, hemodynamics, adverse events and outcomes was gathered and analyzed. RESULTS: A total of 32 547 endomyocardial biopsies were performed between 2012-2020; 31 298 (96.5%) elective and 1133 (3.5%) were non-elective biopsies. Non-elective biopsy was more commonly performed in infants and in those above 18 years of age, in female and in Black race patients and in those with non-private insurance (all p < .05) and showed hemodynamic derangements. Overall rate of complications was low. Combined major adverse events were more common in non-elective patients, with sicker patient profile, use of general anesthesia and femoral access with overall decline in these events over time. CONCLUSIONS: This large-scale analysis shows safety of surveillance biopsies and that non-elective biopsies carry a small but significant risk of major adverse event. Patient profile impacts the safety of the procedure. These data may serve as important comparison point for newer non-invasive tests and for bench marking, especially in children.

Fidelity, adaptation and integration of whole-school health promotion within Dutch schools: a cross-sectional survey study.

Implementing comprehensive health promotion programs in the school setting can be challenging, as schools can be considered complex adaptive systems. As a first step towards understanding what works in improving implementation for which schools and under which conditions, this study aimed to examine the degree of implementation of health promoting school (HPS) programs, in terms of five dimensions of fidelity (adherence, dose, participant responsiveness, quality of delivery and program differentiation), and the dimensions of adaptation and integration. The HPS Implementation Questionnaire was distributed among ±â€…2400 primary, secondary, secondary vocational and special needs schools in the Netherlands. Employees of 535 schools (22.3%) filled out the questionnaire. Data were analysed by descriptive statistics and ANOVA tests. The average degree of implementation was 2.55 (SD = 0.58, range = 0.68-3.90; scaled 0-4). The lowest scores were achieved for participant responsiveness and adherence, and the highest for integration and adaptation. Schools that identified as HPS reported significantly higher overall degree of implementation, adherence, dose, participant responsiveness, program differentiation and adaptation than schools that didn't. Primary schools achieved a significantly higher degree of implementation, dose, participant responsiveness, quality of delivery and integration than other school types. In conclusion, many schools work on student health and well-being to some extent, but the vast majority have much room for improvement. Higher implementation scores for schools that identified as HPS underline the value of HPS programs. A broader perspective on health and more insight into conditions for effectiveness and implementation in secondary and secondary vocational schools are needed.

Long-Term Connectome Analysis Reveals Reshaping of Visual, Spatial Networks in a Model With Vascular Dementia Features.

BACKGROUND: Connectome analysis of neuroimaging data is a rapidly expanding field that offers the potential to diagnose, characterize, and predict neurological disease. Animal models provide insight into biological mechanisms that underpin disease, but connectivity approaches are currently lagging in the rodent. METHODS: We present a pipeline adapted for structural and functional connectivity analysis of the mouse brain, and we tested it in a mouse model of vascular dementia. RESULTS: We observed lacunar infarctions, microbleeds, and progressive white matter change across 6 months. For the first time, we report that default mode network activity is disrupted in the mouse model. We also identified specific functional circuitry that was vulnerable to vascular stress, including perturbations in a sensorimotor, visual resting state network that were accompanied by deficits in visual and spatial memory tasks. CONCLUSIONS: These findings advance our understanding of the mouse connectome and provide insight into how it can be altered by vascular insufficiency.

Pancreas MRI Segmentation Into Head, Body, and Tail Enables Regional Quantitative Analysis of Heterogeneous Disease.

BACKGROUND: Quantitative imaging studies of the pancreas have often targeted the three main anatomical segments, head, body, and tail, using manual region of interest strategies to assess geographic heterogeneity. Existing automated analyses have implemented whole-organ segmentation, providing overall quantification but failing to address spatial heterogeneity. PURPOSE: To develop and validate an automated method for pancreas segmentation into head, body, and tail subregions in abdominal MRI. STUDY TYPE: Retrospective. SUBJECTS: One hundred and fifty nominally healthy subjects from UK Biobank (100 subjects for method development and 50 subjects for validation). A separate 390 UK Biobank triples of subjects including type 2 diabetes mellitus (T2DM) subjects and matched nondiabetics. FIELD STRENGTH/SEQUENCE: A 1.5 T, three-dimensional two-point Dixon sequence (for segmentation and volume assessment) and a two-dimensional axial multiecho gradient-recalled echo sequence. ASSESSMENT: Pancreas segments were annotated by four raters on the validation cohort. Intrarater agreement and interrater agreement were reported using Dice overlap (Dice similarity coefficient [DSC]). A segmentation method based on template registration was developed and evaluated against annotations. Results on regional pancreatic fat assessment are also presented, by intersecting the three-dimensional parts segmentation with one available proton density fat fraction (PDFF) image. STATISTICAL TEST: Wilcoxon signed rank test and Mann-Whitney U-test for comparisons. DSC and volume differences for evaluation. A P value < 0.05 was considered statistically significant. RESULTS: Good intrarater (DSC mean, head: 0.982, body: 0.940, tail: 0.961) agreement and interrater (DSC mean, head: 0.968, body: 0.905, tail: 0.943) agreement were observed. No differences (DSC, head: P = 0.4358, body: P = 0.0992, tail: P = 0.1080) were observed between the manual annotations and our method's segmentations (DSC mean, head: 0.965, body: 0.893, tail: 0.934). Pancreatic body PDFF was different between T2DM and nondiabetics matched by body mass index. DATA CONCLUSION: The developed segmentation's performance was no different from manual annotations. Application on type 2 diabetes subjects showed potential for assessing pancreatic disease heterogeneity. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 3.

Evaluation of quantitative MRCP (MRCP+) for risk stratification of primary sclerosing cholangitis: comparison with morphological MRCP, MR elastography, and biochemical risk scores.

OBJECTIVES: To study the association of MRCP+ parameters with biochemical scoring systems and MR elastography (MRE) in primary sclerosing cholangitis (PSC). To evaluate the incremental value of combining MRCP+ with morphological scores in associating with biochemical scores. METHODS AND MATERIALS: MRI images, liver stiffness measurements by MRE, and biochemical testing of 65 patients with PSC that were retrospectively enrolled between January 2014 and December 2015 were obtained. MRCP+ was used to post-process MRCP images to obtain quantitative measurements of the bile ducts and biliary tree. Linear regression analysis was used to test the associations. Bootstrapping was used as a validation method. RESULTS: The total number of segmental strictures had the strongest association with Mayo Risk Score (R2 = 0.14), minimum stricture diameter had the highest association with Amsterdam Oxford Prognostic Index (R2 = 0.12), and the percentage of duct nodes with width 0-3 mm had the strongest association with PSC Risk Estimate Tool (R2 = 0.09). The presence of Ducts with medians > 9 mm had the highest association with MRE (R2= 0.21). The strength of association of MRCP+ to Mayo Risk Score was similar to ANALI2 and weaker than MRE (R2 = 0.23, 0.24, 0.38 respectively). MRCP+ enhanced the association of ANALI 2 and MRE with the Mayo Risk Score. CONCLUSIONS: MRCP+ demonstrated a significant association with biochemical scores and MRE. The association of MRCP+ with the biochemical scores was generally comparable to ANALI scores. MRCP+ enhanced the association of ANALI2 and MRE with the Mayo Risk Score. KEY POINTS: • MRCP+ has the potential to act as a risk stratfier in PSC. • MRE outperformed MRCP+ for risk stratifcation. • Combination of MRCP+ with MRE and ANALI scores improved overall performace as risk stratifiers.

The degree of consistency of applying parental dietary and sedentary behavior rules as indicators for overweight in children: a cross-sectional study.

BACKGROUND: Review studies increasingly emphasize the importance of the role of parenting in interventions for preventing overweight in children. The aim of this study was to examine typologies regarding how consistently parents apply energy-balance related behavior rules, and the association between these typologies and socio-demographic characteristics, energy balance-related behaviors among school age children, and the prevalence of being overweight. METHODS: For this cross-sectional study, we had access to a database managed by a Municipal Health Service Department in the Netherlands. In total, 4,865 parents with children 4-12 years of age participated in this survey and completed a standardized questionnaire. Parents classified their consistency of applying rules as "strict", "indulgent", or "no rules". Typologies were identified using latent class analyses. We used regression analyses to examine how the typologies differed with respect to the covariates socio-demographic characteristics, children's energy balance-related behaviors, and weight status. RESULTS: We identified four stable, distinct parental typologies with respect to applying dietary and sedentary behavior rules. Overall, we found that parents who apply "overall strict EBRB rules" had the highest level of education and that their children practiced healthier behaviors compared to the children of parents in the other three classes. In addition, we found that parents who apply "indulgent dietary rules and no sedentary rules" had the lowest level of education and the highest percentage of non-Caucasians; in addition, their children 8-12 years of age had the highest likelihood of being overweight compared to children of parents with "no dietary rules". CONCLUSIONS: Parents' consistency in applying rules regarding dietary and sedentary behaviors was associated with parents' level of education and ethnic background, as well as with children's dietary and sedentary behaviors and their likelihood of becoming overweight. Our results may contribute to helping make healthcare professionals aware that children of parents who do not apply sedentary behavior rules are more likely to become overweight, as well as the importance of encouraging parents to apply strict dietary and sedentary behavior rules. These results can serve as a starting point for developing effective strategies to prevent overweight among children.

Lessons Learned from Infants with Late Detection of Critical Congenital Heart Disease.

Late detection of critical congenital heart disease (CCHD) is multifactorial and ill defined. We investigated the results of pulse oximetry screening (POS) and points in the care chain that contribute to delayed detection of CCHD. The medical records of 13 infants with delayed detection at a single pediatric cardiac center between 2013 and 2016 were identified and reviewed. Left heart obstructive lesions were the most common diagnosis (n = 8; 62%) and included coarctation of the aorta (n = 6), interrupted aortic arch with ventricular septal defect (n = 1), and critical aortic stenosis (n = 1). Tetralogy of Fallot (TOF) (n = 2), truncus arteriosus (n = 1), pulmonary atresia with ventricular septal defect (n = 1), and total anomalous pulmonary venous drainage (n = 1) made up the remainder of the conditions. Routine prenatal care was reported in most infants (10/13). Infants with late detection had either a true negative POS (10/13 infants) or no POS performed (3/13 infants). At the time of detection, 5/6 (83%) infants with coarctation had normal pulse oximetry values, whereas 6/7 (86%) infants with other CCHD developed abnormal pulse oximetry values. At diagnosis, 11/13 (85%) infants had significant signs or symptoms of clinical deterioration; only 2 infants were completely asymptomatic. Late detection of CCHD is uncommon and multifactorial. Eliminating late detection is dependent upon improving detection on screening obstetrical ultrasounds, enforcement of universal POS, and attention to the neonatal physical exam.

Cardiac Effects of COVID-19 Infection, MIS-C, and the Vaccine in Infants and Children: What Is Known and Future Implications.

The cardiac effects of novel coronavirus disease 2019 (COVID-19) infection on the pediatric heart has become an area of particular interest as elevated cardiac enzymes and abnormalities on echocardiogram and electrocardiogram were seen in a portion of children affected by the virus. In this article, we review the cardiac manifestations of acute COVID-19 infection, multisystem inflammatory syndrome in children, and postvaccine myocarditis. The limited research on the effects of COVID-19 on neonates and infants is also reported. KEY POINTS: · Cardiac involvement from MIS-C is much higher than the risk of COVID-19 vaccine-induced myocarditis.. · Neonates and infants have overall been less affected by COVID-19 than adults and older children.. · At this point in time, there is limited research on the cardiac effects of COVID-19 in neonates..

Rethinking Pulse Oximetry Screening in the Level-IV Neonatal Intensive Care Unit.

OBJECTIVE: This study aimed to evaluate the outcomes of newborn pulse oximetry screening in a level IV, tertiary care neonatal intensive care unit (NICU). STUDY DESIGN: This is a retrospective cohort study of neonates who received newborn pulse oximetry screening after being admitted to a single-center, level-IV NICU between 2014 and 2021. Neonates with known critical congenital heart disease were excluded from the study. RESULTS: Of the 4,493 neonates who had pulse oximetry screening, there were three positive screens (fail rate of 0.067%, 0.67 per 1,000 screened). The average age of screening was 818 hours. There were no positive screens of newborns who were admitted during their initial birth hospitalization and were screened while off oxygen. There were no new diagnoses of critical congenital heart disease (true positives) and there were no known false negatives. CONCLUSION: The results bring into question whether pulse oximetry screening with the current AAP-endorsed algorithm should be re-evaluated for a level-IV NICU at a children's hospital. However, the results may not be generalizable to other NICU's where echocardiography and prenatal echocardiograms are not as readily available. KEY POINTS: · Pulse oximetry has been shown to be effective in decreasing delayed diagnosis of critical congenital heart disease (CCHD); however, there are limited prior studies on newborn pulse oximetry in the NICU.. · In our study of over 4,000 neonates admitted to a level IV tertiary care NICU, there were no true positives (no new diagnoses of CCHD).. · Special considerations may be needed for pulse oximetry screening in the NICU setting..

Current Postlaunch Implementation of State Mandates of Newborn Screening for Critical Congenital Heart Disease by Pulse Oximetry in U.S. States and Hospitals.

OBJECTIVE: Our objective was to gauge adherence to nationally endorsed protocols in implementation of pulse oximetry (POx) screening for critical congenital heart disease (CCHD) in infants after mandate by all states and to assess associated characteristics. STUDY DESIGN: Between March and October 2019, an online questionnaire was administered to nurse supervisors who oversee personnel conducting POx screening. The questionnaire used eight questions regarding performance and interpretation of screening protocols to measure policy consistency, which is adherence to nationally endorsed protocols for POx screening developed by professional medical societies. Multilevel linear regression models evaluated associations between policy consistency and characteristics of hospitals and individuals, state of hospital location, early versus late mandate adopters, and state reporting requirements. RESULTS: Responses from 189 nurse supervisors spanning 38 states were analyzed. Only 17% received maximum points indicating full policy consistency, and 24% selected all four options for potential hypoxia that require a repeat screen. Notably, 33% did not recognize ≤90% SpO2 as an immediate failed screen and 31% responded that an infant with SpO2 of 89% in one extremity will be rescreened by nurses in an hour rather than receiving an immediate physician referral. Lower policy consistency was associated with lack of state reporting mandates (beta = -1.23 p = 0.01) and early adoption by states (beta = -1.01, p < 0.01). CONCLUSION: When presented with SpO2 screening values on a questionnaire, a low percentage of nurse supervisors selected responses that demonstrated adherence to nationally endorsed protocols for CCHD screening. Most notably, almost one-third of respondents did not recognize ≤90% SpO2 as a failed screen that requires immediate physician follow-up. In addition, states without reporting mandates and early adopter states were associated with low policy consistency. Implementing state reporting requirements might increase policy consistency, but some inconsistency may be the result of unique protocols in early adopter states that differ from nationally endorsed protocols. KEY POINTS: · Low adherence to nationally endorsed protocols.. · Inconsistent physician follow-up to hypoxia.. · Reporting improved consistency with national policy..

Facilitators and Barriers to Patient-Delivered Partner Therapy Acceptance for Chlamydia trachomatis Among Young African American Men Who Have Sex With Women in a Southern Urban Epicenter.

BACKGROUND: Chlamydia trachomatis (Ct) disproportionately affects African American young people living in the Southern United States and can have negative consequences if left untreated. Patient-delivered partner therapy (PDPT) is an evidence-based practice in which individuals diagnosed with Ct can provide treatment directly to their sex partners. However, PDPT acceptance rates need improvement. Although reasons for PDPT acceptance have been explored previously, the facilitators and barriers to expedited partner therapy acceptance among young southern African American men who have sex with women have not yet been examined. METHODS: Twenty semistructured interviews were conducted as part of a community-based Ct screening and treatment intervention among African American men aged 15 to 25 years who had female sex partners. Participants were asked about why they did or did not accept PDPT for their sex partners. Data were transcribed and analyzed in NVivo qualitative software using an inductive thematic approach. RESULTS: Participants' decision making was multifaceted. Facilitators for PDPT acceptance included being able to cure their partner, convenient access to treatment, believing it was the right thing to do, having a close relationship with a partner, concern for the partner's well-being, and the perceived severity of Ct. Barriers to PDPT acceptance were the belief that a partner did not need treatment, not having a close relationship with the partner, being unable to contact the partner, and fear of conflict. CONCLUSIONS: Findings had similarities to other studies, indicating some universal messaging may be warranted alongside culturally tailored interventions for specific patient populations to increase PDPT acceptance. Implications for patient-provider communication are provided.

Acute correction of severe complex adolescent late-onset tibia vara by minimally invasive osteotomy and simple circular fixation: a case series with 2-year minimum follow-up.

BACKGROUND: Despite multiple published reviews, the optimum method of correction and stabilisation of Blount's disease remains controversial. The purpose of this study is to evaluate the clinical and radiological outcomes of acute correction of late-onset tibial vara by percutaneous proximal tibial osteotomy with circular external fixation using two simple rings. Weighing up the pros and cons and to establish if this method would be the method of choice in similar severe cases especially in a context of limited resources. METHODS: This study was conducted between November 2016 and July 2020. We retrospectively reviewed the clinical notes and radiographs of 30 patients (32 tibiae) who had correction of severe late-onset tibia vara by proximal tibial osteotomy and Ilizarov external fixator. The mean age at the time of the operation was 16.6 (± 2.7) years (range 13-22). RESULTS: The mean proximal tibial angle was 65.7° (± 7.8) preoperatively and 89.8° (± 1.7) postoperatively (p < 0.001). The mean mechanical axis deviation improved from 56.2 (± 8.3) preoperatively to 2.8 (± 1.6) mm postoperatively (p < 0.001). The mean femoral-tibial shaft angle was changed from -34.3° (± 6.7) preoperatively to 5.7° (± 2.8) after correction, with degree of correction ranging from 25° to 45°. Complications included overcorrection (three cases 9%) and pin tract infection (eight cases 25%). The mean Hospital for Special Surgery knee scoring system (HSS) improved from 51.03 (± 11.24) preoperatively to 94.2 (± 6.8) postoperatively (p < 0.001). The mean length of follow up period 33.22 (± 6.77) months, (rang: 25-46 months). At final follow up, all patients had full knee range of motion and normal function. All cases progressed to union and there were no cases of recurrence of deformity. CONCLUSION: This simple procedure provides secure fixation allowing early weight bearing and early return to function. It can be used in the context of health care systems with limited resources. It has a relatively low complication rate. Our results suggest that acute correction and simple circular frame fixation is an excellent treatment choice for cases of late-onset tibia vara, especially in severe deformities.