Automated profiling of gene function during embryonic development.

Systematic functional profiling of the gene set that directs embryonic development is an important challenge. To tackle this challenge, we used 4D imaging of C. elegans embryogenesis to capture the effects of 500 gene knockdowns and developed an automated approach to compare developmental phenotypes. The automated approach quantifies features-including germ layer cell numbers, tissue position, and tissue shape-to generate temporal curves whose parameterization yields numerical phenotypic signatures. In conjunction with a new similarity metric that operates across phenotypic space, these signatures enabled the generation of ranked lists of genes predicted to have similar functions, accessible in the PhenoBank web portal, for ∼25% of essential development genes. The approach identified new gene and pathway relationships in cell fate specification and morphogenesis and highlighted the utilization of specialized energy generation pathways during embryogenesis. Collectively, the effort establishes the foundation for comprehensive analysis of the gene set that builds a multicellular organism.

Predictors of Invasive Bacterial Infection in Febrile Infants Aged 2 to 6 Months in the Emergency Department.

Our goal was to identify predictors of invasive bacterial infection (ie, bacteremia and bacterial meningitis) in febrile infants aged 2-6 months. In our multicenter retrospective cohort, older age and lower temperature identified infants at low risk for invasive bacterial infection who could safely avoid routine testing.

Contaminant Organism Growth in Febrile Infants at Low Risk for Invasive Bacterial Infection.

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures.

Perioperative Outcomes After Adrenalectomy for Secondary Adrenal Malignancy.

INTRODUCTION: The risk of adverse outcomes after adrenal metastasectomy is not well defined. Knowledge of these risks is essential to guide patient counseling. METHODS: The 2015-2020 National Surgical Quality Improvement Program datasets were combined. Patients who underwent adrenalectomy for secondary adrenal malignancy (SM) and benign nonfunctional (BNF) adrenal neoplasms were identified; BNF neoplasms were chosen as a comparison as functional neoplasms can contribute to comorbidity. Patients who had additional surgery at the time of adrenalectomy were excluded. Patient demographics, comorbidities, perioperative factors, and outcomes were compared between groups. Multivariable logistic regression analysis was performed. RESULTS: Of 3496 adrenalectomy patients, 332 had SM and 3164 had BNF neoplasms. Patients with SM were older (65 versus 54 y) and more often had chronic obstructive pulmonary disease (7.5% versus 4.4%), chronic steroid use (10.5% versus 3.8%), and bleeding disorders (4.5% versus 2.2%) than patients with BNF, respectively (P < 0.01 for all). Laparoscopic adrenalectomy was the most common operative approach for both groups (74.7% versus 88.3%). Rates of mortality, morbidity, reoperation, readmission, and nonhome discharge did not differ significantly between groups. Patients with SM had higher rates of postoperative bleeding than patients with BNF (6.3% versus 2.6%, P < 0.001). This persisted on multivariable regression analysis that adjusted for demographics, comorbidities, and operative approach (odds ratio 2.34, 95% confidence interval 1.19-4.64). CONCLUSIONS: Adrenalectomy for SM is associated with an increased risk of postoperative bleeding compared to adrenalectomy for BNF adrenal neoplasms. Patients with SM that meet criteria for adrenal metastasectomy should be counseled appropriately.

Adrenalectomy Outcome Variations Across Different Functional Adrenal Tumors.

INTRODUCTION: Adrenalectomy generally has favorable outcomes. It is unknown if patients with functional adrenal tumors experience different clinical outcomes than those with benign adrenal tumors, due to the presence of comorbid conditions secondary to the functional tumor. We investigated outcomes following open and laparoscopic adrenalectomy for benign nonfunctional (BNF) versus functional adrenal masses. METHODS: Patients undergoing adrenalectomy were identified in the 2015-2020 National Surgical Quality Improvement Program database, then categorized as BNF, hyperaldosteronism, hypercortisolism, and pheochromocytoma. The primary outcome of interest was 30-d morbidity and secondary outcomes included 30-d mortality, 30-d readmission, and postoperative length of stay (LOS). Subgroup analysis was performed based upon surgical approach. Univariate analysis was performed, followed by multivariable logistic regression for individual outcomes that differed significantly between patients with BNF and functional neoplasm, factoring in patient demographics and operative approach with statistical significance on univariate analysis. Descriptive statistics and outcomes were analyzed using Pearson's χ2 test and Mann-Whitney U-test as appropriate. RESULTS: There were 3291 patients with BNF while 484 had hyperaldosteronism, 263 hypercortisolism, and 46 pheochromocytomas. Within the laparoscopic group of 3615 (88.5%) of adrenalectomy patients, compared to BNF patients, patients with hyperaldosteronism had lower rates of postoperative morbidity (1.9% versus 5.2%, P < 0.001) and shorter LOS (1 d, interquartile range (IQR) [1-1] versus 1d IQR [1-2], P = 0.003); these persisted on multivariate analysis (OR 0.32, 95% confidence interval [CI] 0.14-0.74 and odds ratio 0.47, 95% CI 0.36-0.60, P < 0.001). Patients with hypercortisolism had higher morbidity (7.3% versus 5.2%, P < 0.001), 30-d readmission rates (5.3% versus 2.9%, P = 0.042) and longer LOS (2d, IQR [1-3] versus 1d, IQR [1-2, P < 0.001). On multivariate analysis, presence of hypercortisolism was independently associated with increased likelihood of readmission within 30 d (OR 2.20, 95% CI 1.11-2.99, P = 0.012) and longer LOS (>1 d) (OR 1.79, 95% CI 1.33-2.40, P < 0.001). Compared to BNF patients, patients with pheochromocytoma had higher rates of postoperative morbidity (6.2% versus 5.2%, P < 0.001). Within the open group of 469 (11.5% of adrenalectomy patients), there were no statistically significant differences in outcomes between patients with BNF and functional adrenal masses. CONCLUSIONS: Outcomes after adrenalectomy performed for functional neoplasms differ based on surgical indication.

Wilms Tumor With Raised Serum Alpha-Fetoprotein: Highlighting the Need for Novel Circulating Biomarkers.

Wilms tumor (WT) is the commonest cause of renal cancer in children. In Europe, a diagnosis is made for most cases on typical clinical and radiological findings, prior to pre-operative chemotherapy. Here, we describe a case of a young boy presenting with a large abdominal tumor, associated with raised serum alpha-fetoprotein (AFP) levels at diagnosis. Given the atypical features present, a biopsy was taken, and histology was consistent with WT, showing triphasic WT, with epithelial, stromal, and blastemal elements present, and positive WT1 and CD56 immunohistochemical staining. During pre-operative chemotherapy, serial serum AFP measurements showed further increases, despite a radiological response, before a subsequent fall to normal following nephrectomy. The resection specimen was comprised of ~55% and ~45% stromal and epithelial elements, respectively, with no anaplasia, but immunohistochemistry using AFP staining revealed positive mucinous intestinal epithelium, consistent with the serum AFP observations. The lack of correlation between tumor response and serum AFP levels in this case highlights a more general clinical unmet need to identify WT-specific circulating tumor markers.

A case of restrictive dermopathy in a Hutterite newborn: Diagnosis and creative skin-directed management.

Restrictive dermopathy is a lethal autosomal recessive disease characterized by tightly adherent skin, distinctive facial dysmorphisms, arthrogryposis, and pulmonary hypoplasia. While clinical findings are unique, histopathology and genetic analysis are critical for early diagnostic confirmation and to initiate appropriate management for this lethal disease. We report on a preterm Hutterite male neonate with biallelic ZMPSTE24 mutations to highlight the clinical and histopathological features of restrictive dermopathy and share our skin-directed management strategies.

Overcoming NMR line broadening of nitrogen containing compounds: A simple solution.

This study presents a straightforward solution to the challenge of elucidating the structures of nitrogen containing compounds undergoing isomerization. When spectral line broadening occurs related to isomerization, be it prototropic tautomerism or bond rotations, this poses a significant obstacle to structural elucidation. By adding acids, we demonstrate a simple approach to overcome this issue and effectively sharpen NMR signals for acid stable prototropic tautomers as well as the conformational isomers containing a morpholine or piperazine ring.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

INTRODUCTION: We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. METHODS: We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain  = 2632; NAPOE-interaction  = 1810). RESULTS: Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (ß = -3.89 mL [-5.81, -1.97], Padjusted  < 0.05); these were largely attenuated in fully adjusted models (ß = -1.59 mL [-3.55, 0.36], P = 0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. DISCUSSION: We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Exploring the Interactions between Plant Proanthocyanidins and Thiabendazole: Insights from Isothermal Titration Calorimetry.

Anthelmintic resistance in gastrointestinal nematodes produces substantial challenges to agriculture, and new strategies for nematode control in livestock animals are called for. Natural compounds, including tannins, with proven anthelmintic activity could be a functional option as structurally diverse complementary compounds to be used alongside commercial anthelmintics. However, the dual use of two anthelmintic components requires an understanding of the pharmacological effects of the combination, while information concerning the interactions between plant-based polyphenols and commercial anthelmintics is scarce. We studied the direct interactions of proanthocyanidins (PAs, syn. condensed tannins) and a commercial anthelmintic thiabendazole, as a model substance of benzimidazoles, by isothermal titration calorimetry (ITC). Our results show evidence of a direct interaction of an exothermic nature with observed enthalpy changes ranging from 0 to -30 kJ/mol. The strength of the interaction between PAs and thiabendazole is mediated by structural characteristics of the PAs with the strongest positive correlation originating from the presence of galloyl groups and the increased degree of polymerization.

Interactions of Galloylated Polyphenols with a Simple Gram-Negative Bacterial Membrane Lipid Model.

Differential scanning calorimetry (DSC) was used to explore the interactions of isolated polyphenolic compounds, including (-)-epigallocatechin gallate ((-)-EGCg), tellimagrandins I and II (Tel-I and Tel-II), and 1,2,3,4,6-penta-O-galloyl-d-glucose (PGG), with a model Gram-negative bacterial membrane with a view to investigating their antimicrobial properties. The model membranes comprised 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) and 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), fabricated to mimic the domain formation observed in natural membranes, as well as ideally mixed lipid vesicles for the interaction with (-)-EGCg. Polyphenols induced changes in lipid mixing/de-mixing depending on the method of vesicle preparation, as was clearly evidenced by alterations in the lipid transition temperatures. There was a distinct affinity of the polyphenols for the DPPG lipid component, which was attributed to the electrostatic interactions between the polyphenolic galloyl moieties and the lipid headgroups. These interactions were found to operate through either the stabilization of the lipid headgroups by the polyphenols or the insertion of the polyphenols into the membrane itself. Structural attributes of the polyphenols, including the number of galloyl groups, the hydrophobicity quantified by partition coefficients (logP), and structural flexibility, exhibited a correlation with the temperature transitions observed in the DSC measurements. This study furthers our understanding of the intricate interplay between the structural features of polyphenolic compounds and their interactions with model bacterial membrane vesicles towards the exploitation of polyphenols as antimicrobials.

Parental leave experiences for the non-childbearing general surgery resident parent: A qualitative analysis.

BACKGROUND: Stigma surrounds parental leave during general surgery residency, yet 25% to 29% of general surgery residents have children. Parental leave experiences of non-childbearing general surgery resident parents have not been described. This study aimed to describe the non-childbearing population's parental leave experiences. METHODS: Using a purposive sampling strategy, semi-structured interviews (n = 20) were conducted via Zoom (August 2021-March 2022) with current general surgery residents or fellows who had at least 1 child during residency as the non-childbearing parent. Interviews explored participants' experiences with parental leave policies, timing, structure, motivations/influences for taking leave, career/training impacts, and reflections on their experiences. Transcripts were analyzed using thematic content analysis. Participant demographics were analyzed using univariate analysis. RESULTS: Of the 20 participants, there were 31 unique parental leave experiences. The following 6 themes were identified from interviews: program/professional policies, cultural climate, support (institutional and social), parental leave experiences, impact, and recommendations. Participants cited needing to rely on informal support (eg, the assistance of other residents) to arrange leave and feeling compelled not to take the full time allowed in order to not burden co-residents or because others took less time. Overall, participants felt dissatisfied with their parental leave experiences. CONCLUSION: Non-childbearing general surgery resident parents underuse parental leave due to perceived or actual lack of access to leave and stigma. This results in dissatisfaction with their parental leave experiences and has the potential to lead to negative professional and personal outcomes. There is a critical need for improved support through cultural change and policy revision, implementation, and adherence.

Safety of thyroidectomy in hospitalized patients: A descriptive analysis of the NSQIP thyroidectomy-targeted data.

BACKGROUND: Some patients undergo thyroidectomy while hospitalized for a related or independent indication. Outcomes have not been described in this group. METHODS: The 2016-2018 thyroidectomy-targeted NSQIP datasets were queried for patients admitted for ≥1 day preoperatively. 1:1 propensity score matching was employed to compare the outcomes of admitted patients to outpatients, including surgical and thyroidectomy-specific outcomes. Multivariable logistic regression determined factors associated with poor outcomes. RESULTS: Of 18,078 patients, 312 were admitted at least 1 day prior to surgery. Inpatients had higher ASA classifications and rates of several comorbidities compared to the general population. After propensity score matching, inpatients had higher rates of overall complications, unplanned reoperation, and bleeding. They also experienced higher rates of thyroidectomy-specific complications such as hypocalcemia and neck hematoma. By multivariable regression, admission prior to surgery was associated with development of any complications. CONCLUSION: Thyroidectomy in hospitalized patients carries an increased risk of complications. Patients requiring thyroidectomy while already hospitalized should be counseled accordingly.

An Emergency Department Quality Improvement Project to Decrease Lumbar Puncture Rates in Febrile Infants 22 to 28 Days Old.

Introduction: Most providers have routinely performed universal lumbar puncture (LP) on well-appearing, febrile infants 22 to 28 days old. In 2021, the American Academy of Pediatrics recommended clinicians should perform an LP in this age group if inflammatory markers are abnormal. This quality improvement project aimed to decrease LP rates in febrile infants 22 to 28 days old in the emergency department (ED) within 1 year, regardless of race/ethnicity, from a baseline of 87%. Methods: We used our institution's quality improvement framework to perform multiple Plan-Do-Study-Act cycles. A multidisciplinary team reviewed the febrile infant literature, local epidemiology, and identified key drivers. We provided departmental education, updated our clinical pathway, and used clinical decision support. We analyzed baseline (January 2017-March 2022) and intervention data (April 2022-March 2024) and tracked data using statistical process control charts. Our primary outcome measure was rates of LP in the ED for this cohort. Process measures included rates of infants with procalcitonin results. ED length of stay, rates of first LP attempt after hospitalization, and missed bacterial meningitis were balancing measures. Results: The baseline LP rate of 87% decreased to 44% during the intervention period, resulting in a downward centerline shift. There were no significant differences when LP rates were analyzed by race/ethnicity. There was an upward centerline shift in the process measure of infants with procalcitonin results. There was no observed special cause variation in our balancing measures. Conclusion: Quality improvement efforts, including education, clinical pathway updates, and clinical decision support, safely reduced rates of LPs in febrile infants 22 to 28 days old.

Pain and Its Association with Survival for Black and White Individuals with Advanced Prostate Cancer in the United States.

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. SIGNIFICANCE: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.