A translational model of chronic diabetic nephropathy in the Nile grass rat.

Diabetic nephropathy (DN) is a major healthcare challenge for individuals with diabetes and associated with increased cardiovascular morbidity and mortality. The existing rodent models do not fully represent the complex course of the human disease. Hence, developing a translational model of diabetes that reproduces both the early and the advanced characteristics of DN and faithfully recapitulates the overall human pathology is an unmet need. Here, we introduce the Nile grass rat (NGR) as a novel model of DN and characterize key pathologies underlying DN. NGRs spontaneously developed insulin resistance, reactive hyperinsulinemia, and hyperglycemia. Diabetic NGRs evolved DN and the key histopathological aspects of the human advanced DN, including glomerular hypertrophy, infiltration of mononuclear cells, tubular dilatation, and atrophy. Enlargement of the glomerular tufts and the Bowman's capsule areas accompanied the expansion of the Bowman's space. Glomerular sclerosis, renal arteriolar hyalinosis, Kimmelsteil-Wilson nodular lesions, and protein cast formations in the kidneys of diabetic NGR occurred with DN. Diabetic kidneys displayed interstitial and glomerular fibrosis, key characteristics of late human pathology as well as thickening of the glomerular basement membrane and podocyte effacement. Signs of injury included glomerular lipid accumulation, significantly more apoptotic cells, and expression of KIM-1. Diabetic NGRs became hypertensive, a known risk factor for kidney dysfunction, and showed decreased glomerular filtration rate. Diabetic NGRs recapitulate the breadth of human DN pathology and reproduce the consequences of chronic kidney disease, including injury and loss of function of the kidney. Hence, NGR represents a robust model for studying DN-related complications and provides a new foundation for more detailed mechanistic studies of the genesis of nephropathy, and the development of new therapeutic approaches.

Trapped fat: Obesity pathogenesis as an intrinsic disorder in metabolic fuel partitioning.

Our understanding of the pathophysiology of obesity remains at best incomplete despite a century of research. During this time, two alternative perspectives have helped shape thinking about the etiology of the disorder. The currently prevailing view holds that excessive fat accumulation results because energy intake exceeds energy expenditure, with excessive food consumption being the primary cause of the imbalance. The other perspective attributes the initiating cause of obesity to intrinsic metabolic defects that shift fuel partitioning from pathways for mobilization and oxidation to those for synthesis and storage. The resulting reduction in fuel oxidation and trapping of energy in adipose tissue drives a compensatory increase in energy intake and, under some conditions, a decrease in expenditure. This theory of obesity pathogenesis has historically garnered relatively less attention despite its pedigree. Here, we present an updated comprehensive formulation of the fuel partitioning theory, focused on evidence gathered over the last 80 years from major animal models of obesity showing a redirection of fuel fluxes from oxidation to storage and accumulation of excess body fat with energy intake equal to or even less than that of lean animals. The aim is to inform current discussions about the etiology of obesity and by so doing, help lay new foundations for the design of more efficacious approaches to obesity research, treatment and prevention.

Preferences for Management of Pediatric Pneumonia: A Clinician Survey of Artificially Generated Patient Cases.

BACKGROUND: It is unknown which factors are associated with chest radiograph (CXR) and antibiotic use for suspected community-acquired pneumonia (CAP) in children. We evaluated factors associated with CXR and antibiotic preferences among clinicians for children with suspected CAP using case scenarios generated through artificial intelligence (AI). METHODS: We performed a survey of general pediatric, pediatric emergency medicine, and emergency medicine attending physicians employed by a private physician contractor. Respondents were given 5 unique, AI-generated case scenarios. We used generalized estimating equations to identify factors associated with CXR and antibiotic use. We evaluated the cluster-weighted correlation between clinician suspicion and clinical prediction model risk estimates for CAP using 2 predictive models. RESULTS: A total of 172 respondents provided responses to 839 scenarios. Factors associated with CXR acquisition (OR, [95% CI]) included presence of crackles (4.17 [2.19, 7.95]), prior pneumonia (2.38 [1.32, 4.20]), chest pain (1.90 [1.18, 3.05]) and fever (1.82 [1.32, 2.52]). The decision to use antibiotics before knowledge of CXR results included past hospitalization for pneumonia (4.24 [1.88, 9.57]), focal decreased breath sounds (3.86 [1.98, 7.52]), and crackles (3.45 [2.15, 5.53]). After revealing CXR results to clinicians, these results were the sole predictor associated with antibiotic decision-making. Suspicion for CAP correlated with one of 2 prediction models for CAP (Spearman's rho = 0.25). Factors associated with a greater suspicion of pneumonia included prior pneumonia, duration of illness, worsening course of illness, shortness of breath, vomiting, decreased oral intake or urinary output, respiratory distress, head nodding, focal decreased breath sounds, focal rhonchi, fever, and crackles, and lower pulse oximetry. CONCLUSIONS: Ordering preferences for CXRs demonstrated similarities and differences with evidence-based risk models for CAP. Clinicians relied heavily on CXR findings to guide antibiotic ordering. These findings can be used within decision support systems to promote evidence-based management practices for pediatric CAP.

Mammalian START-like phosphatidylinositol transfer proteins - Physiological perspectives and roles in cancer biology.

PtdIns and its phosphorylated derivatives, the phosphoinositides, are the biochemical components of a major pathway of intracellular signaling in all eukaryotic cells. These lipids are few in terms of cohort of unique positional isomers, and are quantitatively minor species of the bulk cellular lipidome. Nevertheless, phosphoinositides regulate an impressively diverse set of biological processes. It is from that perspective that perturbations in phosphoinositide-dependent signaling pathways are increasingly being recognized as causal foundations of many human diseases - including cancer. Although phosphatidylinositol transfer proteins (PITPs) are not enzymes, these proteins are physiologically significant regulators of phosphoinositide signaling. As such, PITPs are conserved throughout the eukaryotic kingdom. Their biological importance notwithstanding, PITPs remain understudied. Herein, we review current information regarding PITP biology primarily focusing on how derangements in PITP function disrupt key signaling/developmental pathways and are associated with a growing list of pathologies in mammals.

Outcomes after gastrectomy according to the Gastrectomy Complications Consensus Group (GCCG) in the Dutch Upper GI Cancer Audit (DUCA).

BACKGROUND: In 2019, the Gastrectomy Complications Consensus Group (GCCG) published a standardized set of complications aiming toward uniform reporting of post-gastrectomy complications. This study aimed to report outcomes after gastrectomy in the Netherlands according to GCCG definitions and compare them to previously reported national results and the European database reported by the GCCG. METHODS: This nationwide, population-based cohort study included all patients undergoing gastrectomy for gastric cancer registered in the DUCA in 2020-2021. Postoperative morbidity and 30-day/in-hospital mortality were analyzed according to the GCCG definitions. For all patients, baseline characteristics and outcomes were compared with the GCCG cohort consisting of 27 European expert centers (GASTRODATA; 2017-2018). RESULTS: In 2020-2021, 782 patients underwent gastrectomy in the Netherlands. Variation was seen in baseline characteristics between the Dutch and the GCCG cohort (N = 1349), most notably in minimally invasive surgery (80.6% vs 19.6%, p < 0.001). In the Netherlands, 223 (28.5%) patients developed a total of 407 complications, the most frequent being non-surgical infections (28.5%) and anastomotic leakage (13.4%). The overall complication and 30-day mortality rates were similar between the Dutch and GCCG cohort (28.5% vs 29.8%, p = 0.563; 3.7% vs 3.6%, p = 0.953). Higher surgical and endoscopic/radiologic reintervention rates were observed in the Netherlands compared to the GCCG cohort (10.7% vs 7.8%, p = 0.025; 10.9% vs 2.9%, p < 0.001). CONCLUSION: Reporting outcomes according to the standardized GCCG definitions allows for international benchmarking. Postoperative outcomes were comparable between Dutch and GCCG cohorts, but both exceed the international benchmark for expert gastrectomy care, highlighting targets for national and international quality improvement.

The Prognostic Impact of Minimally Invasive Esophagectomy on Survival after Esophagectomy following a Delayed Interval after Chemoradiotherapy; A Secondary Analysis of the DICE Study.

OBJECTIVE: To evaluate prognostic differences between minimally invasive esophagectomy (MIE) and open esophagectomy (OE) in patients with surgery after a prolonged interval (>12 wk) following chemoradiotherapy (CRT). BACKGROUND: Previously, we established that a prolonged interval after CRT prior to esophagectomy was associated with poorer long-term survival. METHODS: This was an international multi-center cohort study involving seventeen tertiary centers, including patients who received CRT followed by surgery between 2010-2020. Patients undergoing MIE were defined as thoracoscopic and laparoscopic approach. RESULTS: 428 patients (145 MIE and 283 OE) had surgery between 12 weeks and two years after CRT. Significant differences were observed in ASA grade, radiation dose, clinical T stage, and histological subtype. There were no significant differences between the groups in age, sex, BMI, pathological T or N stage, resection margin status, tumor location, surgical technique, or 90-day mortality. Survival analysis showed MIE was associated with improved survival in univariate (P=0.014), multivariate analysis after adjustment for smoking, T and N stage, and histology (HR=1.69; 95% CI 1.14 to 2.5) and propensity matched analysis (P=0.02). Further subgroup analyses by radiation dose and interval after CRT showed survival advantage for MIE, in 40-50Gy dose groups (HR=1.9; 95% CI 1.2 to 3.0), and in patients having surgery within six months of CRT (HR=1.6; 95% CI 1.1 to 2.2). CONCLUSION: MIE was associated with an improved overall survival compared to OE in patients with a prolonged interval from CRT to surgery. The mechanism for this observed improvement in survival remains unknown, with potential hypotheses including a reduction in complications and improved functional recovery after MIE.

Children's Hospital Resource Utilization During the 2022 Viral Respiratory Surge.

OBJECTIVES: Multiple viral respiratory epidemics occurred concurrently in 2022 but their true extent is unclear. To aid future surge planning efforts, we compared epidemiology and resource utilization with prepandemic viral respiratory seasons in 38 US children's hospitals. METHODS: We performed a serial cross-sectional study from October 2017 to March 2023. We counted daily emergency department (ED), inpatient, and ICU volumes; daily surgeries; viral tests performed; the proportion of ED visits resulting in revisit within 3 days; and proportion of hospitalizations with a 30-day readmission. We evaluated seasonal resource utilization peaks using hierarchical Poisson models. RESULTS: Peak volumes in the 2022 season were 4% lower (95% confidence interval [CI] -6 to -2) in the ED, not significantly different in the inpatient unit (-1%, 95% CI -4 to 2), and 8% lower in the ICU (95% CI -14 to -3) compared with each hospital's previous peak season. However, for 18 of 38 hospitals, their highest ED and inpatient volumes occurred in 2022. The 2022 season was longer in duration than previous seasons (P < .02). Peak daily surgeries decreased by 15% (95% CI -20 to -9) in 2022 compared with previous peaks. Viral tests increased 75% (95% CI 69-82) in 2022 from previous peaks. Revisits and readmissions were lowest in 2022. CONCLUSIONS: Peak ED, inpatient, and ICU volumes were not significantly different in the 2022 viral respiratory season compared with earlier seasons, but half of hospitals reached their highest volumes. Research on how surges impact boarding, transfer refusals, and patient outcomes is needed as regionalization reduces pediatric capacity.

Decoupling Protein Concentration and Aggregate Content Using Diffusion and Water NMR.

Protein-based biopharmaceutical drugs, such as monoclonal antibodies, account for the majority of the best-selling drugs globally in recent years. For bioprocesses, key performance indicators are the concentration and aggregate level for the product being produced. In water NMR (wNMR), the use of the water transverse relaxation rate [R2(1H2O)] has been previously used to determine protein concentration and aggregate level; however, it cannot be used to separate between them without using an additional technique. This work shows that it is possible to "decouple" these two key characteristics by recording the water diffusion coefficient [D(1H2O)] in conjunction with R2(1H2O), even in the event of overlap in either D(1H2O) or R2(1H2O). This method is demonstrated on three different systems, following appropriate D(1H2O) or R2(1H2O) calibration data acquisition for a protein of interest. Our method highlights the potential use of benchtop NMR as an at-line process analytical technique.

Elucidating the Mechanism of Efficient Eu(III) and Yb(III) Sensitisation from a Re(I) Tetrazolato Triangular Assembly.

The reaction of Re(CO)5Br with deprotonated 1H-(5-(2,2':6',2''-terpyridine)pyrid-2-yl)tetrazole yields a triangular assembly formed by tricarbonyl Re(I) vertices. Photophysical measurements reveal blue-green emission with a maximum at 520 nm, 32% quantum yield, and 2430 ns long-lived excited state decay lifetime in deaerated dichloromethane solution. Coordination of lanthanoid ions to the terpyridine units red-shifts the emission to 570 nm and also reveals efficient (90%) and fast sensitisation to both Eu(III) and Yb(III) at room temperature, with a similar rate constant kET of the order of 107 s-1. Efficient sensitisation of Eu(III) from Re(I) is unprecedented, especially when considering the close proximity in energy between the donor and acceptor excited states. On the other hand, comparative measurements at 77 K reveal that energy transfer to Yb(III) is two orders of magnitude slower than that to Eu(III). A two-step mechanism of sensitisation is therefore proposed, whereby the rate-determining step is a thermally activated energy transfer step between the Re(I) centre and the terpyridine functionality, followed by rapid energy transfer to the respective Ln(III) excited states. At 77 K, the direct Re(I) to Eu(III) energy transfer seems to proceed via a ligand-mediated superexchange Dexter-type mechanism.

Screening and risk assessment for sleep-related breathing disorders in individuals living with spinal cord injury.

OBJECTIVES: This research work was performed: (1) To assess the accessibility of in-laboratory polysomnography for individuals with spinal cord injury (SCI); (2) to evaluate the validity of four screening questionnaires for sleep-related breathing disorders (SRBDs); and (3) to assess the association between anthropometric features and apnea-hypopnea index (AHI). METHODS: An Environmental scan (E-scan) was performed in the province of Ontario, where all sleep clinics were invited to complete the E-scan survey. Furthermore, a cross-sectional study was performed at a rehabilitation hospital (Canada), where consecutive adults with subacute/chronic (>1 month) SCI were recruited. Using a home-based screening sleep test (HBSST), the validity of the Berlin, STOP, Medical Outcomes Study Sleep Scale [MOS-SS], and STOP-Bang screening questionnaires was assessed. The association between AHI and three features (i.e., neck circumference, body mass index [BMI] and oropharynx opening as assessed using the Modified Mallampati classification [MMC]) was evaluated. RESULTS: According to the E-scan, access to polysomnography is limited for the SCI population in Ontario. Of the 28 participants with SCI (11 females, 17 males; mean age: 54.9 years) included in the cross-sectional study, 32.1 % were diagnosed with moderate-to-severe SRBD. The performance of the questionnaires was considered insufficient for screening of individuals living with SCI. AHI was not associated with neck circumference, BMI, or MMC. CONCLUSIONS: Those results suggest that the use of a HBSST could overcome the barriers for individuals with SCI to access diagnostic testing of SRBDs. The use of screening questionnaires and risk assessment for SRBDs in the SCI population is unreliable.

Surgeon Preference and Clinical Outcome of 3D Vision Compared to 2D Vision in Laparoscopic Surgery: Systematic Review and Meta-Analysis of Randomized Trials.

Objective: To assess the added value of 3-dimensional (3D) vision, including high definition (HD) technology, in laparoscopic surgery in terms of surgeon preference and clinical outcome. Background: The use of 3D vision in laparoscopic surgery has been suggested to improve surgical performance. However, the added value of 3D vision remains unclear as a systematic review of randomized controlled trials (RCTs) comparing 3D vision including HD technology in laparoscopic surgery is currently lacking. Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines with a literature search up to May 2023 using PubMed and Embase (PROSPERO, CRD42021290426). We included RCTs comparing 3D versus 2-dimensional (2D) vision in laparoscopic surgery. The primary outcome was operative time. Meta-analyses were performed using the random effects model to estimate the pooled effect size expressed in standard mean difference (SMD) with corresponding 95% confidence intervals (CIs). The level of evidence and quality was assessed according to the Cochrane risk of bias tool. Results: Overall, 25 RCTs with 3003 patients were included. Operative time was reduced by 3D vision (-8.0%; SMD, -0.22; 95% CI, -0.37 to -0.06; P = 0.007; n = 3003; 24 studies; I 2 = 75%) compared to 2D vision. This benefit was mostly seen in bariatric surgery (-16.3%; 95% CI, -1.28 to -0.21; P = 0.006; 2 studies; n = 58; I 2 = 0%) and general surgery (-6.7%; 95% CI, -0.34 to -0.01; P = 0.036; 9 studies; n = 1056; I 2 = 41%). Blood loss was nonsignificantly reduced by 3D vision (SMD, -0.33; 95% CI, -0.68 to 0.017; P = 0.060; n = 1830; I 2 = 92%). No differences in the rates of morbidity (14.9% vs 13.5%, P = 0.644), mortality (0% vs 0%), conversion (0.8% vs 0.9%, P = 0.898), and hospital stay (9.6 vs 10.5 days, P = 0.078) were found between 3D and 2D vision. In 15 RCTs that reported on surgeon preference, 13 (87%) reported that the majority of surgeons favored 3D vision. Conclusions: Across 25 RCTs, this systematic review and meta-analysis demonstrated shorter operative time with 3D vision in laparoscopic surgery, without differences in other outcomes. The majority of surgeons participating in the RCTs reported in favor of 3D vision.

High-Output Heart Failure in Multiple Myeloma: Novel Application of Tc-99m MAA to Identify Intramedullary Shunting.

We introduce the innovative use of technetium-99m-labeled macroaggregated albumin to diagnose high-output heart failure in a patient with multiple myeloma with persistent congestion symptoms. Symptom resolution occurred with lenalidomide and steroids. This marks the first clinical use of technetium-99m-labeled macroaggregated albumin for clarifying high-output heart failure etiology.

Survivin as a Therapeutic Target for the Treatment of Human Cancer.

Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.

Sleep Apnea and Stroke: A Narrative Review.

TOPIC IMPORTANCE: Stroke is the second-leading cause of death worldwide. OSA is an independent risk factor for stroke and is associated with multiple vascular risk factors. Poststroke OSA is prevalent and closely linked with various stroke subtypes, including cardioembolic stroke and cerebral small vessel disease. Observational studies have shown that untreated poststroke OSA is associated with an increased risk of recurrent stroke, mortality, poorer functional recovery, and longer hospitalizations. REVIEW FINDINGS: Poststroke OSA tends to be underdiagnosed and undertreated, possibly because stroke patients with OSA present atypically compared with the general population with OSA. Objective testing, such as the use of ambulatory sleep testing or in-laboratory polysomnography, is recommended for diagnosing OSA. The gold standard for treating OSA is CPAP therapy. Randomized controlled trials (RCTs) have shown that treatment of poststroke OSA using CPAP improves nonvascular outcomes such as cognition and neurologic recovery. However, findings from RCTs that have evaluated the effect of CPAP on recurrent stroke risk and mortality have been largely negative. SUMMARY: There is a need for high-quality RCTs in poststroke OSA that may provide evidence to support the utility of CPAP (and/or other treatment modalities) in reducing recurrent vascular events and mortality. This goal may be achieved by examining treatment strategies that have yet to be trialed in poststroke OSA, tailoring interventions according to poststroke OSA endotypes and phenotypes, selecting high-risk populations, and using metrics that reflect the physiological abnormalities that underlie the harmful effects of OSA on cardiovascular outcomes.

Community-Acquired Pneumonia Diagnosis Following Emergency Department Visits for Respiratory Illness.

Community-acquired pneumonia (CAP) is often considered for children presenting to the emergency department (ED) with respiratory symptoms. It is unclear how often children are diagnosed with CAP following an ED visit for respiratory illness. We performed a retrospective case-control study to evaluate 7-day CAP diagnosis among children 3 months to 18 years discharged from the ED with respiratory illness from 2011 to 2021 and who receive care at 4 hospital-affiliated primary care clinics. Logistic regression was performed to assess for predictors of 7-day CAP diagnosis. Seventy-four (0.7%, 95% confidence interval [CI] = 0.6%, 0.9%) of 10 329 children were diagnosed with CAP within 7 days, and fever at the index visit was associated with increased odds of diagnosis (odds ratio [OR] = 3.32, 95% CI = 1.75-6.28). Community-acquired pneumonia diagnosis after discharge from the ED with respiratory illness is rare, even among children who are febrile at time of initial evaluation.

The pluripotency factor NANOG contributes to mesenchymal plasticity and is predictive for outcome in esophageal adenocarcinoma.

BACKGROUND: Despite the advent of neoadjuvant chemoradiotherapy (CRT), overall survival rates of esophageal adenocarcinoma (EAC) remain low. A readily induced mesenchymal transition of EAC cells contributes to resistance to CRT. METHODS: In this study, we aimed to chart the heterogeneity in cell state transition after CRT and to identify its underpinnings. A panel of 12 esophageal cultures were treated with CRT and ranked by their relative epithelial-mesenchymal plasticity. RNA-sequencing was performed on 100 pre-treatment biopsies. After RNA-sequencing, Ridge regression analysis was applied to correlate gene expression to ranked plasticity, and models were developed to predict mesenchymal transitions in patients. Plasticity score predictions of the three highest significant predictive models were projected on the pre-treatment biopsies and related to clinical outcome data. Motif enrichment analysis of the genes associated with all three models was performed. RESULTS: This study reveals NANOG as the key associated transcription factor predicting mesenchymal plasticity in EAC. Expression of NANOG in pre-treatment biopsies is highly associated with poor response to neoadjuvant chemoradiation, the occurrence of recurrences, and median overall survival difference in EAC patients (>48 months). Perturbation of NANOG reduces plasticity and resensitizes cell lines, organoid cultures, and patient-derived in vivo grafts. CONCLUSIONS: In conclusion, NANOG is a key transcription factor in mesenchymal plasticity in EAC and a promising predictive marker for outcome.

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Although chemotherapy combined with radiotherapy (chemoradiotherapy) followed by surgery has improved survival, tumor recurrence and metastatic disease (that has spread to other parts of the body) are often observed after several months. In this study, we assessed the effect of chemoradiotherapy on esophageal cells in the lab to predict the effect in patients with esophageal cancer. To investigate this, genes were assessed from 12 different cell lines and 100 patient tissues. We revealed that levels of one of the genes, NANOG, associates with poor response in patients. NANOG could be a promising marker to predict outcome in patients with esophageal cancer. This knowledge might help clinicians to treat patients with esophageal cancer appropriately, or may lead to new or optimized treatments.