Pla2g5 contributes to viral-like-induced lung inflammation through macrophage proliferation and LA/Ffar1 lung cell recruitment.

Macrophages expressing group V phospholipase A2 (Pla2g5) release the free fatty acid (FFA) linoleic acid (LA), potentiating lung type 2 inflammation. Although Pla2g5 and LA increase in viral infections, their role remains obscure. We generated Pla2g5flox/flox mice, deleted Pla2g5 by using the Cx3cr1cre transgene, and activated bone marrow-derived macrophages (BM-Macs) with poly:IC, a synthetic double-stranded RNA that triggers a viral-like immune response, known Pla2g5-dependent stimuli (IL-4, LPS + IFNγ, IL-33 + IL-4 + GM-CSF) and poly:IC + LA followed by lipidomic and transcriptomic analysis. Poly:IC-activated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs had downregulation of major bioactive lipids and critical enzymes producing those bioactive lipids. In addition, AKT phosphorylation was lower in poly:IC-stimulated Pla2g5flox/flox;Cx3cr1cre/+ BM-Macs, which was not restored by adding LA to poly:IC-stimulated BM-Macs. Consistently, Pla2g5flox/flox;Cx3cr1cre/+ mice had diminished poly:IC-induced lung inflammation, including inflammatory macrophage proliferation, while challenging Pla2g5flox/flox;Cx3cr1cre/+ mice with poly:IC + LA partially restored lung inflammation and inflammatory macrophage proliferation. Finally, mice lacking FFA receptor-1 (Ffar1)-null mice had reduced poly:IC-induced lung cell recruitment and tissue macrophage proliferation, not corrected by LA. Thus, Pla2g5 contributes to poly:IC-induced lung inflammation by regulating inflammatory macrophage proliferation and LA/Ffar1-mediated lung cell recruitment and tissue macrophage proliferation.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

Microglial proliferation and astrocytic protein alterations in the human Huntington's disease cortex.

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.

BACKGROUND & AIMS: At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. METHODS: Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179. RESULTS: Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). CONCLUSIONS: In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate.

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate. Video Abstract.

Clinical impact of whole-body MRI in staging and surveillance of patients with myxoid liposarcoma: a 14-year single-centre retrospective study.

OBJECTIVE: To assess the clinical impact of regular whole-body magnetic resonance imaging (WBMRI) surveillance in myxoid liposarcoma patients. METHODS: This was a retrospective cohort study of myxoid liposarcoma patients who underwent at least one WBMRI at our institution between October 2006 and December 2020. The effect of WBMRI on clinical management, namely treatment modification or additional diagnostic investigations was studied. A standardised WBMRI surveillance protocol was instituted in 2015. We compared patient outcomes for the metastatic patients who had and had not received regular WBMRI surveillance and performed survival analysis for both subgroups. RESULTS: Of the 56 patients (60.7% male, median age: 48.1 years) who underwent 345 WBMRI, 17 (30.3%) had metastases, and 168 WBMRI were performed in this group. The median imaging follow-up for the entire cohort was 35 months; the metastatic group had a median follow-up of 42 months. WBMRI changed the clinical management in 13 (76.5%) metastatic patients, with 33 instances of treatment modification. Thirty-five lesions were labelled 'indeterminate,' 16 (45.7%) had additional investigations/interventions, and 4 (11.4%) were confirmed to be metastatic. Twenty-one metastatic lesions were missed initially on WBMRI and confirmed on subsequent WBMRI, of which 5 (23.8%) were clinically significant. The 5-year survival since the detection of metastasis was better in the regular surveillance subgroup (85.7% vs. 45%), but this was not statistically significant (p = 0.068). Five patients (8.9%) developed their first metastasis more than 5 years after diagnosing the primary lesion. CONCLUSION: Regular WBMRI surveillance of myxoid liposarcoma patients considerably impacts clinical management by frequently influencing treatment decisions. CLINICAL RELEVANCE STATEMENT: WBMRI has been recently recommended as an imaging option for the staging and surveillance of myxoid liposarcoma patients. Our study highlights the impact of regular WBMRI surveillance on the clinical management of these patients and how it affects their survival.

Sex differences in clinical risk factors in obese ischemic stroke patients with a history of smoking.

Clinical risk factors associated obesity and smoking, as well as their combined effect, are not fully understood. This study aims to determine sex differences in risk factors in a population of acute ischemic stroke (AIS) patients who are obese and with a history of previous or current smoking. METHODS: A retrospective analysis of risk factors in male and female AIS patients with baseline data of obesity and current or previous history of smoking, smoking, and obesity alone was determined. The primary predictor and outcome are risk factors associated with male and female AIS patients. Baseline risk factors were analyzed using a multivariate regression analysis to determine specific risk factors linked with the combined effect of obesity and current or previous history of smoking''. RESULTS: Male obese AIS patients who are current or previous smokers were more likely to be older patients(OR = 1.024, 95% CI, 1.022-1.047, P = 0.033) that present with coronary artery disease (OR = 1.806, 95% CI, 1.028-3.174, P = 0.040), a history of alcohol use (OR = 2.873, 95% CI, 1.349-6.166, P = 0.006), elevated serum creatinine (OR = 4.724, 95% CI, 2.171-10.281, P < 0.001) and systolic blood pressure (OR = 1.029, 95% CI, 1.011-1.047, P < 0.002). Females were more associated with depression (OR = 0.432, 95% CI, 0.244-0.764, P = 0.004), previous TIA (OR = 0.319, 95% CI, 0.142-0.714, P < 0.005), and higher levels of HDL (OR = 0.938, 95% CI, 0.915-0.962, P < 0.001). CONCLUSION: Our results reveal sex differences in risk factors in obese AIS patients with a current or past history of smoking. This finding emphasizes the need to develop management strategies to improve the care of obese AIS patients who are either current or former smokers.

A Qualitative Investigation of the Experiences of Women with Perinatal Depression and Anxiety during the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic has had significant impacts on maternal mental health. We explored the lived experiences of women with perinatal depression and anxiety to elucidate their perceptions of how the pandemic influenced their mental health and access to care. METHODS: We conducted a qualitative descriptive study using semi-structured interviews. From March to October 2021, purposive sampling was used to recruit a socio-demographically diverse sample of women with self-reported perinatal depression or anxiety who were pregnant or within one year postpartum between March 2020 and October 2021. Interviews were conducted remotely and thematically analyzed. RESULTS: Fourteen women were interviewed. Three major themes arose. Theme 1, Negative impacts of COVID-19 on symptoms of depression and anxiety, described how the pandemic magnified underlying symptoms of depression and anxiety, increased social isolation, generated anxiety due to fears of COVID-19 infection, and caused economic stress. In theme 2, Negative impacts of COVID-19 on access to and quality of health care, women described stressful and isolating delivery experiences, negative psychological impact of partners not being able to participate in their perinatal health care, interruptions and barriers to mental health treatment, and challenges in using telehealth services for mental health care. Theme 3, Positive impacts of COVID-19 on mental health, identified advantages of increased telehealth access and ability to work and study from home. CONCLUSIONS FOR PRACTICE: The COVID-19 pandemic negatively affected women with perinatal depression and anxiety by magnifying underlying symptoms, increasing stress and social isolation, and disrupting access to mental health care. Findings provide support for policies and interventions to prevent and address social isolation, as well as optimization of telehealth services to prevent and address gaps in perinatal mental health treatment.

Editorial Commentary: Cadaveric Biomechanical Orthopaedic Research Is Essential and Requires Quality and Validity Metrics.

Evidence-based medicine is the commanding philosophy of patient care in the field of orthopaedic surgery, and analysis of clinical research is facilitated by instruments and scales developed for assessing methodologic quality and validity of conclusions. In contrast, little consideration has been given to developing metrics to assess the quality and validity of orthopaedic ex vivo and laboratory research. This is easier said than done because these studies may be heterogeneous and complex in design, and methodologic details may not be intuitive to (non-engineer) readers. The recently described Biomechanics Objective Basic Science Quality Assessment Tool (BOBQAT) represents a reliable means to assess cadaveric biomechanical studies. The BOBQAT emphasizes essential study elements including a clinically relevant, answerable purpose; detailed description of the specimens studied; thorough description of surgical technique; and careful consideration of loading conditions including clinically relevant cyclic loading. The BOBQAT provides a logical recipe for the design of future studies, a mechanism of quality assessment for systematic reviews, and a framework for readers to assess biomechanical research consistent with the ethos of evidence-based medicine.

Editorial Commentary: Bone Marrow Stimulation for Osteochondral Lesions of the Tibial Plafond Shows Generally Favorable Results.

Osteochondral lesions of the ankle are common, but only a small proportion of these lesions are found on the tibial plafond (osteochondral lesions of the tibial plafond, ie, OLTP). By and large, surgical treatment strategies for OLTP have been derived from techniques employed for those of the talus (ie, osteochondral lesion of the talus). Despite the clinical success of surgical treatments for osteochondral lesion of the talus, namely bone marrow stimulation, it is quite possible that OLTP may not respond similarly, given the unique anatomy and biomechanical properties of the tibia. To this end, the literature surrounding OLTP is relatively sparse, and studies evaluating the clinical and radiographic outcomes of treatments specific to OLTP are necessary. Still, if it works for the talus, it seems sensible that it could work for the plafond. Pending future research, there is no need to reinvent the wheel.

On legal guardianship: An exploratory assessment of knowledge, attitudes and practices of resident physicians.

BACKGROUND: Clinicians encounter patients under legal guardianship. We aimed to assess the knowledge, attitudes and practices (KAP) on legal guardianship in residents. METHODS: A KAP pilot survey about legal guardianship was developed by an interdisciplinary medicine-law-public health team and was distributed via institutional email to internal medicine, psychiatry, and neurology residents in a single academic institution. RESULTS: Of the 172 invited residents, 105 (61%) responded and 102 surveys were included in the final analysis. Most respondents (58% women; internal medicine 73%, neurology 15%, psychiatry 12%) had attended 42 medical schools from 16 countries and had heard about guardianship (88%), but only 23% reported having received training on guardianship during medical school or residency. The vast majority (97%) understood the intended benefit of guardianship, but only 22.5% reported knowing that guardianship removed an individual's decision-making rights. Nearly half (47%) of respondents reported never having asked for documentation to prove that an individual was a patient's guardian, and only 15% expected to see a court order as proof of guardianship status. CONCLUSIONS: Although most residents intuitively understood the intended benefit of guardianship, they did not understand its full implications for clinical practice. Training interventions are warranted.

Comorbidities in patients with vascular dementia and Alzheimer's disease with Neuropsychiatric symptoms.

INTRODUCTION: This study aimed to examine baseline risk factors in Alzheimer's Disease (AD) and Vascular dementia (VaD) patients with neuropsychiatry symptoms (NPS), and determine whether specific risk factors differ by subtypes of dementia for AD and VaD patients with NPS. METHODS: A retrospective data analysis was conducted to evaluate similarities and differences in the risk factors for AD and VaD with NPS. The analysis included 2949 patients with VaD and 6341 patients with clinical confirmation of AD and VaD with or without NPS collected between February 2016 and August 2021. The multivariate logistic regression analysis was used to determine the risk factors associated with AD and VaD with NPS, by predicting the increasing odds (odds ratios (ORs) of an association of a specific baseline risk factor with AD or VaD with NPS. The validity of the regression models was tested using a Hosmer-Lemeshow test, while the Receiver Operating Curve (ROC) was used to test the sensitivity of the models. RESULTS: In the adjusted analysis TSH (OR = 1.781, 95 % CI, p = 0.0025) and CHF (OR = 1.620, 95 %, p = 0.016) were associated with VaD with NPS, while a history of emergency department(ED) admission (OR = 0.277, 95 % CI, p = 0.003) likely to be associated with VaD patients without NPS. For AD patients, a history of CVA (OR = 1.395, 95 % CI, p = 0.032) and cancer (OR = 1.485, 95 % CI, p = 0.013) were associated with AD patients with NPS. DISCUSSION: The findings of this study indicate that an abnormal thyroid gland and CHF were linked to VaD patients with behavioral disturbances, while CVA and cancer were linked to AD patients with behavioral disturbances. These findings suggest the need to develop management strategies for the care of patients with AD and VaD with NPS.

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model.

OBJECTIVE: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). BACKGROUND: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. METHODS: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. RESULTS: ILC animals demonstrated a 19% greater reduction in PN calories ( P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P =0.03) and 1.9-fold higher crypt cell proliferation ( P =0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 ( P = 0.02), eicosapentaenoic acid ( P < 0.0001), docosahexaenoic acid ( P = 0.004), vitamin A ( P = 0.02), low-density lipoprotein ( P = 0.02), and high-density lipoprotein ( P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. CONCLUSIONS: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

Quantification of tumorsphere migration with a physics-based machine learning method.

Current analysis techniques available for migration assays only provide quantitative measurements for overall migration. However, the potential of regional migration analyses can open further insight into migration patterns and more avenues of experimentation with the same assays. Previously, we developed an analysis pipeline utilizing the finite element (FE) method to show its potential in analyzing glioblastoma (GBM) tumorsphere migration, especially in characterizing regional changes in the migration pattern. This study aims to streamline and further automate the analysis system by integrating the machine-learning-based U-Net segmentation with the FE method. Our U-Net-based segmentation achieved a 98% accuracy in segmenting our tumorspheres. From the segmentations, FE models made up of 3D hexahedral elements were generated, and the migration patterns of the tumorspheres were analyzed under treatments B and C (under non-disclosure agreements). Our results show that our overall migration analysis correlated very strongly (R2 of 0.9611 and 0.9986 for treatments B and C, respectively) with ImageJ's method of migration area analysis, which is the most common method of tumorsphere migration analysis. Additionally, we were able to quantitatively represent the regional migration patterns in our FE models, which the methods purely based on segmentations could not do. Moreover, the new pipeline improved the efficiency and accessibility of the initial pipeline by implementing machine learning-based automated segmentation onto a mainly open-sourced FE analysis platform. In conclusion, our algorithm enables the development of a high-content and high-throughput in vitro screening platform to elucidate anti-migratory molecules that may reduce the invasiveness of these malignant tumors.

Maximizing the impact of reach out and read literacy promotion:anticipatory guidance and modeling.

BACKGROUND: Reach Out and Read (ROR) is a multi-component pediatric literacy promotion intervention. However, few studies link ROR components to outcomes. We examine associations between receipt of (1) multiple ROR components and (2) clinician modeling, a potential best practice, with enhanced home literacy environments (EHLEs) among Latino families. METHODS: We conducted secondary analyses of cross-sectional enrollment data from a randomized clinical trial at three urban community health centers between November 2020 and June 2023. Latino parents with infants 6-<9 months old were surveyed about ROR component receipt (children's book, anticipatory guidance, modeling) and EHLE (StimQ2- Infant Read Scale). We used mixed models with clinician as a random effect, adjusting for covariates. RESULTS: 440 Latino parent-infant dyads were included. With no components as the reference category, receipt of 1 component was not associated with EHLE. Receipt of 2 components (standardized beta = 0.27; 95%CI: 0.12-0.42) and 3 components (standardized beta = 0.33; 95% CI: 0.19-0.47) were associated with EHLE. In separate analyses, modeling was associated with EHLE (standardized beta = 0.16; 95%CI: 0.06-0.26). CONCLUSION: Findings support modeling as a core ROR component. Programs seeking to enhance equity by promoting EHLE should utilize such strategies as anticipatory guidance and clinician modeling in addition to book distribution. IMPACT: Reach Out and Read, a multi-component literacy promotion intervention, leverages primary care to promote equity in children's early language experiences. However, few studies link Reach Out and Read components to outcomes. Among Latino parent-infant dyads, we found that implementation of two and three components, compared to none, was associated with enhanced home literacy environments, following a dose response pattern. Parent report of clinician modeling was associated with enhanced home literacy environments. Literacy promotion programs seeking to enhance equity by promoting enhanced home literacy environments should utilize strategies in addition to book distribution, including anticipatory guidance and modeling, to maximize impact.

Omental vascularized lymph node transplant for the treatment of breast lymphedema: A case report.

Breast lymphedema is a type of breast cancer related lymphedema that leads to significant discomfort and negative impact on body image. Conservative therapy and lymphovenous bypass have been previously described as possible treatment methods for breast lymphedema, however, a unified approach to treatment is lacking. The current report describes a case of breast lymphedema successfully treated with vascularized lymph node transfer (VLNT) after failed attempt at management with conservative therapy. The patient is a 48-year-old female with right-sided breast cancer who underwent breast conservation therapy in 2015 and subsequently developed pain and swelling of the right breast. The diagnosis of breast lymphedema was supported by clinical evaluation as well as MRI, lymphoscintigraphy, and lymphography. In consultation with a breast surgeon, breast lymphedema was determined not to be an indication for mastectomy. The patient was offered and underwent an omental VLNT to the right breast. A 20 cm segment of omentum with associated gastroepiploic vessels and lymph nodes was harvested, transferred to the right axilla and gastroepiploic vessels were anastomosed to the recipient thoracodorsal vessels. The patient tolerated the procedure well and there were no complications. Additional donor sites were considered, such as the groin and submental regions, but an omental flap was favored in this case because of the lower risk of donor site lymphedema. In the years following, the patient reported significant improvement in symptoms as well as objective reduction of edema on MRI. We propose the consideration of VLNT for breast lymphedema refractory to other methods of management.

A comparison of rapid weight loss practices within international, national and regional powerlifters.

Background: Rapid weight loss (RWL) practices are common amongst strength-sport athletes to 'make weight' for a chosen weight class. Aim: This study compared the RWL practices of International Powerlifting Federation (IPF) powerlifters from Great Britain. Methods: Participants (n = 69, male = 36, female = 33) were recruited from IPF lifting populations (mandatory <2-hour competition weigh-in). Participants were categorised based on highest level of competition (regional, national and international) and also sex (male and female). The previously validated 'Rapid Weight Loss Questionnaire' established RWL practices, however also included an open-ended question regarding thoughts, feeling and mood during RWL. Results: Nearly all participants (97%) had purposely acutely reduced body mass to compete, with an average typical pre-competition loss of 4.2%. Regional competitors reported a higher 'typical' body mass loss compared to international competitors (5.5% vs 3.3%, p = 0.004). Females reported a greater 'highest' body mass loss than males (6.7% vs 5.3%, p = 0.028). Fluid restriction (86.5%), water loading (67.2%) and increased exercise (49.2%) were the RWL methods most commonly used 'always' or 'sometimes'. Content analysis revealed a predominance of negative perceptions during RWL with the emergence of codes; fatigue, sensations, anxiety, low mood and irritation, accounting for ∼70% of responses. Conclusion: Prevalence of RWL is high amongst competitive powerlifters, with many competitors attributing negative perceptions during the weight-cutting process. The magnitude of reported acute RWL within regional lifters was beyond where performance decrements are commonly seen (>5%), this should be cautioned against given the IPF's mandatory <2-hour competition weigh-in.

Obstetric Neuropathy in Diabetic Patients: The "Double Hit Hypothesis".

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.

Rapid Weight Loss Practices Within Olympic Weightlifters.

ABSTRACT: Gee, TI, Campbell, P, Bargh, MJ, and Martin, D. Rapid weight loss practices within Olympic weightlifters. J Strength Cond Res 37(10): 2046-2051, 2023-Rapid weight loss (RWL) practices are common among athletes to "make weight" for a chosen bodyweight class. This study's purpose was to investigate RWL prevalence, magnitude, and methods within Olympic weightlifters from Great Britain. Subjects (n = 39, male = 22, female = 17) were recruited from International Weightlifting Federation lifting populations (mandatory two-hour competition weigh-in). Subjects were categorized into competitive groups based on Sinclair coefficient total (high, mid, low) and also gender (male, female). The validated Rapid Weight Loss Questionnaire was used to establish RWL magnitude and practices. Of respondents, 33 of 39 (84.6%) had purposely acutely reduced body mass to compete, a higher proportion present within females (94.1%) than males (77.3%). The cohort's mean habitual precompetition acute body mass loss was 3.8 ± 1.7% and the "rapid weight loss score" (RWLS) was 23.6 ± 9.5. Across competitive groups there were no significant differences in habitual or highest precompetition body mass loss, postcompetition body mass gain or RWLS (p > 0.05). However, females attributed a significantly greater "highest" relative precompetition body mass loss compared with males (7.4 vs 4.9%, p = 0.045). For RWL methods used, frequencies of "always" and "sometimes" were reported highest for "restricting fluid ingestion" (81.8%), "gradual dieting" (81.8%), and "water loading" (54.5%). The prevalence of RWL is high among competitive Olympic weightlifters, and especially within the sampled female athletes. Magnitude of RWL was similar across different standards of athlete; however, female lifters demonstrated a higher maximum precompetition RWL.

Autophagy blockade potentiates cancer-associated immunosuppression through programmed death ligand-1 upregulation in bladder cancer.

A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer-associated immunosuppression in BC remains undetermined. In this study, we observed a negative correlation between the autophagy-related markers LC3-II and programmed death ligand-1 (PD-L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf-A1) increased PD-L1 expression in BC cells through the ERK-JNK-c-Jun signal-transduction pathway. Moreover, the treatment of BC cells with CQ and Baf-A1 inhibited hsa-microRNA-34a (miR-34a) expression and miR-34a overexpression in BC cells prevented the autophagy blockade-induced PD-L1 expression; a negative correlation between miR-34a and PD-L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR-34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer-associated immunosuppression through PD-L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD-L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.