Human liver afferent and efferent nerves revealed by 3-D/Airyscan super-resolution imaging.

Neural regulation of hepatic metabolism has long been recognized. However, the detailed afferent and efferent innervation of the human liver has not been systematically characterized. This is largely due to the liver's high lipid and pigment contents, causing false-negative (light scattering and absorption) and false-positive (autofluorescence) results in in-depth fluorescence imaging. Here, to avoid the artifacts in three-dimensional (3-D) liver neurohistology, we embed the bleached human liver in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution imaging. Importantly, using the paired substance P (SP, sensory marker) and PGP9.5 (pan-neuronal marker) labeling, we detect the sensory nerves in the portal space, featuring the SP+ varicosities in the PGP9.5+ nerve bundles/fibers, confirming the afferent liver innervation. Also, using the tyrosine hydroxylase (TH, sympathetic marker) labeling, we identify 1) condensed TH+ sympathetic nerves in the portal space, 2) extension of sympathetic nerves from the portal to the intralobular space, in which the TH+ nerve density is 2.6 ± 0.7-fold higher than that of the intralobular space in the human pancreas, and 3) the TH+ nerve fibers and varicosities contacting the ballooning cells, implicating potential sympathetic influence on hepatocytes with macrovesicular fatty change. Finally, using the vesicular acetylcholine transporter (VAChT, parasympathetic marker), PGP9.5, and CK19 (epithelial marker) labeling with panoramic-to-Airyscan super-resolution imaging, we detect and confirm the parasympathetic innervation of the septal bile duct. Overall, our labeling and 3-D/Airyscan imaging approach reveal the hepatic sensory (afferent) and sympathetic and parasympathetic (efferent) innervation, establishing a clinically related setting for high-resolution 3-D liver neurohistology.NEW & NOTEWORTHY We embed the human liver (vs. pancreas, positive control) in the high-refractive-index polymer for tissue clearing and antifade 3-D/Airyscan super-resolution neurohistology. The pancreas-liver comparison reveals: 1) sensory nerves in the hepatoportal space; 2) intralobular sympathetic innervation, including the nerve fibers and varicosities contacting the ballooning hepatocytes; and 3) parasympathetic innervation of the septal bile duct. Our results highlight the sensitivity and resolving power of 3-D/Airyscan super-resolution imaging in human liver neurohistology.

Barriers to engagement in the care cascade for tuberculosis disease in India: A systematic review of quantitative studies.

BACKGROUND: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease in India. METHODS AND FINDINGS: We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. CONCLUSIONS: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps-particularly regarding TB care for children or in the private sector-to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade.

Association of Egg Intake With Alzheimer's Dementia Risk in Older Adults: The Rush Memory and Aging Project.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with increasing prevalence due to population aging. Eggs provide many nutrients important for brain health, including choline, omega-3 fatty acids, and lutein. Emerging evidence suggests that frequent egg consumption may improve cognitive performance on verbal tests, but whether consumption influences the risk of Alzheimer's dementia and AD is unknown. OBJECTIVES: To examine the association of egg consumption with Alzheimer's dementia risk among the Rush Memory and Aging Project cohort. METHODS: Dietary assessment was collected using a modified Harvard semiquantitative food frequency questionnaire. Participants' first food frequency questionnaire was used as the baseline measure of egg consumption. Multivariable adjusted Cox proportional hazards regression models were used to investigate the associations of baseline egg consumption amount with Alzheimer's dementia risk, adjusting for potential confounding factors. Subgroup analyses using Cox and logistic regression models were performed to investigate the associations with AD pathology in the brain. Mediation analysis was conducted to examine the mediation effect of dietary choline in the relationship between egg intake and incident Alzheimer's dementia. RESULTS: This study included 1024 older adults {mean [±standard deviation (SD)] age = 81.38 ± 7.20 y}. Over a mean (±SD) follow-up of 6.7 ± 4.8 y, 280 participants (27.3%) were clinically diagnosed with Alzheimer's dementia. Weekly consumption of >1 egg/wk (hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.34, 0.83) and ≥2 eggs/wk (HR: 0.53; 95% CI: 0.35, 0.81) was associated with a decreased risk of Alzheimer's dementia. Subgroup analysis of brain autopsies from 578 deceased participants showed that intakes of >1 egg/wk (HR: 0.51; 95% CI: 0.35, 0.76) and ≥2 eggs/wk (HR: 0.62; 95% CI: 0.44, 0.90) were associated with a lower risk of AD pathology in the brain. Mediation analysis showed that 39% of the total effect of egg intake on incident Alzheimer's dementia was mediated through dietary choline. CONCLUSIONS: These findings suggest that frequent egg consumption is associated with a lower risk of Alzheimer's dementia and AD pathology, and the association with Alzheimer's dementia is partially mediated through dietary choline.

Defining "low-carb" in the scientific literature: A scoping review of clinical studies.

There remains a lack of scientific consensus on what level of carbohydrate intake constitutes low-carbohydrate diets. We conducted a scoping review to understand how low-carbohydrate diets were defined in the peer-reviewed literature. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement scoping review extension. Three electronic databases were searched for clinical studies in English. We identified 508 articles (317 randomized controlled, 99 cross-over, 33 before-and-after, 12 non-randomized, and 47 other clinical trials). Most examined effects of low-carbohydrate diets in healthy adults (62.4%), 40 to 59 years old (55.5%), with obesity or overweight (66.1%). The majority reported effects on weight or body composition (29.9%), diabetes (18.7%), or cardiovascular risk factors (12.9%) as primary outcomes. Most articles (56.9%) reported percent of energy from carbohydrates, and of those, 60.3% defined low-carbohydrate diets as being ≤30% of energy from carbohydrates. Some articles (22.9%) reported grams of carbohydrates per day, and of those, most defined low-carbohydrate diets as being under ∼100 grams of carbohydrates per day. Systematic reviews and dose-response meta-regressions utilizing patient-level data on carbohydrate intake, status markers (e.g., RQ/ketones), and health outcomes would be useful in informing consensus around a standardized definition.

The longitudinal association between caregivers' perceived competence and autonomy and children's dietary consumption before and 10 months into the COVID-19 pandemic.

The COVID-19 pandemic has been stressful, potentially affecting caregivers' feeding choices. Caregivers play a role in shaping children's diets, yet few studies have explored how their competence and autonomy, defined by the Self-Determination Theory, impact children's diets. We examined the relationship between caregivers' autonomy and competence and their feeding practices before and during the first year of the pandemic. A national convenience sample of caregivers with 3-12-year-old children completed an online survey during two time-periods. Questions adapted from the Intrinsic Motivation Inventory measured perceived competence and autonomy for feeding fruits and vegetables (F/V) and limiting sugar-sweetened beverages (SSBs) and desserts. National Health and Nutrition Examination Survey Dietary Screener questions measured children's consumption of F/V, SSBs, and desserts. Paired t-tests examined how child consumption and caregiver's perceived competence and autonomy changed, and logistic regressions examined whether caregivers' competence and autonomy predicted the change in child consumption and if changes in competence and autonomy were associated with changes in child consumption. Caregivers (n = 597) were mostly Black/African American (33.0%) or Latina/o/x (42.7%) and older than 30 years (84.1%). Children's consumption did not change overall, but caregivers' competence for feeding F/V increased, and their competence for limiting SSBs and desserts decreased. Caregiver competence and autonomy before COVID-19 did not predict child dietary consumption during the pandemic. However, change in competence was a significant predictor of the change in child consumption of F/V [OR (95%CI): 0.70 (0.57, 0.86)]. The association between caregiver's perceived competence for feeding F/V and child consumption remained positive and significant in both periods [OR (95%CI) pre and during COVID: 2.09 (1.69, 2.57) - 2.40 (1.88, 3.06)]. This study can inform behavioral interventions supporting caregivers' competence and autonomy around feeding choices.

The Role of Dietary Acid Load on Progression of Estimated Glomerular Filtration Rate Among Individuals Diagnosed With Chronic Kidney Disease.

OBJECTIVE: Individuals with chronic kidney disease (CKD) are at an increased risk for developing metabolic acidosis. Metabolic acidosis has been shown to worsen kidney function and exacerbate systemic inflammation. Diets high in protein foods can exacerbate metabolic acidosis as protein foods tend to be more acidic, while fruits and vegetables are more alkalotic. The main objective of this systematic review was to determine if higher consumption of fruits and vegetables in adults with CKD stages 1-5 reduces the rate of decline of estimated glomerular filtration rate. METHODS: Searches of Cumulated Index to Nursing and Allied Health Literature (CINAHL -Elton B. Stephens Company [EBSCO]), Cochrane Library (Wiley), Dissertation & Thesis Global (ProQuest), Embase (Elsevier), Medline (OVID), PubMed (National Library of Medicine), Scopus (Elsevier), and Web of Sciences (Clarivate) identified 1,451 articles published between January 2015 and June 2023. RESULTS: After independent review, 7 total studies were included. Six of the studies found an association between dietary acid load and progression of CKD. CONCLUSIONS: Dietary counseling focusing on decreasing dietary acid load may be beneficial for individuals with CKD.

Association Between Surgical Opioid Prescriptions and Opioid Initiation by Opioid-naïve Spouses.

OBJECTIVE: To determine whether surgical opioid prescriptions are associated with increased risk of opioid initiation by operative patients' spouses. SUMMARY OF BACKGROUND DATA: Adverse effects of surgical opioids on operative patients have been well described. Whether risks of surgical opioids extend to operative patients' family members is unknown. METHODS: This was a retrospective cohort study of opioid-naïve, married patients undergoing 1 of 11 common surgeries from January 1, 2011 to June 30, 2017. The adjusted association between surgical opioid prescriptions and opioid initiation by the operative patient's spouse in the 6-months after surgery was assessed. Secondary analyses assessed how this association varied with postoperative time. RESULTS: There were 318,022 patients (mean ± standard deviation age 48.8 ±9.3 years; 49.5% women). Among the 50,833 (16.0%) patients that did not fill a surgical opioid prescription, 2152 (4.2%) had spouses who filled an opioid prescription within 6-months of their surgery. In comparison, among the 267,189 (84.0%) patients who filled a surgical opioid prescription, 15,026 (5.6%) had spouses who filled opioid prescriptions within 6-months of their surgery [unadjusted P < 0.001; adjusted odds ratio (aOR) 1.37, 95% confidence interval (CI) 1.31-1.43, P < 0.001]. Associated risks were only mildly elevated in postoperative month 1 (aOR 1.11, 95% CI 1.00-1.23, P = 0.04) before increasing to a peak in postoperative month 3 (aOR 1.57,95% CI 1.391.76, P < 0.001). CONCLUSIONS: Surgical opioid prescriptions were associated with increased risk of opioid initiation by spouses of operative patients, suggesting that risks associated with surgical opioids may extend beyond the surgical patient. These findings may highlight the importance of preoperative counseling on safe opioid use, storage, and disposal for both patients and their partners.

Systematic Review and Meta-Analysis to Estimate a Reference Range for Circulating Ionized Magnesium Concentrations in Adult Populations.

BACKGROUND: There is a lack of consensus on a reference range for ionized magnesium (iMg2+) in blood as a measure of the status of circulating iMg2+ for the screening of populations. OBJECTIVES: We estimated the reference range of iMg2+ levels for healthy adult populations and the ranges for populations with cardiovascular disease (CVD), type 2 diabetes, hypertension, and renal disease. We also estimated 95% ranges for circulating magnesium (Mg) in healthy and those with cardiometabolic diseases. METHODS: We searched Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Embase through 24 July, 2020 to identify articles. We included English, peer-reviewed, randomized controlled trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies that measured iMg2+ in blood or circulating Mg at baseline. The protocol was registered on PROSPERO (CRD42020216100). Estimated ranges were calculated by employing a frequentist random-effects model using extracted (or calculated) means and SDs from each included study. We determined the 95% confidence interval of the pooled mean. RESULTS: A total of 95 articles were included with 53 studies having data for healthy participants and 42 studies having data for participants with cardiometabolic diseases. The estimated reference range for iMg2+ for healthy populations was 0.40-0.68 mmol/L, 0.38-0.64 mmol/L for CVD, 0.34-0.66 mmol/L for type 2 diabetes, 0.39-1.04 mmol/L for hypertension, and 0.40-0.76 mmol/L for renal disease. For circulating Mg, the estimated range was 0.72-1.0 mmol/L for healthy adults, 0.56-1.05 mmol/L for CVD, 0.58-1.14 mmol/L for type 2 diabetes, 0.60-1.08 mmol/L for hypertension, and 0.59-1.26 mmol/L for renal disease. CONCLUSIONS: Estimated reference ranges for cardiometabolic disease states for both iMg2+ and circulating Mg were broad and overlapped with the estimated range for healthy populations (0.40-0.68 mmol/L). Further studies should evaluate whether iMg2+ can be used as a biomarker of cardiometabolic disease.

Neurally adjusted ventilatory assist for rapid weaning in preterm infants.

BACKGROUND: Neurally adjusted ventilatory assist (NAVA) is a new mode of subject-triggered ventilation. Experience with the use of NAVA in preterm infants is limited. This study compared the effects of invasive mechanical ventilation with NAVA to conventional intermittent mandatory ventilation (CIMV) in terms of reducing the duration of oxygen requirement and invasive ventilator support in preterm infants. METHODS: This was a prospective study. We enrolled infants of less than 32 weeks' gestation who were then randomized to receive either NAVA or CIMV support during hospitalization. We recorded and analyzed data on the maternal history during pregnancy, use of medications, neonatal data at admission, neonatal diseases, and respiratory support in the neonatal intensive care unit. RESULTS: There were 26 preterm infants in the NAVA group and 27 preterm infants in the CIMV group. Significantly fewer infants in the NAVA group received supplemental oxygen at 28 days of age (12 [46%] vs. 21 [78%], p = 0.0365), and they required significantly fewer days of invasive ventilator support: 7.73 (± 2.39) vs. 17.26 (± 3.65), p = 0.0343. CONCLUSIONS: Compared with CIMV, NAVA appears to allow for more rapid weaning from invasive ventilation and decreases the incidence of bronchopulmonary dysplasia, especially in preterm infants with severe respiratory distress syndrome treated with surfactants.

Multimodal 3-D/2-D human islet and duct imaging in exocrine and endocrine lesion environment: associated pancreas tissue remodeling.

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC (n = 10, distal) and cadaveric donor pancreases (n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment.NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.

Estimating excess septicaemia mortality and hospitalisation burden associated with influenza in Hong Kong, 1998 to 2019.

Influenza virus infections can lead to a number of secondary complications, including sepsis. We applied linear regression models to mortality and hospital admission data coded for septicaemia from 1998 to 2019 in Hong Kong, and estimated that septicaemia was associated with an annual average excess mortality rate of 0.23 (95% CI 0.04-0.40) per 100 000 persons per year and an excess septicaemia hospitalisation rate of 1.73 (95% CI 0.94-2.50) per 100 000 persons per year. The highest excess morbidity and mortality was found in older adults and young children, and during influenza A(H3N2) epidemics.

Snacking among shiftwork nurses related to non-optimal dietary intake.

AIMS: To compare nurses' non-optimal eating behaviours across different shifts, to examine whether non-day shifts were related to deviation from optimal dietary behaviours compared with day shifts and whether such deviation was related to non-optimal macronutrient intake. DESIGN: This is a 4-day intensive longitudinal study. METHODS: A convenience sample of hospital nurses was recruited in Taiwan. From September 2018 through January 2019, 120 participants completed 4-days of 24-h dietary recalls. One-way ANOVA and Kruskal-Wallis H test were used to compare differences in energy and macronutrient intake and frequency of meals and snacking, respectively. Generalized linear regressions examined (1) the associations between shiftwork schedules and non-optimal eating behaviours and (2) associations between non-optimal eating and high energy contribution of non-optimal macronutrients. RESULTS: Nurses consumed less energy on evening and night shifts compared with day shifts. However, energy intake from snacking was higher on evening and night shifts relative to day shifts. Nurses consumed less meals but had higher snacking frequency on non-day shifts. In addition, high energy intake from snacking was positively associated with high energy intake from saturated fat. CONCLUSIONS: Nurses were more likely to have non-optimal eating behaviours on non-day shifts, which may contribute to an increased intake of saturated fat; thus, increasing their risk of chronic diseases. Strategies to improve non-day shift nurses' non-optimal eating behaviours may be beneficial to their health. IMPACT: Shiftwork is known to affect nurses' eating behaviours; however, which shift is associated with unhealthy eating remains inconclusive. Despite lower energy intakes, nurses had higher intake by snacking on evening and night shifts. High snacking intake was associated with a high intake of saturated fat. Hospitals can increase the availability of healthy foods on evening or night shifts, which may improve non-day shift nurses' non-optimal eating behaviours.

A Room-Temperature Surface Acoustic Wave Ammonia Sensor Based on rGO/DPP2T-TT Composite Films.

Surface acoustic wave (SAW) sensors based on reduced graphene oxide/poly (diketopyrrolopyrrolethiophene-thieno [3,2-b]thiophene-thiophene) (rGO/DPP2T-TT) composite sensing films for the detection of ammonia were investigated at room temperature in this study. The rGO/DPP2T-TT composite films were deposited onto ST-X quartz SAW resonators by a drop-casting method. FESEM, EDS, and XRD characterizations showed that the rGO/DPP2T-TT composite film was successfully synthesized and exhibited numerous wrinkles and a rough structure, which are crucial for gas adsorption. The frequency response to 500-1400 ppb ammonia shown by the prepared SAW sensor coated with rGO/DPP2T-TT composite film increased linearly as the ammonia concentration increased. The sensor based on a rGO/DPP2T-TT composite film exhibited a positive frequency shift of 55 Hz/ppm, and its frequency response to 500 ppb ammonia was 35 Hz. The sensors thus show promising potential in detecting sub-ppm concentration levels of NH3 at room temperature, which opens up possibilities for applications in the noninvasive detection of NH3 in the breath. As a result, the rGO/DPP2T-TT composite sensor can be a good candidate for in situ medical diagnosis and indoor/outdoor environment monitoring.

Local islet remodelling associated with duct lesion-islet complex in adult human pancreas.

AIMS/HYPOTHESIS: Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)-islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN-islet complex. METHODS: Cadaveric donor pancreases (26-65 years old, n = 10) were fixed and sectioned (350 µm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. RESULTS: In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion-islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion-islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct-islet cell contacts, forming a cluster. The duct-islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. CONCLUSIONS/INTERPRETATION: We identify local islet remodelling associated with PanIN-islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN-islet complex is derived from tissue repair after a local injury.

Heterogeneity and neurovascular integration of intraportally transplanted islets revealed by 3-D mouse liver histology.

Intraportal islet transplantation has been clinically applied for treatment of unstable type 1 diabetes. However, in the liver, systematic assessment of the dispersed islet grafts and the graft-hepatic integration remains difficult, even in animal models. This is due to the lack of global and in-depth analyses of the transplanted islets and their microenvironment. Here, we apply three-dimensional (3-D) mouse liver histology to investigate the islet graft microstructure, vasculature, and innervation. Streptozotocin-induced diabetic mice were used in syngeneic intraportal islet transplantation to achieve euglycemia. Optically cleared livers were prepared to enable 3-D morphological and quantitative analyses of the engrafted islets. 3-D image data reveal the clot- and plaque-like islet grafts in the liver: the former are derived from islet emboli and associated with ischemia, whereas the latter (minority) resemble the plaques on the walls of portal vessels (e.g., at the bifurcation) with mild, if any, perigraft tissue damage. Three weeks after transplantation, both types of grafts are revascularized, yet significantly more lymphatics are associated with the plaque- than clot-like grafts. Regarding the islet reinnervation, both types of grafts connect to the periportal nerve plexus and develop peri- and intragraft innervation. Specifically, the sympathetic axons and varicosities contact the α-cells, highlighting the graft-host neural integration. We present the heterogeneity of the intraportally transplanted islets and the graft-host neurovascular integration in mice. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue and cellular analyses of human islet grafts in the liver.NEW & NOTEWORTHY Modern 3-D histology identifies the clot- and plaque-like islet grafts in the mouse liver, which otherwise cannot be distinguished with the standard microtome-based histology. The two types of grafts are similar in blood microvessel density and sympathetic reinnervation. Their differences, however, are their locations, severity of associated liver injury, and access to lymphatic vessels. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue/cellular analyses of human islet grafts in the liver.

Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation.

The bone morphogenetic protein (BMP) signaling pathway, including antagonists, functions in lung development and regeneration of tracheal epithelium from basal stem cells. Here, we explore its role in the alveolar region, where type 2 epithelial cells (AT2s) and Pdgfrα+ type 2-associated stromal cells (TASCs) are components of the stem cell niche. We use organoids and in vivo alveolar regrowth after pneumonectomy (PNX) - a process that requires proliferation of AT2s and differentiation into type 1 cells (AT1s). BMP signaling is active in AT2s and TASCs, transiently declines post-PNX in association with upregulation of antagonists, and is restored during differentiation of AT2s to AT1s. In organoids, BMP4 inhibits AT2 proliferation, whereas antagonists (follistatin, noggin) promote AT2 self-renewal at the expense of differentiation. Gain- and loss-of-function genetic manipulation reveals that reduced BMP signaling in AT2s after PNX allows self-renewal but reduces differentiation; conversely, increased BMP signaling promotes AT1 formation. Constitutive BMP signaling in Pdgfrα+ cells reduces their AT2 support function, both after PNX and in organoid culture. Our data reveal multiple cell-type-specific roles for BMP signaling during alveolar regeneration.

Local treatment for triple-negative breast cancer patients undergoing chemotherapy: breast-conserving surgery or total mastectomy?

BACKGROUND: Because there is no exact therapeutic target, the systemic treatment of triple-negative breast cancer (TNBC) still relies on chemotherapy. In terms of local treatment, based on the highly malignant characteristics of TNBC, it is still uncertain whether patients should be given more aggressive local treatment. METHODS: This study was based on the SEER database. 13,262 TNBC patients undergoing chemotherapy were included. According to local treatment methods, patients were divided into breast-conserving surgery with radiotherapy (BCS + RT), total mastectomy alone and total mastectomy with radiotherapy (Mastectomy+RT). Kaplan-Meier survival analysis drew the survival curves of Overall Survival (OS) and Breast Cancer Specific Survival (BCSS), and Cox proportional risk regression models were used to analyze the impact of different local treatments on OS and BCSS. RESULTS: After adjusting confounding factors, Mastectomy alone group (HR = 1.57; 95%CI: 1.40-1.77) and Mastectomy+RT group (HR = 1.28; 95%CI: 1.12-1.46) were worse in OS than BCS + RT group, and Mastectomy+RT group (HR = 0.81; 95%CI: 0.73-0.91) was better in OS than Mastectomy alone group. The effect of local treatment for BCSS was similar to that of OS. After stratification according to age, tumor size and lymph node status, when the age was less than 55 years old, at T4, N2 or N3 category, there was no statistical significance between the BCS + RT group and the Mastectomy+RT group in OS or BCSS (all P > 0.05). When the age was less than 65 years old, at T1, T2 or N0 category, there was no statistical significance between the Mastectomy alone group and the Mastectomy+RT group in OS or BCSS (all P > 0.05). The results of other stratified analyses were basically consistent with the results of total population analysis. CONCLUSION: The survival benefit of breast-conserving surgery with radiotherapy was higher than or similar to that of total mastectomy TNBC patients.

Knowledge Translation and WIC Food Package Regulation Change.

OBJECTIVE: Knowledge Translation (KT) is the exchange, synthesis, and ethically-sound application of knowledge. A case study methodology is used to examine KT at the organizational level of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program. METHOD: The study used purposeful sampling to select WIC informants from state WIC agencies to participate in semi-structured interviews about their individual experiences during the 2009 WIC regulation change process. Thematic coding of retrospective semi-structured interviews with key informants from WIC state agencies revealed key components of the state-level WIC regulation implementation process, and key constructs of Organizational Readiness for Knowledge Translation in the WIC program. RESULTS: WIC informants highlight that decisions made by WIC state agencies regarding how to appraise, synthesize, and adapt evidence or regulation change are constrained by the KT decisions made by federal agencies. WIC state agencies should assess their level of readiness for KT in terms of 1) innovation readiness; 2) personal readiness; and 3) institutional readiness. CONCLUSIONS: This WIC case study can help decision-makers to understand the KT process of implementing evidence-informed regulation changes, identify factors that could influence states' ability to be prepared for implementing changes, and gauge "practicality" of future WIC regulation changes.

Vitamin D and Calcium in Children 0-36 Months: A Scoping Review of Health Outcomes.

METHODS: Updated literature searches were conducted across 5 electronic databases to identify all randomized controlled trials, cohort studies, nested case-control or case-cohort studies, and systematic reviews published after the 2009 U.S. Agency for Healthcare Research and Quality's (AHRQ) evidence report, Vitamin D and Calcium: a Systematic Review of Health Outcomes. In total, 65 studies were summarized and analyzed in the present review. RESULTS: There was a steady increasing trend in the number of publications reporting outcomes related to skeletal health, growth, and infectious disease from 2008 to 2019, although the number of published vitamin D studies was much larger than calcium studies. CONCLUSIONS: The data presented in this review can facilitate assessment of the variety of outcomes and the amount of potentially useful literature available for each outcome. The results of this scoping review can be used to guide the undertaking of the subsequent systematic reviews.

Knowledge and Perceptions of Carbohydrates among Nutrition-Major and Nutrition-Elective Undergraduate Students in Canada.

Objective: The purpose of the study was to assess knowledge and perceptions related to carbohydrates, including sugars, among Canadian nutrition-major undergraduates compared to those enrolled in elective nutrition courses (i.e., "nutrition-elective students").Methods: Cross-sectional surveys were distributed during class time at eight Canadian universities, which included 32 questions on demographics, knowledge and perceptions of carbohydrates and sugars. Descriptive analyses were performed. Differences between groups were tested by Chi-squared statistics.Results: A total of 1207 students (60% nutrition-majors) participated in the survey (January 2016-February 2017). Internet-based sources accounted for one-third of the sources where students obtained nutrition information. About 61% of internet-bases sources were "online" or "website" with no qualifiers, and about a quarter was from social media. A higher percentage of nutrition-majors correctly answered knowledge questions of carbohydrates compared with nutrition-elective students (p < 0.01); no difference was observed for sugars-related knowledge questions. The perceptions of sugars were generally negative and did not differ between groups.Conclusions: Several knowledge gaps and common perceptions on topics related to carbohydrates and sugars were identified; nutrition-major students performed better than nutrition-elective students on carbohydrate knowledge questions, but not sugars. These results highlight the importance of identifying methods to help students bridge knowledge gaps and develop skills to critically evaluate nutrition information from various resources and challenge personal biases.