Splice factor polypyrimidine tract-binding protein 1 (Ptbp1) primes endothelial inflammation in atherogenic disturbed flow conditions.

NF-κB-mediated endothelial activation drives leukocyte recruitment and atherosclerosis, in part through adhesion molecules Icam1 and Vcam1. The endothelium is primed for cytokine activation of NF-κB by exposure to low and disturbed blood flow (LDF)but the molecular underpinnings are not fully understood. In an experimental in vivo model of LDF, platelets were required for the increased expression of several RNA-binding splice factors, including polypyrimidine tract binding protein (Ptbp1). This was coordinated with changes in RNA splicing in the NF-κB pathway in primed cells, leading us to examine splice factors as mediators of priming. Using Icam1 and Vcam1 induction by tumor necrosis factor (TNF)-α stimulation as a readout, we performed a CRISPR Cas9 knockout screen and identified a requirement for Ptbp1 in priming. Deletion of Ptbp1 had no effect on cell growth or response to apoptotic stimuli, but reversed LDF splicing patterns and inhibited NF-κB nuclear translocation and transcriptional activation of downstream targets, including Icam1 and Vcam1. In human coronary arteries, elevated PTBP1 correlates with expression of TNF pathway genes and plaque. In vivo, endothelial-specific deletion of Ptbp1 reduced Icam1 expression and myeloid cell infiltration at regions of LDF in atherosclerotic mice, limiting atherosclerosis. This may be mediated, in part, by allowing inclusion of a conserved alternative exon in Ripk1 leading to a reduction in Ripk1 protein. Our data show that Ptbp1, which is induced in a subset of the endothelium by platelet recruitment at regions of LDF, is required for priming of the endothelium for subsequent NF-κB activation, myeloid cell recruitment and atherosclerosis.

The Natural History of Splenic Artery Aneurysms: Factors That Predict Aneurysm Growth.

PURPOSE: To examine the natural history of splenic artery aneurysms (SAAs) at a single institution and assess the effect of patient factors and aneurysm characteristics on aneurysm growth. MATERIALS AND METHODS: This single-center retrospective study included patients with SAAs who underwent serial imaging over 30 years (1990-2020). Data regarding patient demographics and aneurysm characteristics were collected. The variables contributing to aneurysm growth were assessed using nonparametric tests for continuous variables and chi-square test for categorical variables. Multivariable linear regression was performed using aneurysm growth rate as a continuous dependent variable. RESULTS: A total of 132 patients were included in this study. The median maximum diameter of the SAAs was 15.8 mm (range, 4.0-50.0 mm). Growth over time was observed in 39% of the aneurysms, whereas the remaining 61% were stable in size. Of aneurysms that increased in size, the median aneurysm growth rate was 0.60 mm/y (range, 0.03-5.00 mm/y). Maximum aneurysm diameter of >2 cm and the presence of >50% mural thrombus were significant positive predictors for aneurysm growth (P = .020 and P = .022, respectively). Greater than 50% rim calcification was a significant negative predictor for aneurysm growth (P = .009) in multivariate analysis. CONCLUSIONS: A larger baseline SAA size, presence of mural thrombus, and lack of rim calcification are associated with increased aneurysm growth rate.

Molecular mechanisms of poor osseointegration in irradiated bone: In vivo study in a rat tibia model.

AIM: Radiotherapy is associated with cell depletion and loss of blood supply, which are linked to compromised bone healing. However, the molecular events underlying these effects at the tissue-implant interface have not been fully elucidated. This study aimed to determine the major molecular mediators associated with compromised osseointegration due to previous exposure to radiation. MATERIALS AND METHODS: Titanium implants were placed in rat tibiae with or without pre-exposure to 20 Gy irradiation. Histomorphometric, biomechanical, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses were performed at 1 and 4 weeks after implantation. RESULTS: The detrimental effects of irradiation were characterized by reduced bone-implant contact and removal torque. Furthermore, pre-exposure to radiation induced different molecular dysfunctions such as (i) increased expression of pro-inflammatory (Tnf) and osteoclastic (Ctsk) genes and decreased expression of the bone formation (Alpl) gene in implant-adherent cells; (ii) increased expression of bone formation (Alpl and Bglap) genes in peri-implant bone; and (iii) increased expression of pro-inflammatory (Tnf) and pro-fibrotic (Tgfb1) genes in peri-implant soft tissue. The serum levels of pro-inflammatory, bone formation and bone resorption proteins were greater in the irradiated rats. CONCLUSIONS: Irradiation causes the dysregulation of multiple biological activities, among which perturbed inflammation seems to play a common role in hindering osseointegration.

A Prospective, Observational Cost Comparison of Laparoscopic and Open Appendicectomy in Three Tertiary Hospitals in Nigeria.

BACKGROUND: The clinical benefits of laparoscopic appendicectomy are well recognized over open appendicectomy. However, laparoscopic procedures are not frequently conducted in many low-and middle-income countries (LMICs) for several reasons, including perceived higher costs. The aim of this study was to assess the feasibility and cost of laparoscopic appendicectomy compared to open appendicectomy in Nigeria. METHODS: A multicenter, prospective, cohort study among patients undergoing appendicectomy was conducted at three tertiary hospitals in Nigeria. Data were collected from October 2020 to February 2022 and analyses compared the average healthcare costs at 30 days after surgery. Quantile regression was conducted to identify variables that had an impact on the costs, reported in Nigerian Naira (Naira) and US dollars ($), with standard deviations (SD). FINDINGS: This study included 105 patients, of which 39 had laparoscopic appendicectomy and 66 had open appendicectomy. The average healthcare cost of laparoscopic appendicectomy (147,562 Naira (SD: 97,130) or $355 (SD: 234)) was higher than open appendicectomy (113,556 Naira (SD: 88,559) or $273 (SD: 213)). The average time for return to work was shorter with laparoscopic than open appendicectomy (mean: 8 days vs. 14 days). At the average daily income of $5.06, laparoscopic appendicectomy was associated with 9778 Naira or $24 cost savings in return to work. Further, 5.1% of laparoscopic appendicectomy patients had surgical site infections compared to 22.7% for open appendicectomy. Regression analysis results showed that laparoscopic appendicectomy was associated with $14 higher costs than open appendicectomy, albeit non-significant (p = 0.53). INTERPRETATION: Despite selection bias in this real-world study, laparoscopic appendicectomy was associated with a slightly higher overall cost, a lower societal cost, a lower infection rate, and a faster return to work, compared to open appendicectomy. It is technically and financially feasible, and its provision in Nigeria should be expanded.

In situ bone regeneration of large cranial defects using synthetic ceramic implants with a tailored composition and design.

The repair of large cranial defects with bone is a major clinical challenge that necessitates novel materials and engineering solutions. Three-dimensionally (3D) printed bioceramic (BioCer) implants consisting of additively manufactured titanium frames enveloped with CaP BioCer or titanium control implants with similar designs were implanted in the ovine skull and at s.c. sites and retrieved after 12 and 3 mo, respectively. Samples were collected for morphological, ultrastructural, and compositional analyses using histology, electron microscopy, and Raman spectroscopy. Here, we show that BioCer implants provide osteoinductive and microarchitectural cues that promote in situ bone regeneration at locations distant from existing host bone, whereas bone regeneration with inert titanium implants was confined to ingrowth from the defect boundaries. The BioCer implant promoted bone regeneration at nonosseous sites, and bone bonding to the implant was demonstrated at the ultrastructural level. BioCer transformed to carbonated apatite in vivo, and the regenerated bone displayed a molecular composition indistinguishable from that of native bone. Proof-of-principle that this approach may represent a shift from mere reconstruction to in situ regeneration was provided by a retrieved human specimen, showing that the BioCer was transformed into well-vascularized osteonal bone, with a morphology, ultrastructure, and composition similar to those of native human skull bone.

Inflammatory and differentiation cellular response to calcium silicate cements: An in vitro study.

AIM: Inflammatory-regenerative cell interaction is believed to mediate hard tissue formation. This study aimed to investigate the interaction between human inflammatory monocytes with human regenerative fibroblasts after exposure to different calcium silicate materials. METHODOLOGY: Human monocytes were cultured on three materials, polystyrene (PS), mineral trioxide aggregates (MTA) and biodentine (BD), in the presence or absence of lipopolysaccharide (LPS). Half of the monocyte-conditioned media (MoCM) of each group was used to analyse inflammatory cytokine secretion, namely TNF-α, IL-1ß, IL-1RA and IL-6. The remaining MoCM was used to culture recipient fibroblasts, measuring the cell number (proliferation) and levels of alkaline phosphatase (differentiation) and lactic acid dehydrogenase (cytotoxicity). RESULTS: In absence of LPS, MTA was associated with higher secretion of TNF-α and lower secretion of IL-1ß, while BD triggered higher secretions of both cytokines when both materials were compared to control (PS). When LPS was added, higher levels of all analysed cytokines were observed in the PS and BD groups, whereas for the MTA group, only TNF-α and IL-6 were increased. Fibroblasts responded differently to the MoCM from the different groups, revealing significant increases in proliferation and differentiation capacities, particularly when cultured in CM from monocytes exposed to MTA. The morphological evaluation revealed different patterns of fibroblast shape and spread in the different MoCM groups. CONCLUSION: Calcium silicate materials modulate the monocyte inflammatory response, which subsequently induce differential effects on the recipient fibroblasts. MTA appears to promote the secretion of prodifferentiation signals from the monocytes, which are received by fibroblasts, promoting their proliferation and differentiation. The model represents a promising tool to evaluate the interaction of different cells in response to different materials.

Inflammatory response to epoxy resin and calcium silicate sealers preheated with different temperatures: an in vivo study.

OBJECTIVE: To determine the impact of heat exposure of different sealers on inflammatory cytokine secretions and tissue response in vivo. MATERIALS AND METHODS: Silicone tubes were prefilled with epoxy resin (ER) or calcium silicate (CS) sealers, preheated at 37, 60, or 120 °C, and implanted in rat subcutaneous site. Peri-implant exudate and tissue were analyzed after 1 and 4 weeks for cytokine secretions and tissue organization. RESULTS: At 1 week, 120 °C-preheated CS and ER induced higher secretions of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), respectively, as compared to sham/empty tube groups. At 4 weeks, whereas TNF-α secretion was reduced in CS, it increased in ER group, particularly for 120 °C. Both sealers revealed high IL-6 after 4 weeks as compared to sham/empty tube, and generally, higher IL-6 secretions were associated with ER. Histology at 1 week revealed lower degree of inflammatory infiltrate in the groups of the highest preheating temperature (120 °C). Nonetheless, at 4 weeks, whereas fibrous capsule area and inflammatory infiltrate remained low in the CS120 group, they were high in ER120. CONCLUSION: Preheating ER sealer to 120 °C induced high and prolonged secretion of proinflammatory cytokines (TNF-α and IL-6), whereas this effect was transient for the CS sealer. This was associated with increased fibrous capsule and inflammatory infiltrate in response to 120 °C-preheated ER. CLINICAL RELEVANCE: Heat-induced changes in sealer properties alter the inflammatory response in vivo, which may affect the clinical outcome. This will not only help appropriate selection of obturation technique for different sealers, but also for optimizing the properties of new generation of sealers.

A method for rapid flow-cytometric isolation of endothelial nuclei and RNA from archived frozen brain tissue.

Endothelial cells are important contributors to brain development, physiology, and disease. Although RNA sequencing has contributed to the understanding of brain endothelial cell diversity, bulk analysis and single-cell approaches have relied on fresh tissue digestion protocols for the isolation of single endothelial cells and flow cytometry-based sorting on surface markers or transgene expression. These approaches are limited in the analysis of the endothelium in human brain tissues, where fresh samples are difficult to obtain. Here, we developed an approach to examine endothelial RNA expression by using an endothelial-specific marker to isolate nuclei from abundant archived frozen brain tissues. We show that this approach rapidly and reliably extracts endothelial nuclei from frozen mouse brain samples, and importantly, from archived frozen human brain tissues. Furthermore, isolated RNA transcript levels are closely correlated with expression in whole cells from tissue digestion protocols and are enriched in endothelial markers and depleted of markers of other brain cell types. As high-quality RNA transcripts could be obtained from as few as 100 nuclei in archived frozen human brain tissues, we predict that this approach should be useful for both bulk analysis of endothelial RNA transcripts in human brain tissues as well as single-cell analysis of endothelial sub-populations.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

The effect of cigarette smoke condensate (CSC) on Pseudomonas aeruginosa virulence and antibiotic sensitivity.

AIMS: Despite a decline in tobacco smoking in the developed world, the developing world has witnessed an increase in such activity over recent years. An increase in antibiotic resistance has accompanied this increase in tobacco use, and we suggest that the two may be linked. This study aims to investigate the effect of cigarette smoke exposure on bacterial virulence and susceptibility to antibiotics. METHODS AND RESULTS: Pseudomonas aeruginosa passaged in the presence of Cigarette Smoke Condensate (CSC) exhibited reduced susceptibility towards Amikacin (p = 0.02), Tobramycin (p = 0.03) and Aztreonam (p = 0.007) and was accompanied by changes in growth dynamics as exposure to CSC increased. These observed changes persisted after passaging bacteria in CSC-free medium for 10 days. The genotoxicity of CSC on P. aeruginosa was evaluated by the standard Comet assay, which demonstrated DNA damage in the P. aeruginosa genome in Passage 15 compared to the CSC-unexposed cells. Gene expression analysis on selected virulence and quorum sensing genes showed that both flagellar (fliC and fleR) and quorum sensing (lasI/R and rhII) genes were significantly up-regulated in Passage 15. CONCLUSIONS: Results confirm the genotoxic effect of cigarette smoke manifested in an increased antibiotic resistance, coupled with increased bacterial virulence SIGNIFICANCE AND IMPACT OF STUDY: This study is the first to elucidate a clear link between tobacco smoke residues and both increases in antibiotic resistance and the up-regulation of bacterial virulence markers.

Sexual harassment: perception and experience among female college students of Kafrelsheikh University.

BACKGROUND: Increasing concerns are rising over women and adolescence in Arabic societies generally, and in Egyptian society specifically. OBJECTIVES: To identify the profile and reasons of the problem of sexual harassments among female college students. METHODS: A cross-sectional study including randomly selected 976 female students from different faculties of Kafrelsheikh University using a predesigned questionnaire sheet. RESULTS: The main perceived concept of sexual harassment was touching body (63.9%) followed by uncomfortable behaviors by the assault (51.8%). Among urban students, 47.1% reported frequent sexual harassment as compared to 26.5% among rural students. The main motives to harassment were absence of sanctions (42.8%) followed by masculine culture. Absence of punishment ranked first (54.1%) as one of reasons for the phenomenon of harassments in the community followed by wrong concepts about women (46%). The main reaction to harassment was feeling bad and wishing to act (32.9%) followed by feeling bad but helpless (26.0%). Only 25.5% reported taking proper action. Experience of harassment was significantly more reported by urban students compared to rural ones (12.6% and 4.1%, respectively (P = 0.001). CONCLUSION: Sexual harassment is not uncommon from of violence especially in urban areas mainly due to absence of sanctions and majority did not have capacity to take proper actions.

Monocytes and pyrophosphate promote mesenchymal stem cell viability and early osteogenic differentiation.

Pyrophosphate-containing calcium phosphate implants promote osteoinduction and bone regeneration. The role of pyrophosphate for inflammatory cell-mesenchymal stem cell (MSC) cross-talk during osteogenesis is not known. In the present work, the effects of lipopolysaccharide (LPS) and pyrophosphate (PPi) on primary human monocytes and on osteogenic gene expression in human adipose-derived MSCs were evaluated in vitro, using conditioned media transfer as well as direct effect systems. Direct exposure to pyrophosphate increased nonadherent monocyte survival (by 120% without LPS and 235% with LPS) and MSC viability (LDH) (by 16-19% with and without LPS). Conditioned media from LPS-primed monocytes significantly upregulated osteogenic genes (ALP and RUNX2) and downregulated adipogenic (PPAR-γ) and chondrogenic (SOX9) genes in recipient MSCs. Moreover, the inclusion of PPi (250 µM) resulted in a 1.2- to 2-fold significant downregulation of SOX9 in the recipient MSCs, irrespective of LPS stimulation or culture media type. These results indicate that conditioned media from LPS-stimulated inflammatory monocytes potentiates the early MSCs commitment towards the osteogenic lineage and that direct pyrophosphate exposure to MSCs can promote their viability and reduce their chondrogenic gene expression. These results are the first to show that pyrophosphate can act as a survival factor for both human MSCs and primary monocytes and can influence the early MSC gene expression. Graphical abstract.

Matrix Metalloproteinases in Dental and Periodontal Tissues and Their Current Inhibitors: Developmental, Degradational and Pathological Aspects.

OBJECTIVES: This review article aims to describe some of the roles of Matrix metalloproteinases (MMPs) in enamel, dentine, dental caries, hybrid layer degradation, pulp and periodontal tissues, throwing light on their current inhibitors. The article addresses the potential of MMPs to serve as biomarkers with diagnostic and therapeutic value. DESIGN: The sections of this review discuss MMPs' involvement in developmental, remodeling, degradational and turnover aspects of dental and periodontal tissues as well as their signals in the pathogenesis, progress of different lesions and wound healing of these tissues. The literature was searched for original research articles, review articles and theses. The literature search was conducted in PubMed and MEDLINE for articles published in the last 20 years. RESULTS: 119 published papers, two textbooks and two doctoral theses were selected for preparing the current review. CONCLUSIONS: MMPs are significant proteases, of evident contribution in dental and periapical tissue development, health and disease processes, with promising potential for use as diagnostic and prognostic disease biomarkers. Continuing understanding of their role in pathogenesis and progress of different dental, periapical and periodontal lesions, as well as in dentine-pulp wound healing could be a keystone to future diagnostic and therapeutic regimens.

PinMol: Python application for designing molecular beacons for live cell imaging of endogenous mRNAs.

Molecular beacons are nucleic acid oligomers labeled with a fluorophore and a quencher that fold in a hairpin-shaped structure, which fluoresce only when bound to their target RNA. They are used for the visualization of endogenous mRNAs in live cells. Here, we report a Python program (PinMol) that designs molecular beacons best suited for live cell imaging by using structural information from secondary structures of the target RNA, predicted via energy minimization approaches. PinMol takes into account the accessibility of the targeted regions, as well as the inter- and intramolecular interactions of each selected probe. To demonstrate its applicability, we synthesized an oskar mRNA-specific molecular beacon (osk1236), which is selected by PinMol to target a more accessible region than a manually designed oskar-specific molecular beacon (osk2216). We previously demonstrated osk2216 to be efficient in detecting oskar mRNA in in vivo experiments. Here, we show that osk1236 outperformed osk2216 in live cell imaging experiments.

Habitual caffeine intake affects implant osseointegration: An in vivo study.

OBJECTIVES: This study aimed to evaluate the effect of habitual caffeine (CAF) intake on stability, bone regeneration, and expression of bone markers at the bone-implant interface. BACKGROUND: Studies show that habitual CAF alters bone health and remodeling. Yet, there is no information regarding CAF effects on osseointegration of bone-anchored implants. METHODS: Wistar rats were divided into two groups: one received tap drinking water alone (control) and the other received tap water with CAF (300 mg/L). After 12 weeks, their tibiae received screw-shaped titanium implants. After another 12 weeks, CAF (n = 5) and control (n = 5) animals were sacrificed and the implant stability was evaluated using a removal torque (RTQ) device. Thereafter, the implants were processed for gene expression analysis, and the implantation sites were harvested for histology. Implants with the surrounding bone were dissected en bloc and subjected to micro-computed tomography (micro-CT). RESULTS: The results showed that implants in the CAF group had an 87% significant increase in RTQ compared to the control. Further, micro-CT revealed a higher proportion of mineralized bone filling the implant threads in the CAF group. The molecular analysis indicated higher expression of bone formation (ALP), remodeling (CatK), and vascularization (VEGF) genes in implant-adherent cells in the CAF group. Histology suggested increased vascularity in the tissue surrounding the implant in the CAF group. CONCLUSIONS: Within the limit of this study, it is concluded that habitual CAF intake conveys a positive, promoting effect on long-term osseointegration. Clinical studies are worth pursuing to verify this experimental observation.

A mysterious sensation about sleep and health: the role of interoception.

BACKGROUND: Interoception is mental awareness, recognition and acknowledgement of physiological body signals. Understanding the role of sleep and interoception may provide a better understanding surrounding the sleep-health connection. Our primary objective was to examine the potential relationships between subjective sleep quality and multiple dimensions of interoceptive abilities in a large sample of young adults, a group who are vulnerable to sleep impairment and its widespread health consequences. METHODS: We conducted an online cross-sectional survey targeting young adults, aged 18-25 years. The Pittsburgh Sleep Quality Index (PSQI) was used to identify subjective sleep quality and the Multidimensional Assessment of Interoceptive Awareness Version 2 was used to assess eight domains of interoception. We conducted a series of Spearman's bivariate correlations to assess the relationships between global sleep quality as well as the seven PSQI sub-components in relation to the eight interoception outcomes. We then conducted quantile regression to assess if global PSQI score was an independent predictor of interoception. Participants (n = 609) consented and provided data. RESULTS: After adjustment, the global PSQI was a significant predictor of 'Non-Distracting', 'Emotional Awareness' and 'Trusting', where ß = - 0.10 (95% CI: - 0.14, - 0.07), ß = 0.05 (0.01, 0.09), and ß = - 0.10 (- 0.14, - 0.05), respectively. CONCLUSIONS: Our findings reveal a small, significant relationship between sleep quality and interoceptive abilities amongst young adults. Sleep impairment may inhibit interoceptive skills, thus adding value to the mechanistic explanation of the sleep-health relationship. Experimental and prospective studies are needed to determine temporal associations.

Reductive Amination Reaction for the Functionalization of Cellulose Nanocrystals.

Cellulose nanocrystals (CNCs) represent intriguing biopolymeric nanocrystalline materials, that are biocompatible, sustainable and renewable, can be chemically functionalized and are endowed with exceptional mechanical properties. Recently, studies have been performed to prepare CNCs with extraordinary photophysical properties, also by means of their functionalization with organic light-emitting fluorophores. In this paper, we used the reductive amination reaction to chemically bind 4-(1-pyrenyl)butanamine selectively to the reducing termini of sulfated or neutral CNCs (S_CNC and N_CNC) obtained from sulfuric acid or hydrochloric acid hydrolysis. The functionalization reaction is simple and straightforward, and it induces the appearance of the typical pyrene emission profile in the functionalized materials. After a characterization of the new materials performed by ATR-FTIR and fluorescence spectroscopies, we demonstrate luminescence quenching of the decorated N_CNC by copper (II) sulfate, hypothesizing for these new functionalized materials an application in water purification technologies.

Association between country preparedness indicators and quality clinical care for cardiovascular disease risk factors in 44 lower- and middle-income countries: A multicountry analysis of survey data.

BACKGROUND: Cardiovascular diseases are leading causes of death, globally, and health systems that deliver quality clinical care are needed to manage an increasing number of people with risk factors for these diseases. Indicators of preparedness of countries to manage cardiovascular disease risk factors (CVDRFs) are regularly collected by ministries of health and global health agencies. We aimed to assess whether these indicators are associated with patient receipt of quality clinical care. METHODS AND FINDINGS: We did a secondary analysis of cross-sectional, nationally representative, individual-patient data from 187,552 people with hypertension (mean age 48.1 years, 53.5% female) living in 43 low- and middle-income countries (LMICs) and 40,795 people with diabetes (mean age 52.2 years, 57.7% female) living in 28 LMICs on progress through cascades of care (condition diagnosed, treated, or controlled) for diabetes or hypertension, to indicate outcomes of provision of quality clinical care. Data were extracted from national-level World Health Organization (WHO) Stepwise Approach to Surveillance (STEPS), or other similar household surveys, conducted between July 2005 and November 2016. We used mixed-effects logistic regression to estimate associations between each quality clinical care outcome and indicators of country development (gross domestic product [GDP] per capita or Human Development Index [HDI]); national capacity for the prevention and control of noncommunicable diseases ('NCD readiness indicators' from surveys done by WHO); health system finance (domestic government expenditure on health [as percentage of GDP], private, and out-of-pocket expenditure on health [both as percentage of current]); and health service readiness (number of physicians, nurses, or hospital beds per 1,000 people) and performance (neonatal mortality rate). All models were adjusted for individual-level predictors including age, sex, and education. In an exploratory analysis, we tested whether national-level data on facility preparedness for diabetes were positively associated with outcomes. Associations were inconsistent between indicators and quality clinical care outcomes. For hypertension, GDP and HDI were both positively associated with each outcome. Of the 33 relationships tested between NCD readiness indicators and outcomes, only two showed a significant positive association: presence of guidelines with being diagnosed (odds ratio [OR], 1.86 [95% CI 1.08-3.21], p = 0.03) and availability of funding with being controlled (OR, 2.26 [95% CI 1.09-4.69], p = 0.03). Hospital beds (OR, 1.14 [95% CI 1.02-1.27], p = 0.02), nurses/midwives (OR, 1.24 [95% CI 1.06-1.44], p = 0.006), and physicians (OR, 1.21 [95% CI 1.11-1.32], p < 0.001) per 1,000 people were positively associated with being diagnosed and, similarly, with being treated; and the number of physicians was additionally associated with being controlled (OR, 1.12 [95% CI 1.01-1.23], p = 0.03). For diabetes, no positive associations were seen between NCD readiness indicators and outcomes. There was no association between country development, health service finance, or health service performance and readiness indicators and any outcome, apart from GDP (OR, 1.70 [95% CI 1.12-2.59], p = 0.01), HDI (OR, 1.21 [95% CI 1.01-1.44], p = 0.04), and number of physicians per 1,000 people (OR, 1.28 [95% CI 1.09-1.51], p = 0.003), which were associated with being diagnosed. Six countries had data on cascades of care and nationwide-level data on facility preparedness. Of the 27 associations tested between facility preparedness indicators and outcomes, the only association that was significant was having metformin available, which was positively associated with treatment (OR, 1.35 [95% CI 1.01-1.81], p = 0.04). The main limitation was use of blood pressure measurement on a single occasion to diagnose hypertension and a single blood glucose measurement to diagnose diabetes. CONCLUSION: In this study, we observed that indicators of country preparedness to deal with CVDRFs are poor proxies for quality clinical care received by patients for hypertension and diabetes. The major implication is that assessments of countries' preparedness to manage CVDRFs should not rely on proxies; rather, it should involve direct assessment of quality clinical care.

Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end-stage renal disease.

End-stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear-cell RCCs (ESRD-ccRCCs) and acquired cystic disease (ACD)-associated RCCs. However, their genetic and epigenetic alterations are still poorly understood. Here, we investigated somatic mutations, copy number alterations (CNAs), and DNA methylation profiles in 9 ESRD-ccRCCs and 7 ACD-associated RCCs to identify their molecular alterations and cellular origins. Targeted sequencing of 409 cancer-related genes, including VHL, PBRM1, SETD2, BAP1, KDM5C, MET, KMT2C (MLL3), and TP53, showed ESRD-ccRCCs harbored frequent VHL mutations, while ACD-associated RCCs did not. CNA analysis showed that ESRD-ccRCCs had a frequent loss of chromosome 3p while ACD-associated RCCs had a gain of chromosome 16. Beadarray methylation analysis showed that ESRD-ccRCCs had methylation profiles similar to those of sporadic ccRCCs, while ACD-associated RCCs had profiles similar to those of papillary RCCs. Expression analysis of genes whose expression levels are characteristic to individual segments of a nephron showed that ESRD-ccRCCs and ACD-associated RCCs had high expression of proximal tubule cell marker genes, while chromophobe RCCs had high expression of distal tubule cell/collecting duct cell marker genes. In conclusion, ESRD-ccRCCs and ACD-associated RCCs had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively, and these 2 histopathological types of RCCs were indicated to have originated from proximal tubule cells of the nephron.

Hypertension and diabetes in Zanzibar - prevalence and access to care.

BACKGROUND: Cardiovascular diseases are among the most common causes of hospital admissions and deaths in Zanzibar. This study assessed prevalence of, and antecedent factors and care access for the two common cardiovascular risk factors, hypertension and diabetes, to support health system improvements. METHODS: Data was from a population based nationally representative survey. Prevalence of hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or a self-reported diagnosis of hypertension; diabetes was defined as a fasting blood glucose ≥6.1 mmol/L or a self-reported diagnosis of diabetes. Care-cascades for hypertension and diabetes were created with four stages: being tested, diagnosed, treated, and achieving control. Multivariable logistic regression models were constructed to evaluate individual-level factors - including symptoms of mental illness - associated with having hypertension or diabetes, and with progressing through the hypertension care cascade. Whether people at overt increased risk of hypertension or diabetes (defined as > 50 years old, BMI > 30 kg/m2, or currently smoking) were more likely to be tested was assessed using chi squared. RESULTS: Prevalence of hypertension was 33.5% (CI 30.6-36.5). Older age (OR 7.7, CI 4.93-12.02), some education (OR 0.6, CI 0.44-0.89), obesity (OR 3.1, CI 2.12-4.44), and raised fasting blood glucose (OR 2.4, CI 2.38) were significantly independently associated with hypertension. Only 10.9% (CI 8.6-13.8) of the entire hypertensive population achieved blood pressure control, associated factors were being female (OR 4.8, CI 2.33-9.88), formally employed (OR 3.0, CI 1.26-7.17), and overweight (OR 2.5, CI 1.29-4.76). The prevalence of diabetes was 4.4% (CI 3.4-5.5), and associated with old age (OR 14.1, CI 6.05-32.65) and almost significantly with obesity (OR 2.1, CI 1.00-4.37). Only 11.9% (CI 6.6-20.6) of the diabetic population had achieved control. Individuals at overt increased risk were more likely to have been tested for hypertension (chi2 19.4) or diabetes (chi2 33.2) compared to the rest of the population. Symptoms of mental illness were not associated with prevalence of disease or progress through the cascade. CONCLUSION: High prevalence of hypertension and suboptimal management along the care cascades indicates a large unmet need for hypertension and diabetes care in Zanzibar.