Sex-specific relevance of diabetes to occlusive vascular and other mortality : a collaborative meta-analysis of individual data from 980 793 adults from 68 prospective studies

Background: Several studies have shown that diabetes confers a higher relative risk of vascular mortality among women than among men, but whether this increased relative risk in women exists across age groups and within defined levels of other risk factors is uncertain. We aimed to determine whether differences in established risk factors, such as blood pressure, BMI, smoking, and cholesterol, explain the higher relative risks of vascular mortality among women than among men. Methods: In our meta-analysis, we obtained individual participant-level data from studies included in the Prospective Studies Collaboration and the Asia Pacific Cohort Studies Collaboration that had obtained baseline information on age, sex, diabetes, total cholesterol, blood pressure, tobacco use, height, and weight. Data on causes of death were obtained from medical death certificates. We used Cox regression models to assess the relevance of diabetes (any type) to occlusive vascular mortality (ischaemic heart disease, ischaemic stroke, or other atherosclerotic deaths) by age, sex, and other major vascular risk factors, and to assess whether the associations of blood pressure, total cholesterol, and body-mass index (BMI) to occlusive vascular mortality are modified by diabetes. Findings: Individual participant-level data were analysed from 980793 adults. During 9 center dot 8 million person-years of follow-up, among participants aged between 35 and 89 years, 19686 (25 center dot 6%) of 76965 deaths were attributed to occlusive vascular disease. After controlling for major vascular risk factors, diabetes roughly doubled occlusive vascular mortality risk among men (death rate ratio [RR] 2 center dot 10, 95% CI 1 center dot 97-2 center dot 24) and tripled risk among women (3 center dot 00, 2 center dot 71-3 center dot 33; x(2) test for heterogeneity p<0 center dot 0001). For both sexes combined, the occlusive vascular death RRs were higher in younger individuals (aged 35-59 years: 2 center dot 60, 2 center dot 30-2 center dot 94) than in older individuals (aged 70-89 years: 2 center dot 01, 1 center dot 85-2 center dot 19; p=0 center dot 0001 for trend across age groups), and, across age groups, the death RRs were higher among women than among men. Therefore, women aged 35-59 years had the highest death RR across all age and sex groups (5 center dot 55, 4 center dot 15-7 center dot 44). However, since underlying confounder-adjusted occlusive vascular mortality rates at any age were higher in men than in women, the adjusted absolute excess occlusive vascular mortality associated with diabetes was similar for men and women. At ages 35-59 years, the excess absolute risk was 0 center dot 05% (95% CI 0 center dot 03-0 center dot 07) per year in women compared with 0 center dot 08% (0 center dot 05-0 center dot 10) per year in men; the corresponding excess at ages 70-89 years was 1 center dot 08% (0 center dot 84-1 center dot 3 2) per year in women and 0 center dot 91% (0 center dot 77-1 center dot 05) per year in men. Total cholesterol, blood pressure, and BMI each showed continuous log-linear associations with occlusive vascular mortality that were similar among individuals with and without diabetes across both sexes. Interpretation: Independent of other major vascular risk factors, diabetes substantially increased vascular risk in both men and women. Lifestyle changes to reduce smoking and obesity and use of cost-effective drugs that target major vascular risks (eg, statins and antihypertensive drugs) are important in both men and women with diabetes, but might not reduce the relative excess risk of occlusive vascular disease in women with diabetes, which remains unexplained

Organs to Cells and Cells to Organoids: The Evolution of in vitro Central Nervous System Modelling

With 100 billion neurons and 100 trillion synapses, the human brain is not just the most complex organ in the human body, but has also been described as “the most complex thing in the universe.” The limited availability of human living brain tissue for the study of neurogenesis, neural processes and neurological disorders has resulted in more than a century-long strive from researchers worldwide to model the central nervous system (CNS) and dissect both its striking physiology and enigmatic pathophysiology. The invaluable knowledge gained with the use of animal models and post mortem human tissue remains limited to cross-species similarities and structural features, respectively. The advent of human induced pluripotent stem cell (hiPSC) and 3-D organoid technologies has revolutionised the approach to the study of human brain and CNS in vitro, presenting great potential for disease modelling and translational adoption in drug screening and regenerative medicine, also contributing beneficially to clinical research. We have surveyed more than 100 years of research in CNS modelling and provide in this review an historical excursus of its evolution, from early neural tissue explants and organotypic cultures, to 2-D patient-derived cell monolayers, to the latest development of 3-D cerebral organoids. We have generated a comprehensive summary of CNS modelling techniques and approaches, protocol refinements throughout the course of decades and developments in the study of specific neuropathologies. Current limitations and caveats such as clonal variation, developmental stage, validation of pluripotency and chromosomal stability, functional assessment, reproducibility, accuracy and scalability of these models are also discussed

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Allelic imbalance at 1p36 may predict prognosis of chemoradiation therapy for bladder preservation in patients with invasive bladder cancer

Invasive bladder cancers have been treated by irradiation combined with cis- platinum (CDDP) as a bladder preservative option. The aim of this study was to find a marker for predicting patient outcome as well as clinical response after chemoradiation therapy (CRT) by investigating allelic loss of apoptosis-related genes. A total of 67 transitional cell carcinomas of the bladder treated by CRT (median dose: 32.4 Gy of radiation and 232 mg of CDDP) were studied. We investigated allelic imbalances at 14 loci on chromosomes 17p13 and 1p36 including the p53 and p73 gene regions by fluorescent multiplex PCR based on DNA from paraffin-embedded tumour specimens and peripheral blood. The response to CRT was clinical response (CR) in 21 patients (31%), partial response (PR) in 31 (46%), and no change(NC) in 15 (22%). There was no statistical correlation between treatment response and clinical parameters, such as tumour grade, stage, radiation dose, or CDDP dose. The frequencies of allelic imbalance for TP53 and TP73 were 21 and 56%, respectively; neither was correlated with clinical treatment response and tumour stage or grade. There was no statistical correlation between treatment response and allelic imbalance at the other 12 loci. We found a significant correlation between cancer-specific survival and an imbalance of D1S243 (P=0.0482) or TP73 (P=0.0013) using a Log-rank test, although other loci including TP53 did not correlate with survival (P=0.4529 Multivariate analysis showed performance status (P=0.0047), recurrence (P=0.0017), and radiation doses (P=0.0468) were independent predictive factors for cancer-specific survival. However, an allelic imbalance of TP73 was the most remarkable independent predictive factor of poor patient survival (P=0.0002, risk ratio: 3382). Our results suggest that the allelic loss of the p73 gene predicts a clinical outcome of locally advanced bladder cancer when treated by CRT

Intraoperative ultrasound-guided iodine-125 seed implantation for unresectable pancreatic carcinoma

<p>Abstract</p> <p>Background</p> <p>To assess the feasibility and efficacy of using ¹²⁵I seed implantation under intraoperative ultrasound guidance for unresectable pancreatic carcinoma.</p> <p>Methods</p> <p>Fourteen patients with pancreatic carcinoma that underwent laparotomy and considered unresectable were included in this study. Nine patients were pathologically diagnosed with Stage II disease, five patients with Stage III disease. Fourteen patients were treated with ¹²⁵I seed implantation guided by intraoperative ultrasound and received D₉₀of ¹²⁵I seeds ranging from 60 to 140 Gy with a median of 120 Gy. Five patients received an additional 35–50 Gy from external beam radiotherapy after seed implantation and six patients received 2–6 cycles of chemotherapy.</p> <p>Results</p> <p>87.5% (7/8) of patients received partial to complete pain relief. The response rate of tumor was 78.6%, One-, two-and three-year survival rates were 33.9% and 16.9%, 7.8%, with local control of disease achieved in 78.6% (11/14), and the median survival was 10 months (95% CI: 7.7–12.3).</p> <p>Conclusion</p> <p>There were no deaths related to ¹²⁵I seed implant. In this preliminary investigation, ¹²⁵I seed implant provided excellent palliation of pain relief, local control and prolong the survival of patients with stage II and III disease to some extent.</p

Long-term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer.

We conducted a phase I/II study investigating synchronous chemoradiotherapy with mitomycin C and infusional 5-fluorouracil (5-FU) in muscle invasive bladder cancer. Early dose escalation results were previously published. We report the long-term toxicity and efficacy results with the optimised regimen. Patients with muscle invasive bladder cancer with glomerular filtration rate >25 ml min(-1) were eligible. Mitomycin (12 mg m(-2) on day 1 only) and infusional 5-FU (500 mg m(-2) day(-1)) for 5 days were administered during weeks 1 and 4 of radiotherapy of 55 Gy in 20 fractions. A total of 41 patients were enrolled, median age was 68 years, 33 were male and eight female patients. Out of the 41 patients, 20 (49%) had hydronephrosis at presentation and 25 (62%) had T3b or T4 disease. Four patients experienced Grade III thrombocytopenia and three patients had Grade III neutropenia. There were no episodes of febrile neutropenia. Four patients experienced Grade III diarrhoea and 1 Grade III urgency and dysuria. Six patients did not undergo cystoscopic evaluation due to early metastatic spread although there was no clinical suggestion of bladder failure. In all, out of 35 evaluable patients, 25 (71%) had macroscopic complete response at 3-month cystoscopy, and biopsy confirmed in 24 out of 25. A total of 16 (39%) patients remain alive with a median follow-up of 50.7 (range 23.5-68.8) months, 14 with a functioning bladder with no reported long-term treatment-related bladder or bowel toxicity. Five out of 41 patients have undergone salvage cystectomy: two for persistent CIS, two T1 and one muscle invasive recurrence. Four patients have received intravesical chemotherapy, of whom two remain alive with a functioning bladder. Overall 12-, 24- and 60-month (m) survival rates were 68, 49 and 36%. Local and distant progression free rates were 82 and 86% at 12-m and 79 and 75% at 24-m. Organ preservation using multimodality therapy is feasible and safe, even in patients with poor renal reserve, and does not compromise salvage therapies. A national phase III trial BC2001 (www.bc2001.org.uk) exploring the effects of synchronous chemoradiotherapy with this regimen is currently recruiting

Serum neutralization profiles of straw-colored fruit bats (Eidolon helvum) in Makurdi (Nigeria), against four lineages of Lagos bat lyssavirus

Lagos bat lyssavirus (LBV) comprising four lineages (A, B, C and D) can potentially cause the fatal disease rabies. Although LBV-B was initially isolated in Nigeria in 1956, there is no information on LBV lineages circulating in Nigeria. This study was undertaken for the first time to measure the neutralizing antibodies against four lineages of LBVs in straw-colored fruit bats (Eidolon helvum) in Makurdi, Nigeria. Serum samples (n = 180) collected during two periods (November 2017–March 2018 and November 2018–March 2019) from terminally bled bats captured for human consumption were tested using a modified fluorescent antibody virus neutralization (mFAVN) assay. A high proportion of bat sera (74%) neutralized at least one lineage of LBV (with reciprocal titers from 9 to >420.89) and most of them neutralized LBV-A (63%), followed by LBV-D (49%), LBV-C (45%) and LBV-B (24%). The majority of positive sera (75%, n = 100) neutralized multiple LBV lineages while the remaining 25% (n = 33) neutralized only a single lineage, i.e., LBV-A (n = 23), LBV-D (n = 8) and LBV-C (n = 2). None exclusively neutralized LBV-B. The results suggest that exposure to LBV is common in E. helvum and that LBV-A (but not LBV-B) is likely to be circulating in this region of Nigeria.The UK Department for Environment, Food and Rural Affairs (Defra), the Scottish Government and the Welsh Government, the European Union’s Horizon 2020 research and innovation program and University of Pretoria Doctoral Research Bursary.https://www.mdpi.com/journal/virusesdm2022Veterinary Tropical Disease