Cyclical heat stress during lactation influences the microstructure of the bovine mammary gland.

This study aimed to evaluate the impact of heat stress on mammary epithelial cell (MEC) losses into milk, secretory mammary tissue structure, and mammary epithelial cell activity. Sixteen multiparous Holstein cows (632 ± 12 kg BW) approximately 100 d in milk housed in climate-controlled rooms were paired by body weight and randomly allocated to one of 2 treatments, heat stress (HS) or pair feeding thermoneutral (PFTN) using 2 cohorts. Each cohort was subjected to 2 periods of 4 d each. In period 1, both treatments had ad libitum access to a common total mixed ration and were exposed to a controlled daily temperature-humidity index (THI) of 64. In period 2, HS cows were exposed to controlled cyclical heat stress (THI: 74 to 80), while PFTN cows remained at 64 THI and daily dry matter intake was matched to HS. Cows were milked twice daily, and milk yield was recorded at each milking. Individual milk samples on the last day of each period were used to quantify MEC losses by flow cytometry using butyrophilin as a cell surface marker. On the final day of period 2, individual bovine mammary tissue samples were obtained for histomorphology analysis, assessment of protein abundance, and evaluation of gene expression of targets associated with cellular capacity for milk and milk component synthesis, heat response, cellular proliferation, and autophagy. Statistical analysis was performed using the GLIMMIX procedure of SAS. Milk yield was reduced by 4.3 kg by HS (n = 7) compared with PFTN (n = 8). Independent of treatment, MEC in milk averaged 174 cells/mL (2.9% of total cells). There was no difference between HS vs. PFTN cows for MEC shed or concentration in milk. Alveolar area was reduced 25% by HS, and HS had 4.1 more alveoli than PFTN. Total number of nucleated MEC per area were greater in HS (389 ± 1.05) compared with PFTN (321 ± 1.05); however, cell number per alveolus was similar between groups (25 ± 1.5 vs. 26 ± 1.4). There were no differences in relative fold expression for GLUT1, GLUT8, CSN2, CSN3, LALBA, FASN, HSPA5, and HSPA8 in HS compared with PFTN. Immunoblotting analyses showed a decrease abundance for phosphorylated STAT5 and S6K1, and an increase in LC3 II in HS compared with PFTN. These results suggest that even if milk yield differences and histological changes occur in the bovine mammary gland after 4 d of heat exposure, MEC loss into milk, nucleated MEC number per alveolus, and gene expression of nutrient transport, milk component synthesis, and heat stress related targets are unaffected. In contrast, the abundance of proteins related to protein synthesis and cell survival decreased significantly, while an upregulation of proteins associated with autophagy in HS compared with PFTN.

Development of the FAST-M maternal sepsis bundle for use in low-resource settings: a modified Delphi process.

OBJECTIVE: To develop a sepsis care bundle for the initial management of maternal sepsis in low resource settings. DESIGN: Modified Delphi process. SETTING: Participants from 34 countries. POPULATION: Healthcare practitioners working in low resource settings (n = 143; 34 countries), members of an expert panel (n = 11) and consultation with the World Health Organization Global Maternal and Neonatal Sepsis Initiative technical working group. METHODS: We reviewed the literature to identify all potential interventions and practices around the initial management of sepsis that could be bundled together. A modified Delphi process, using an online questionnaire and in-person meetings, was then undertaken to gain consensus on bundle items. Participants ranked potential bundle items in terms of perceived importance and feasibility, considering their use in both hospitals and health centres. Findings from the healthcare practitioners were then triangulated with those of the experts. MAIN OUTCOME MEASURE: Consensus on bundle items. RESULTS: Consensus was reached after three consultation rounds, with the same items deemed most important and feasible by both the healthcare practitioners and expert panel. Final bundle items selected were: (1) Fluids, (2) Antibiotics, (3) Source identification and control, (4) Transfer (to appropriate higher-level care) and (5) Monitoring (of both mother and neonate as appropriate). The bundle was given the acronym 'FAST-M'. CONCLUSION: A clinically relevant maternal sepsis bundle for low resource settings has been developed by international consensus. TWEETABLE ABSTRACT: A maternal sepsis bundle for low resource settings has been developed by international consensus.

Reduced late urinary toxicity with high-dose intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer

Background/purpose. To evaluate the impact of intensity-modulated radiotherapy (IMRT) with intra-prostate fiducial markers image-guided radiotherapy (IGRT) on the incidence of late urinary toxicity compared to 3D conformal radiotherapy (3DCRT) for patients with prostate cancer (PC). Methods and materials. We selected 733 consecutive patients with localized PC treated with dose-escalation radiotherapy between 2001 and 2014. Eligibility criteria were radiation dose >72.0 Gy, no pelvic RT and minimum follow-up 24 months. 438 patients were treated with 3DCRT and 295 with IMRT. Acute and late urinary complications were assessed using the EORTC/RTOG and CTCAEs v3.0 definition. The Cox regression model was used to compare grade ≥2 urinary toxicity between both techniques. The median follow-up was 75 months (range 24-204). Results. The median isocenter radiation dose was 78.7 Gy for 3DCRT and 80.7 Gy for IMRT/IGRT (p < 0.001). The 5-year incidence of late grade ≥2 urinary toxicity was 6.4% for IMRT and 10.8% for 3DCRT [hazard ratio (HR) 0.575, p = 0.056]. The corresponding 5-year estimates of late grade ≥2 hematuria were 2% for IMRT and 5.3% for 3DCRT (HR 0.296, p = 0.024). On multivariate analysis, the antecedent of prior transurethral resection of the prostate was also a strong predictor of a higher risk of urinary complications (HR 2.464, p = 0.002) and of hematuria (HR 5.196, p < 0.001). Conclusion. Compared with 3DCRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary complications in spite of higher radiation dose (AU)

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Reduced late urinary toxicity with high-dose intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer.

BACKGROUND/PURPOSE: To evaluate the impact of intensity-modulated radiotherapy (IMRT) with intra-prostate fiducial markers image-guided radiotherapy (IGRT) on the incidence of late urinary toxicity compared to 3D conformal radiotherapy (3DCRT) for patients with prostate cancer (PC). METHODS AND MATERIALS: We selected 733 consecutive patients with localized PC treated with dose-escalation radiotherapy between 2001 and 2014. Eligibility criteria were radiation dose >72.0 Gy, no pelvic RT and minimum follow-up 24 months. 438 patients were treated with 3DCRT and 295 with IMRT. Acute and late urinary complications were assessed using the EORTC/RTOG and CTCAEs v3.0 definition. The Cox regression model was used to compare grade ≥2 urinary toxicity between both techniques. The median follow-up was 75 months (range 24-204). RESULTS: The median isocenter radiation dose was 78.7 Gy for 3DCRT and 80.7 Gy for IMRT/IGRT (p < 0.001). The 5-year incidence of late grade ≥2 urinary toxicity was 6.4% for IMRT and 10.8% for 3DCRT [hazard ratio (HR) 0.575, p = 0.056]. The corresponding 5-year estimates of late grade ≥2 hematuria were 2% for IMRT and 5.3% for 3DCRT (HR 0.296, p = 0.024). On multivariate analysis, the antecedent of prior transurethral resection of the prostate was also a strong predictor of a higher risk of urinary complications (HR 2.464, p = 0.002) and of hematuria (HR 5.196, p < 0.001). CONCLUSION: Compared with 3DCRT, high-dose IMRT/IGRT is associated with a lower rate of late urinary complications in spite of higher radiation dose.

Large-scale whole genome sequencing of M. tuberculosis provides insights into transmission in a high prevalence area.

To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21-0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time.

Gastric Malignancy Survival in Zambia, Southern Africa: A Two Year Follow up Study.

Background: Gastric cancer poses a significant global health burden. It is the second most common cause of cancer death worldwide and the ninth leading cause of cancer mortality in Zambia, at a rate of 3.8/100,000; comparable to USA (2/100,000) and UK (3.4/100,000). Survival data on gastric malignancy in Zambia is not known. Objectives: To provide preliminary survival rates of patients with histologically proven gastric adenocarcinoma in Zambia. Study Design: Using our prospective gastric cancer research database, we conducted a retrospective audit of patients diagnosed with gastric cancer at the University Teaching Hospital, Zambia, from June 2010 until January 2012. We contacted patients or their relatives using phone numbers provided at time of enrollment. Main Outcomes: We reviewed age, sex, demographic data (income, education), body mass index, symptoms, duration of symptoms, treatment (surgery, chemotherapy, radiotherapy or combination) and survival outcome. Analysis was performed using Kaplan-Meier models and log rank test. Results: Fifty one patients were diagnosed with gastric adenocarcinoma during the study period, but follow-up data were available for 50. Median survival was 142 days. Age, sex, income, education, BMI, tumor location, and treatment modality were not significantly associated with overall survival. In Cox regression models, covariates associated with survival were a history of regular alcohol intake (HR 0.49, 95%CI 0.26,0.92; P=0.025) and intestinal type cancer histology (HR 0.40, 95%CI 0.19,0.83; P=0.01). Conclusion: Prognosis of newly diagnosed gastric cancer in Zambia is poor with significant mortality within 1 year of diagnosis, particularly among patients with weight loss and dysphagia.

Cancer incidence in Blantyre, Malawi 1994-1998.

In this paper, we report the first results from the population-based cancer registry for Blantyre district, Malawi, for the period 1994-1998. In this 5-year period, 1245 cases were recorded in males (an estimated age-standardized incidence of 92.0 per 100,000) and 1003 in females (an age standardised rate (ASR) of 88.8 per 105). The overall percentage of cases with histological verification was just 41.8%, indicating that case-finding outside the laboratory had been quite successful; nevertheless the rather low rates suggest possible underdiagnosis of cancer, as well as cases missed. As in other reports from the region, the contemporary pattern is dominated by Kaposi's sarcoma (KS) (55.2% cancers in men, 28% in women), the effect of the evolving epidemic of AIDS. The incidence of cervix cancer in women is high (ASR 26.2 per 105), and there are moderately high rates of oesophageal cancer (ASR 15.4 per 105 in men, 9.3 per 105 in women). In childhood, the cancer profile is dominated by Burkitt's lymphoma, which accounts for 42.4% of cancers; KS is now the second most frequent cancer of childhood.

Spectrum of childhood cancers in Malawi 1985-1993.

An analysis of seven hundred and ninety one children aged 0.2 to 14 years with confirmed malignant disease recorded by the Malawi National Cancer Registry over a period of 9 years is presented. Childhood cancer constituted 6.9% of all malignancies recorded during the study period. The top ten neoplasms in descending order of frequency were: non-Hodgkin's lymphoma 434 (54.9%), retinoblastoma 89 (11.3%), nephroblastoma 50 (6.3%), epithelial carcinoma 45 (5.7%), Hodgkin's disease 38 (4.8%), soft tissue sarcoma (excluding Kaposi): 34(4.3%), Kaposi's sarcoma 32 (4.0%), malignant tumours (not specified): 20 (2.5%), acute leukaemias 18(2.3%) and osteogenic sarcoma 16 (2.0%). Some differences noted in the pattern of neoplasms in this study from those of developed and developing African countries are discussed. The findings highlight the most common childhood malignancies in Malawi where intense research should be directed so that meaningful and cost effective therapeutic intervention programmes can be planned and developed.