Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Deep inspiratory breath hold assisted by continuous positive airway pressure ventilation for lung stereotactic body radiotherapy.

PURPOSE: Continuous positive airway pressure (CPAP) ventilation hyperinflates the lungs and reduces diaphragmatic motion. We hypothesized that CPAP could be safely combined with deep inspiratory breath hold (CPAP-DIBH) during lung stereotactic radiotherapy (SBRT). MATERIAL AND METHODS: Patients with stage-1 lung cancer or lung metastasis treated with CPAP-DIBH SBRT between 3/2017-5/2021 were analyzed retrospectively. Patient characteristics, treatment parameters, duration of breath holds in all sessions and tolerance to CPAP-DIBH were recorded. Local control (LC) was assessed from CT or PET-CT imaging. The distances between the tumor and mediastinal organs at risk (OAR) in centrally located tumors using either free breathing (FB) or CPAP-DIBH were compared. Toxicity was graded retrospectively. RESULTS: Forty-five patients with 71 lesions were treated with CPAP-DIBH SBRT. Indications for CPAP-DIBH were prior radiation (35/71, 65%), lower lobe location (34/71, 48%), multiple lesions (26/71, 36.6%) and proximity to mediastinal OAR (7/71, 10%). Patient characteristics were: F:M 43%: 57%; mean gross tumor volume 4.5cm3 (SD 7.9), mean planning target volume 20cm3 (SD 27), primary: metastatic lesions (7%:93%). Mean radiation dose was 52.5 Gray (SD3.5). Mean lung volume was 5292cm3 (SD 1106). Mean duration of CPAP-DIBH was 41.3s (IQR 31-46.8). LC at 2 years was 89.5% (95% CI 76-95.5). In patients with central lesions, the distance between the tumor and mediastinal OAR increased from 0.84cm (SD 0.65) with FB to 1.23cm (SD 0.8) with CPAP-DIBH (p=0.002). Most patients tolerated CPAP well and completed all treatments after starting therapy. Three patients did not receive treatment: 2 were unable to tolerate CPAP and 1 had syncope (pre-existing). Toxicity was grade 2 in 4/65 (6%) and grade 3 in 1/65 (1.5%). There was no grade 2 or higher esophageal or tracheal toxicities. CONCLUSION: CPAP-DIBH assisted lung SBRT was tolerated well and was associated with minimal toxicity and favorable LC. This technique may be considered when treating multiple lung lesions, lesions located in the lower lobes or adjacent to mediastinal OAR.

Targeting workload to ameliorate risk of heat stress in industrial sugarcane workers.

OBJECTIVE: The aim of this study was to quantify the physiological workload of manual laborers in industrial sugarcane and assess the effect of receiving a rest, shade, and hydration intervention to reduce heat stress exposure risk. METHODS: In an observational study, physiological workload was evaluated for burned cane cutters (BCC), seed cutters (SC) and drip irrigation repair workers (DIRW) using heart rate (HR) recorded continuously (Polar®) across a work shift. Workers' percentage of maximal HR (%HRmax), time spent in different HR zones, and estimated core temperature (ECTemp) were calculated. The effect of increasing rest across two harvests was evaluated for BCC and SC. RESULTS: A total of 162 workers participated in this study [52 BCC (all male), 71 SC (13 female) and 39 DIRW (16 female)]. Average %HRmax across a work shift was similar between BCC and SC (BCC: 58%, SC: 59%), but lower in DIRW (51%). BCC and SC spent similar proportions of work shifts at hard/very hard intensities (BCC: 13%, SC: 15%), versus DIRW who worked mostly at light (46%) or light-moderate (39%) intensities. SC maximum ECTemp reached 38.2°C, BCC 38.1°C; while DIRW only reached 37.7°C. Females performed at a higher %HRmax than males across work shifts (SC 64% versus 58%; DIRW 55% versus 49%). An additional rest period was associated with a lower average %HRmax across a work shift in BCC. CONCLUSION: In this setting, BCC and SC both undertake very physiologically demanding work. Females maintained a higher workload than male co-workers. Regulated rest periods each hour, with water and shade access, appears to reduce physiological workload/strain.

Workplace Intervention for Heat Stress: Essential Elements of Design, Implementation, and Assessment.

Heat stress is associated with numerous health effects that potentially harm workers, especially in a warming world. This investigation occurred in a setting where laborers are confronted with occupational heat stress from physically demanding work in high environmental temperatures. Collaboration with a major Nicaraguan sugarcane producer offered the opportunity to study interventions to prevent occupational heat-stress-related kidney disease. Two aims for this study of a rest-shade-water intervention program were: (1) describe the evolving intervention, summarize findings that motivated proposed improvements, assess impact of those improvements, and identify challenges to successful implementation and (2) extract primary lessons learned about intervention research that have both general relevance to investigations of work-related disease prevention and specific relevance to this setting. The learning curve for the various stakeholders as well as the barriers to success demonstrate that effectiveness of an intervention cannot be adequately assessed without considerations of implementation. Designing, effectively implementing, and assessing both health impacts and implementation quality is a resource-intensive endeavor requiring a transdisciplinary approach. Both general and specific lessons learned are presented for decisions on study design and study elements, implementation assessment, and management engagement in understanding how productivity and health can be successfully balanced and for building effective communication between investigators and all levels of management.

Laboratory experiments reveal intrinsic self-sustained oscillations in ocean relevant rotating fluid flows.

Several ocean Western Boundary Currents (WBCs) encounter a lateral gap along their path. Examples are the Kuroshio Current penetrating into the South China Sea through the Luzon Strait and the Gulf of Mexico Loop Current leaping from the Yucatan peninsula to Florida as part of the Gulf Stream system. Here, we present results on WBC relevant flows, generated in the world's largest rotating platform, where the Earth's sphericity necessary to support WBCs is realized by an equivalent topographic effect. The fluid is put in motion by a pump system, which produces a current that is stationary far from the gap. When the jet reaches the gap entrance, time-dependent patterns with complex spatial structures appear, with the jet leaking, leaping or looping through the gap. The occurrence of these intrinsic self-sustained periodic or aperiodic oscillations depending on current intensity is well known in nonlinear dynamical systems theory and occurs in many real systems. It has been observed here for the first time in real rotating fluid flows and is thought to be highly relevant to explain low-frequency variability in ocean WBCs.

The Prevention of Occupational Heat Stress in Sugarcane Workers in Nicaragua-An Interpretative Phenomenological Analysis.

Background: Chronic kidney disease of non-traditional origin (CKDnt) is an ongoing epidemic that has taken the lives of tens of thousands of people in Mesoamerica, also affecting other tropical geographies. Occupational heat stress, which will increase worldwide as climate change persists, has been identified as a primary trigger of kidney injury and reduced renal function. At Nicaragua's largest sugarcane mill, the water, rest, and shade (WRS) intervention has proven to reduce the risk of heat stress and kidney injury effectively as assessed by the research and policy NGO La Isla Network (LIN) and their academic partners, who have worked with the sugar mill to improve the design of their intervention system. However, discrepancies between intervention design and implementation have been found. This study explores the perceptions of the WRS intervention in the company from the perspective of positions responsible for the workers' environment and heat stress prevention implementation. Methods: A qualitative design was used in the study. Twenty-one key informants of low and middle management, field assistants, and two members from LIN took part in the study. Semi-structured interviews were used to collect the data. Interviews' transcriptions were analyzed using interpretative phenomenological analysis (IPA). Results: Four main themes were developed in the analysis of the data: "A worthwhile struggle," "Culture of care", "Traditional production culture Vs. Culture of care," and "The importance of the formalization of care." Each theme contained sub-themes, all of which were further discussed in the light of organizational psychology. Conclusion and Implications: Discretionary differences resulting in low and middle management prioritizing production over health protection appeared to relate to a fair part of the implementation challenges and indicate that more efforts are needed to align operations' production and health goals. Education enhancement might be necessary, while further focus on health metrics for performance assessment might offer an opportunity to level perceived incentives and value of health and production.

PSMA PET/CT to evaluate response to SBRT for prostate cancer bone metastases.

BACKGROUND: In the current study we evaluated 68Ga PSMA PET/ CT to measure local control of bone metastasis in oligometastatic prostate cancer patients treated with SBRT. MATERIALS AND METHODS: After the institutional review board approval, a retrospective review of medical records of consecutive prostate cancer patients treated between 2014 and 2018 was conducted. Only medical records of patients that were treated with SBRT for bone metastasis and had pre-and post-SBRT 68Ga PSMA PET/CT scans were included in our study. Data extracted from the medical files included patient-related (age), disease-related (Gleason score, site of metastasis), and treatment-related factors and outcomes. RESULTS: During the study period, a total of 12 patients (15 lesions) were included, with a median age of 73 years. The median follow-up was 26.5 months (range 13-45 months). Median time of 68Ga PSMA PET/ CT follow up was 17.0 months (range 3-39 months). The median pre-treatment PSA was 2 ng/mL (range 0.56-44 ng/mL) vs. post treatment PSA nadir of 0.01 ng/mL (0.01-4.32) with a median time to nadir of 7 months (range, 2-12). Local control was 93% during the follow up period and there was correlation with PS MA avidity on PE T. None patients developed recurrences in the treated bone. None of the patients had grade 3 or more toxicities during follow-up. CONCLUSIONS: SBRT is a highly effective and safe method for treatment of prostate cancer bone metastases. More studies are required to determine if SBRT provides greater clinical benefit than standard fractionation for oligometastatic prostate cancer patients. 68Ga PSMA PET/CT should be further investigated for delineation and follow-up.

Salvage re-irradiation using stereotactic body radiation therapy for locally recurrent prostate cancer: the impact of castration sensitivity on treatment outcomes.

BACKGROUND: Advances in imaging, biomaterials and precision radiotherapy provide new opportunities to salvage locally recurrent prostate cancer (PC). This study evaluates the efficacy and safety of re-irradiation using stereotactic body radiation therapy (SBRT). We hypothesized that patients with castrate-resistant PC (CRPC) would benefit less from local salvage. METHODS: A prospective clinical database was reviewed to extract 30 consecutive patients treated with prostate re-irradiation. Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography was performed following prostate-specific antigen failure in all patients and biopsy was obtained in 18 patients (60%). Re-irradiation was either focal (n = 13) or whole-gland (n = 17). Endo-rectal balloons were used in twenty-two patients and hydrogel spacers in eight patients. The median prescription dose was 5 fractions of 6.5 (range: 6-8) Gray (Gy). RESULTS: Median follow-up was 28 months. Failure occurred in 10 (out of 11) CRPC patients versus 6 (out of 19) castrate-sensitive patients (91% vs. 32%, p = 0.008) after a median of 13 and 23 months, respectively. Metastases occurred in 64% (n = 7) of CRPC patients versus 16% (n = 3) of castrate-sensitive patients (p = 0.007). Two patients experienced local in-field recurrence, thus local control was 93%. The 2 and 3-year recurrence-free survival were 84% and 79% for castrate-sensitive patients versus 18% and 9% for CRPC patients (p < 0.001), and 3-year metastasis-free survival was 90% versus 27% (p < 0.01) for castrate-sensitive and CRPC patients, respectively. Acute grade II and III genitourinary (GU) toxicity occurred in 27% and 3%, and late GU toxicity in 30% and 3%, respectively. No ≥ grade II acute gastrointestinal (GI) toxicity occurred, and only one patient (3%) developed late grade II toxicity. CONCLUSIONS: Early delivery of salvage SBRT for local recurrence is associated with excellent 3-year disease control and acceptable toxicity in the castrate-sensitive phenotype. PSMA imaging for detection of local recurrence and the use of precision radiotherapy with rectal protective devices should be further investigated as a novel salvage strategy for radio-recurrent PC.

Benefits of Continuous Positive Airway Pressure (CPAP) During Radiation Therapy: A Prospective Trial.

PURPOSE: This study aimed to study the impact of continuous positive airway pressure (CPAP) on chest anatomy and tumor motion in patients receiving radiation therapy. METHODS AND MATERIALS: Patients with primary or secondary lung tumors, left-sided breast cancer, or liver metastases referred for radiation therapy were trained to breathe with a CPAP device using a face mask to a maximal pressure of 15 cm H2O. Three- and 4-dimensional computed tomography simulation was performed twice for each patient: once with free breathing (FB) and again using CPAP. Volumetric and dosimetric parameters of treatment plans were compared. RESULTS: Forty-nine patients were enrolled, of whom 6 withdrew consent before simulation and 3 withdrew because of discomfort. Thus, a total of 40 patients were analyzed. Twenty-seven patients (67.5%) were treated with CPAP based on confirmation of the volumetric or dosimetric benefit of CPAP. Mean lung volume increased by 37% (P < .001). The mean augmentation was 1283 ± 1128 cm3 (CPAP vs FB; P = .0006) in patients with normal lung function tests and 719 ± 341 cm3 (P = .003) in patients with a restrictive pattern. Increased lung volume was independent of age, body mass index, sex, chronic obstructive pulmonary disease, smoking status, and heart disease. Tumor motion in the lung was decreased as reflected in a mean reduction of planning target volume by 19% (P < .001). The greatest reduction of tumor trajectory and planning target volume occurred in tumors in the lower lung, particularly in the range of up to 6 cm above the dome of the diaphragm. The mean lung dose was reduced by 15%, lung V20 by 20%, lung V5 by 11%, and heart V5 by 16% (P < .01). CONCLUSIONS: In this prospective trial, the use of CPAP was associated with significant volumetric and dosimetric benefits compared with FB. CPAP was safe, simple to implement, and well tolerated by most patients, and it should be studied further as a method to reduce the risk of lung and heart toxicity.

Is Ultra Hypofractionated Radiation Therapy a Safe and Effective Treatment for Invasive Bladder Cancer in the Elderly?: A Retrospective Single Institution Review.

PURPOSE: The aim was to determine the efficacy, safety, and tolerability of weekly ultra hypofractionated radiation therapy for older unfit patients with invasive bladder cancer. METHODS: We retrospectively analyzed a cohort of patients with muscle invasive bladder cancer deemed unfit for chemoradiation therapy and thus treated with 6 weekly doses of 6 Gy using intensity modulated radiotherapy. Charlson comorbidity was calculated retrospectively. Cystoscopy and computed tomography were used to evaluate local control and toxicity using the common terminology criteria. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS: Twenty-two patients with a median age of 84 (range: 70 to 96) years were included. The median comorbidity index was 6±1.5 SD. Nineteen (90%) patients received the full 36 Gy dose. Median follow-up was 10±7 months (range: 6 to 27 mo). Local control in the bladder was achieved in 16 of 19 evaluable patients (84%). One-year overall survival was 62.5%, 1 patient had a retroperitoneal nodal recurrence and 3 patients developed distant metastasis. Grade 3 genitourinary and gastrointestinal toxicity was observed in 4 (18%) and 1 (4.5%) patients, respectively. CONCLUSION: Weekly ultra hypofractionated intensity modulated radiotherapy with image guidance and bladder training is an effective, safe, and well-tolerated regimen for older patients with invasive bladder cancer unfit for radical treatment.

Pathophysiological Mechanisms by which Heat Stress Potentially Induces Kidney Inflammation and Chronic Kidney Disease in Sugarcane Workers.

BACKGROUND: Chronic kidney disease of non-traditional origin (CKDnt) is common among Mesoamerican sugarcane workers. Recurrent heat stress and dehydration is a leading hypothesis. Evidence indicate a key role of inflammation. METHODS: Starting in sports and heat pathophysiology literature, we develop a theoretical framework of how strenuous work in heat could induce kidney inflammation. We describe the release of pro-inflammatory substances from a leaky gut and/or injured muscle, alone or in combination with tubular fructose and uric acid, aggravation by reduced renal blood flow and increased tubular metabolic demands. Then, we analyze longitudinal data from >800 sugarcane cutters followed across harvest and review the CKDnt literature to assess empirical support of the theoretical framework. RESULTS: Inflammation (CRP elevation and fever) and hyperuricemia was tightly linked to kidney injury. Rehydrating with sugary liquids and NSAID intake increased the risk of kidney injury, whereas electrolyte solution consumption was protective. Hypokalemia and hypomagnesemia were associated with kidney injury. DISCUSSION: Heat stress, muscle injury, reduced renal blood flow and fructose metabolism may induce kidney inflammation, the successful resolution of which may be impaired by daily repeating pro-inflammatory triggers. We outline further descriptive, experimental and intervention studies addressing the factors identified in this study.

Preventing kidney injury among sugarcane workers: promising evidence from enhanced workplace interventions.

OBJECTIVES: To assess if improvement of working conditions related to heat stress was associated with improved kidney health outcomes among sugarcane harvest workers in Chichigalpa, Nicaragua, a region heavily affected by the epidemic of chronic kidney disease of non-traditional origin. METHODS: Based on our findings during the 2017-2018 harvest (harvest 1), recommendations that enhanced the rest schedule and improved access to hydration and shade were given before the 2018-2019 harvest (harvest 2). Actual work conditions during harvest 2 were then observed. Serum creatinine (SCr) was measured before and at end-harvest, and cross-harvest changes in estimated glomerular filtration rate (eGFR) and incident kidney injury (IKI, ie, SCr increase by ≥0.30 mg/dL or ≥1.5 times the baseline value) were compared between harvest 1 and harvest 2 for three jobs with different physical workloads using regression modelling. Workers who left during harvest were contacted at home, to address the healthy worker selection effect. RESULTS: In burned cane cutters, mean cross-harvest eGFR decreased 6 mL/min/1.73 m2 (95% CI 2 to 9 mL/min/1.73 m2) less and IKI was 70% (95% CI 90% to 50%) lower in harvest 2 as compared with harvest 1 data. No such improvements were seen among seed cutters groups with less successful intervention implementation. CONCLUSION: Kidney injury risk was again elevated in workers with strenuous jobs. The results support further efforts to prevent kidney injury among sugarcane workers, and other heat-stressed workers, by improving access to water, rest and shade. The distinction between design and implementation of such interventions should be recognised.

Radiation-Associated Secondary Malignancies in BRCA Mutation Carriers Treated for Breast Cancer.

PURPOSE: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM. METHODS AND MATERIALS: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined. RESULTS: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma. CONCLUSIONS: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers.

Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress.

The death toll of the epidemic of chronic kidney disease of nontraditional origin (CKDnt) in Mesoamerica runs into the tens of thousands, affecting mostly young men. There is no consensus on the etiology. Anecdotal evidence from the 1990s pointed to work in sugarcane; pesticides and heat stress were suspected. Subsequent population-based surveys supported an occupational origin with overall high male-female ratios in high-risk lowlands, but small sex differences within occupational categories, and low prevalence in non-workers. CKDnt was reported in sugarcane and other high-intensity agriculture, and in non-agricultural occupations with heavy manual labor in hot environments, but not among subsistence farmers. Recent studies with stronger designs have shown cross-shift changes in kidney function and hydration biomarkers and cross-harvest kidney function declines related to heat and workload. The implementation of a water-rest-shade intervention midharvest in El Salvador appeared to halt declining kidney function among cane cutters. In Nicaragua a water-rest-shade program appeared sufficient to prevent kidney damage among cane workers with low-moderate workload but not among cutters with heaviest workload. Studies on pesticides and infectious risk factors have been largely negative. Non-occupational risk factors do not explain the observed epidemiologic patterns. In conclusion, work is the main driver of the CKDnt epidemic in Mesoamerica, with occupational heat stress being the single uniting factor shown to lead to kidney dysfunction in affected populations. Sugarcane cutters with extreme heat stress could be viewed as a sentinel occupational population. Occupational heat stress prevention is critical, even more so in view of climate change.

La mortalidad por la epidemia de enfermedad renal crónica de origen no tradicional (ERCnt) en Mesoamérica asciende a decenas de miles de personas, principalmente hombres jóvenes. No existe consenso sobre su etiología. En la década de 1990, informes anecdóticos apuntaban como factor de riesgo al trabajo en plantaciones de caña de azúcar; se consideró como posibles causantes a los plaguicidas y el estrés térmico. Estudios de prevalencia de base poblacional subsiguientes apoyaron un origen ocupacional, con una proporción elevada de hombres respecto de las mujeres en las tierras bajas donde el riesgo era elevado, pero con pequeñas diferencias de sexo dentro de las categorías ocupacionales y baja prevalencia en el ámbito no laboral. Se reportó ERCnt en los trabajadores de la caña de azúcar y otros cultivos con alta exigencia física y en ocupaciones no agrícolas que implican trabajo manual intenso en ambientes calurosos, pero no entre los agricultores de subsistencia. Estudios recientes con diseños más sólidos han demostrado cambios en la función renal y en los biomarcadores de hidratación en el curso de los turnos laborales, y disminución de la función renal relacionada con el calor y la carga de trabajo en el curso de la cosecha. La implementación de una intervención basada en la provisión de agua, descanso y sombra a mitad de la cosecha en El Salvador detuvo la disminución de la función renal en los cortadores de caña. En Nicaragua, un programa de provisión de agua, descanso y sombra evitó la lesión renal en los trabajadores de la caña con una carga de trabajo baja y moderada, pero no entre los cortadores, quienes tienen la mayor carga de trabajo. Los estudios sobre plaguicidas y factores de riesgo infecciosos han sido en gran medida negativos. Los factores de riesgo no ocupacionales no explican los patrones epidemiológicos observados. En conclusión, el trabajo es el principal desencadenante de la epidemia de ERCnt en Mesoamérica, y el estrés térmico ocupacional es el único factor que consistentemente conduce a la disfunción renal en las poblaciones afectadas. Los cortadores que trabajan en los ingenios azucareros y están expuestos a un estrés térmico extremo podrían ser considerados una población ocupacional centinela. La prevención del estrés térmico ocupacional es crítica, más aún si se consideran los efectos del cambio climático.

A mortalidade devida à epidemia de doença renal crônica de origem não tradicional (DRCnt) na Mesoamérica atinge dezenas de milhares de pessoas, principalmente homens jovens. Não há consenso sobre a sua etiologia. Na década de 1990, informações empíricas apontavam o trabalho em plantações de cana de açúcar como um fator de risco; pesticidas e estresse térmico também eram considerados causas possíveis. As pesquisas populacionais subsequentes sustentam uma origem ocupacional da doença, com uma elevada proporção de homens quando comparados à de mulheres, em areas de baixa altitude, onde o risco da doença é mais elevado, mas com pequenas diferenças de gênero quando se consideram as categorias ocupacionais e baixa prevalência no ambiente não-ocupacional. A DRCnt foi identificada em trabalhadores agrícolas da cana de açúcar e de outras culturas que exigem trabalho físico de alta intensidade e em ocupações não agrícolas envolvendo um trabalho manual intenso em ambientes quentes, mas não entre os agricultores de subsistência. Estudos recentes com desenhos mais robustos demonstraram mudanças na função renal e nos biomarcadores de hidratação ao longo dos turnos de trabalho, e diminuição da função renal relacionada à exposição ao calor e à carga de trabalho ao longo da colheita. A implementação de uma intervenção de água-descanso-sombra durante a colheita em El Salvador interrompeu o declínio da função renal em cortadores de cana. Na Nicarágua, intervenções água-descanso-sombra parecem ter sido suficientes para evitar lesões renais em trabalhadores canavieiros com cargas de trabalho baixa e moderada, mas não entre os cortadores de cana que têm carga de trabalho mais pesada. Estudos sobre exposição a pesticidas e a fatores de risco de origem infecciosa têm sido largamente negativos. Os fatores de risco não-ocupacionais não explicam os padrões epidemiológicos observados. Em conclusão, ocupação é o principal desencadeador da epidemia de DRCnt na Mesoamérica, e o estresse térmico ocupacional é o único fator comprovado que leva à disfunção renal nas populações afetadas. Os cortadores de cana que trabalham em engenhos de açúcar e expostos a um estresse térmico extremo podem ser considerados uma população ocupacional sentinela. A prevenção do estresse térmico ocupacional é crítica, especialmente considerando os efeitos das mudanças climáticas.

Chronic kidney disease of non-traditional origin in Mesoamerica: a disease primarily driven by occupational heat stress

[ABSTRACT]. The death toll of the epidemic of chronic kidney disease of nontraditional origin (CKDnt) in Mesoamerica runs into the tens of thousands, affecting mostly young men. There is no consensus on the etiology. Anecdotal evidence from the 1990s pointed to work in sugarcane; pesticides and heat stress were suspected. Subsequent population-based surveys supported an occupational origin with overall high male-female ratios in high-risk lowlands, but small sex differences within occupational categories, and low prevalence in non-workers. CKDnt was reported in sugarcane and other high-intensity agriculture, and in non-agricultural occupations with heavy manual labor in hot environments, but not among subsistence farmers. Recent studies with stronger designs have shown cross-shift changes in kidney function and hydration biomarkers and cross-harvest kidney function declines related to heat and workload. The implementation of a water-rest-shade intervention midharvest in El Salvador appeared to halt declining kidney function among cane cutters. In Nicaragua a water-rest-shade program appeared sufficient to prevent kidney damage among cane workers with low-moderate workload but not among cutters with heaviest workload. Studies on pesticides and infectious risk factors have been largely negative. Non-occupational risk factors do not explain the observed epidemiologic patterns. In conclusion, work is the main driver of the CKDnt epidemic in Mesoamerica, with occupational heat stress being the single uniting factor shown to lead to kidney dysfunction in affected populations. Sugarcane cutters with extreme heat stress could be viewed as a sentinel occupational population. Occupational heat stress prevention is critical, even more so in view of climate change.

[RESUMEN]. La mortalidad por la epidemia de enfermedad renal crónica de origen no tradicional (ERCnt) en Mesoamérica asciende a decenas de miles de personas, principalmente hombres jóvenes. No existe consenso sobre su etiología. En la década de 1990, informes anecdóticos apuntaban como factor de riesgo al trabajo en plantaciones de caña de azúcar; se consideró como posibles causantes a los plaguicidas y el estrés térmico. Estudios de prevalencia de base poblacional subsiguientes apoyaron un origen ocupacional, con una proporción elevada de hombres respecto de las mujeres en las tierras bajas donde el riesgo era elevado, pero con pequeñas diferencias de sexo dentro de las categorías ocupacionales y baja prevalencia en el ámbito no laboral. Se reportó ERCnt en los trabajadores de la caña de azúcar y otros cultivos con alta exigencia física y en ocupaciones no agrícolas que implican trabajo manual intenso en ambientes calurosos, pero no entre los agricultores de subsistencia. Estudios recientes con diseños más sólidos han demostrado cambios en la función renal y en los biomarcadores de hidratación en el curso de los turnos laborales, y disminución de la función renal relacionada con el calor y la carga de trabajo en el curso de la cosecha. La implementación de una intervención basada en la provisión de agua, descanso y sombra a mitad de la cosecha en El Salvador detuvo la disminución de la función renal en los cortadores de caña. En Nicaragua, un programa de provisión de agua, descanso y sombra evitó la lesión renal en los trabajadores de la caña con una carga de trabajo baja y moderada, pero no entre los cortadores, quienes tienen la mayor carga de trabajo. Los estudios sobre plaguicidas y factores de riesgo infecciosos han sido en gran medida negativos. Los factores de riesgo no ocupacionales no explican los patrones epidemiológicos observados. En conclusión, el trabajo es el principal desencadenante de la epidemia de ERCnt en Mesoamérica, y el estrés térmico ocupacional es el único factor que consistentemente conduce a la disfunción renal en las poblaciones afectadas. Los cortadores que trabajan en los ingenios azucareros y están expuestos a un estrés térmico extremo podrían ser considerados una población ocupacional centinela. La prevención del estrés térmico ocupacional es crítica, más aún si se consideran los efectos del cambio climático.

[RESUMO]. A mortalidade devida à epidemia de doença renal crônica de origem não tradicional (DRCnt) na Mesoamérica atinge dezenas de milhares de pessoas, principalmente homens jovens. Não há consenso sobre a sua etiologia. Na década de 1990, informações empíricas apontavam o trabalho em plantações de cana de açúcar como um fator de risco; pesticidas e estresse térmico também eram considerados causas possíveis. As pesquisas populacionais subsequentes sustentam uma origem ocupacional da doença, com uma elevada proporção de homens quando comparados à de mulheres, em areas de baixa altitude, onde o risco da doença é mais elevado, mas com pequenas diferenças de gênero quando se consideram as categorias ocupacionais e baixa prevalência no ambiente não-ocupacional. A DRCnt foi identificada em trabalhadores agrícolas da cana de açúcar e de outras culturas que exigem trabalho físico de alta intensidade e em ocupações não agrícolas envolvendo um trabalho manual intenso em ambientes quentes, mas não entre os agricultores de subsistência. Estudos recentes com desenhos mais robustos demonstraram mudanças na função renal e nos biomarcadores de hidratação ao longo dos turnos de trabalho, e diminuição da função renal relacionada à exposição ao calor e à carga de trabalho ao longo da colheita. A implementação de uma intervenção de água-descanso-sombra durante a colheita em El Salvador interrompeu o declínio da função renal em cortadores de cana. Na Nicarágua, intervenções água-descanso-sombra parecem ter sido suficientes para evitar lesões renais em trabalhadores canavieiros com cargas de trabalho baixa e moderada, mas não entre os cortadores de cana que têm carga de trabalho mais pesada. Estudos sobre exposição a pesticidas e a fatores de risco de origem infecciosa têm sido largamente negativos. Os fatores de risco não-ocupacionais não explicam os padrões epidemiológicos observados. Em conclusão, ocupação é o principal desencadeador da epidemia de DRCnt na Mesoamérica, e o estresse térmico ocupacional é o único fator comprovado que leva à disfunção renal nas populações afetadas. Os cortadores de cana que trabalham em engenhos de açúcar e expostos a um estresse térmico extremo podem ser considerados uma população ocupacional sentinela. A prevenção do estresse térmico ocupacional é crítica, especialmente considerando os efeitos das mudanças climáticas.

Workload and cross-harvest kidney injury in a Nicaraguan sugarcane worker cohort.

OBJECTIVES: To examine the association between workload and kidney injury in a fieldworker cohort with different levels of physically demanding work over a sugarcane harvest, and to assess whether the existing heat prevention efforts at a leading occupational safety and health programme are sufficient to mitigate kidney injury. METHODS: Biological and questionnaire data were collected before (n=545) and at the end (n=427) of harvest among field support staff (low workload), drip irrigation workers (moderate), seed cutters (high) and burned sugarcane cutters (very high). Dropouts were contacted (87%) and reported the reason for leaving work. Cross-harvest incident kidney injury (IKI) was defined as serum creatinine increase ≥0.30 mg/dL or ≥1.5 times the baseline value, or among dropouts reporting kidney injury leading to leaving work. RESULTS: Mean cross-harvest estimated glomerular filtration rate change was significantly associated with workload, increasing from 0 mL/min/1.73 m2 in the low-moderate category to -5 mL/min/1.73 m2 in the high and -9 mL/min/1.73 m2 in the very high workload group. A similar pattern occurred with IKI, where low-moderate workload had 2% compared with 27% in the very high workload category. A healthy worker selection effect was detected, with 32% of dropouts reporting kidney injury. Fever and C reactive protein elevation were associated with kidney injury. CONCLUSIONS: Workers considered to have the highest workload had more cross-harvest kidney damage than workers with less workload. Work practices preventing heat stress should be strengthened and their role in preventing kidney damage examined further. Future occupational studies on chronic kidney disease of unknown aetiology should account for a healthy worker effect by pursuing those lost to follow-up.

Radiotherapy with or without androgen deprivation therapy in intermediate risk prostate cancer?

OBJECTIVE: Androgen deprivation therapy (ADT) is beneficial for unfavorable intermediate-risk (IR) prostate cancer patients receiving curative radiotherapy (RT). However, for favorable IR patients the latest NCCN guidelines recommends RT alone. We retrospectively studied treatment patterns and outcomes of patients with IR prostate cancer in our institution over the past two decades. MATERIALS AND METHODS: Three hundred seventy-three IR prostate cancer patients treated with definitive RT between 5/2002-5/2016 were identified in an institutional review board approved database. All patients received conformal RT to the prostate while the vast majority did not receive nodal radiation. ADT was commenced 2 months prior to RT and was continued for 4 months after RT. RESULTS: Compared to RT alone, patients receiving combined RT+ ADT had more positive biopsy cores, higher pre-radiation PSA, more IR factors, and were more likely to receive pelvic lymph node radiation. However, there were no differences in failure either biochemical, local or distal, nor on survival between the favorable RT alone and the unfavorable RT+ ADT cohorts, suggesting a beneficial role for ADT. On multivariate analysis, patients 70 years or younger receiving RT alone were at increased risk for biochemical failure during a 6-year follow-up (HR 3.06, P = 0.025). Biochemical relapse free survival in patients ≤70 years who received RT alone was 82.1% vs 94.0% for RT + ADT (P = 0.030). There was no difference for combined treatment modality in patients > 70 years (P = 0.87). CONCLUSIONS: Men 70 years or younger with favorable IR prostate cancer treated with RT alone to 78 Gy are at increased risk of biochemical failure. Short term ADT should be considered in this cohort of men.

Accelerated Hypofractionated Radiation Therapy for Elderly Frail Bladder Cancer Patients Unfit for Surgery or Chemotherapy.

PURPOSE/OBJECTIVES: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. MATERIALS AND METHODS: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. RESULTS: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index ≥3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). CONCLUSIONS: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT.

Kidney Injury from Recurrent Heat Stress and Rhabdomyolysis: Protective Role of Allopurinol and Sodium Bicarbonate.

BACKGROUND: Heat stress and rhabdomyolysis are major risk factors for the occurrence of repeated acute kidney injury in workers exposed to heat and strenuous work. These episodes, in turn, may progress to chronic kidney disease. OBJECTIVE: The purpose of this study was to test the effect of allopurinol (AP) and sodium bicarbonate on the kidney injury induced by recurrent heat stress dehydration with concomitant repeated episodes of rhabdomyolysis. METHODS: The model consisted of heat stress exposure (1 h, 37°C) plus rhabdomyolysis (R) induced by repetitive IM injections of glycerol (7.5 mL/kg BW days) in the rat. In addition, to replicate the human situation, uricase was inhibited (oxonic acid [OA] 750 mg/K/d) to increase uric acid (UA) levels. Additional groups were treated either with AP 150 mg/L, n = 10, bicarbonate (BC; 160 mM, n = 10), or both (AP + BC, n = 10) in drinking water. We also included 2 control groups consisting of normal controls (N-Ref, n = 5) and uricase-inhibited rats (OA, n = 5) that were not exposed to heat or muscle injury. Groups were studied for 35 days. RESULTS: Uricase-inhibited rats exposed to heat and rhabdomyolysis developed pathway and increased intrarenal oxidative stress and inflammasome activation. Kidney injury could be largely prevented by AP, and also BC, although the treatments were not synergistic. CONCLUSION: Increased levels of UA may play an important role in the renal alterations induced by heat stress and continuous episodes of rhabdomyolysis. Therefore, treatments aimed to reduce hyperuricemia may help to decrease the renal burden in these conditions. Clinical trials are suggested to test whether this is also true in humans.

Respuesta: Pesticidas y estrés térmico en la epidemia global de enfermedad renal crónica de causas no tradicionales / No disponible

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