Relationship Between High Blood Pressure, Atrial Cardiopathy, and Mortality in the General Population.

BACKGROUND: Atrial cardiopathy is associated with an increased risk of mortality. However, it is unclear whether this association is modified by hypertension, a risk factor for both atrial cardiopathy and mortality. METHODS: This analysis included 8,023 participants from the Third National Health and Nutrition Examination Survey. Electrocardiographic deep terminal negativity of P-wave in V1 ≥100 µV defined atrial cardiopathy. National Death Index was used to identify the date and cause of death. Cox proportional hazard analysis was used to examine the association of atrial cardiopathy with mortality among participants stratified by hypertension status. RESULTS: In total 2.7% of the participants had atrial cardiopathy. Over a median follow-up of 14 years, 2,922 all-cause deaths occurred, of which 1,058 were CVD. All-cause death rates were almost double among participants with concomitant atrial cardiopathy and elevated blood pressure (BP) (120-129/<80), stage 1 (130-139/80-89), or stage 2 hypertension (≥140/≥90) compared to their counterparts in the same hypertension stages without atrial cardiopathy (47.8, 61.3, and 80.2 vs. 23, 24.7, and 44.8 per 1,000 person-years (PY), respectively). In multivariable-adjusted models, a stronger association between atrial cardiopathy and all-cause mortality was observed in the presence compared to the absence of hypertension (HR (95% CI): 1.59 (1.25-2.01) vs. 0.67 (0.41-1.10), respectively, interaction P-value = 0.009). Similarly, an association between atrial cardiopathy and cardiovascular disease (CVD) mortality was observed in the presence compared to the absence of hypertension (HR (95% CI): 1.64 (1.08-2.47) vs. 0.63 (0.20-2.00), respectively, interaction P-value = 0.20). CONCLUSIONS: Concomitant presence of high BP and atrial cardiopathy carries a higher risk of mortality, and the risk increases with higher BP levels.

Mummichog gill and operculum exhibit functionally consistent claudin-10 paralog profiles and Claudin-10c hypersaline response.

Claudin (Cldn)-10 tight junction (TJ) proteins are hypothesized to form the paracellular Na+ secretion pathway of hyposmoregulating mummichog (Fundulus heteroclitus) branchial epithelia. Organ-specific expression profiles showed that only branchial organs [the gill and opercular epithelium (OE)] exhibited abundant cldn-10 paralog transcripts, which typically increased following seawater (SW) to hypersaline (2SW) challenge. Post-translational properties, protein abundance, and ionocyte localization of Cldn-10c, were then examined in gill and OE. Western blot analysis revealed two Cldn-10c immunoreactive bands in the mummichog gill and OE at ∼29 kDa and ∼40 kDa. The heavier protein could be eliminated by glycosidase treatment, demonstrating the novel presence of a glycosylated Cldn-10c. Protein abundance of Cldn-10c increased in gill and OE of 2SW-exposed fish. Cldn-10c localized to the sides of gill and OE ionocyte apical crypts and partially colocalized with cystic fibrosis transmembrane conductance regulator and F-actin, consistent with TJ complex localization. Cldn-10c immunofluorescent intensity increased but localization was unaltered by 2SW conditions. In support of our hypothesis, cldn-10/Cldn-10 TJ protein dynamics in gill and OE of mummichogs and TJ localization are functionally consistent with the creation and maintenance of salinity-responsive, cation-selective pores that facilitate Na+ secretion in hyperosmotic environments.

Clinical Outcomes of Rhegmatogenous Retinal Detachment Treated With Pneumatic Retinopexy.

IMPORTANCE: Pneumatic retinopexy (PR) is the only clinic-based method of rhegmatogenous retinal detachment (RRD) repair. Registry-acquired clinical practice setting outcomes data with this procedure have not yet been reported. OBJECTIVE: To describe the clinical outcomes associated with RRD treated primarily with PR. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, data from patients 19 years and older with noncomplex RRD treated at academic and private ophthalmology practices participating in the American Academy of Ophthalmology IRIS Registry (Intelligent Research in Sight) were analyzed. Data were collected from January 1, 2013, to December 31, 2019, and data were analyzed from January to December 2020. EXPOSURES: Data from the IRIS Registry were queried for eyes that underwent PR for noncomplex RRD and had at least 3 months of follow-up. Cases were identified by a combination of diagnosis code for RRD and a Current Procedural Terminology code for PR. MAIN OUTCOMES AND MEASURES: The number of eyes that achieved single-operation success (SOS), defined as retinal reattachment without a subsequent retinal detachment surgery or repeated PR. RESULTS: Of 9553 included patients, 5827 (61.0%) were male, and the mean (SD) age was 62 (10) years. A total of 9659 eyes were identified. SOS was achieved in 6613 eyes (68.5%). Best-corrected visual acuity significantly differed 9 to 12 months after treatment between the SOS group, with a mean of 0.24 logMAR (95% CI, 0.23-0.25; approximate Snellen equivalent, 20/35), and the single-operation failure group, with a mean of 0.43 logMAR (95% CI, 0.40-0.46; approximate Snellen equivalent, 20/54). Among all patients, the mean time to maximal visual recovery was 268 days (95% CI, 260-276). Endophthalmitis was observed in 3 eyes (0.03%). SOS was associated with female sex (odds ratio, 1.51; 95% CI, 1.38-1.65), while current smoking status was associated single-operation failure (odds ratio, 0.78; 95% CI, 0.68-0.91). CONCLUSIONS AND RELEVANCE: In this registry-based study, which encompasses a large number of eyes drawn from multiple, heterogenous electronic health record systems, SOS was achieved in 68.5% of eyes with noncomplex RRD treated by primary PR. It is unknown how these outcomes would have compared with other methods of RRD repair in this cohort.

Ion-poor water and dietary salt deprivation upregulate the ghrelinergic system in the goldfish (Carassius auratus).

Because the ghrelinergic system in teleost fishes is broadly expressed in organs that regulate appetite as well as those that contribute to the regulation of salt and water balance, we hypothesized that manipulating salt and water balance in goldfish (Carassius auratus) would modulate the ghrelinergic system. Goldfish were acclimated to either freshwater (FW) or ion-poor FW (IPW) and were fed either a control diet containing 1% NaCl or low-salt diet containing 0.1% NaCl. Endpoints of salt and water balance, i.e., serum Na+ and Cl- levels, muscle moisture content and organ-specific Na+ -K+ -ATPase (NKA) activity, were examined in conjunction with brain, gill and gut mRNA abundance of preproghrelin and its receptor, growth hormone secretagogue receptor (ghs-r). Acclimation of fish to IPW reduced serum osmolality and Cl- levels and elevated kidney NKA activity, while FW fish fed a low NaCl diet exhibited a modest reduction in muscle moisture content but otherwise no apparent osmoregulatory disturbance. In contrast, a combined treatment of IPW acclimation and low dietary NaCl content reduced serum osmolality and Cl- levels, elevated muscle moisture content and increased gill, kidney and intestinal NKA activity. This intensified response to the combined effects of water and dietary ion deprivation is consistent with an increased effort to enhance ion acquisition. In association with these latter observations, a significant upregulation of preproghrelin mRNA expression in brain and gut was observed. A significant increase in ghs-r mRNAs was also observed in the gill of goldfish acclimated to IPW alone but a reduction in dietary NaCl content did not impact the ghrelinergic system of goldfish in FW. The results support the hypothesis that the ghrelinergic system is modulated in response to manipulated salt and water balance. Whether the central and peripheral ghrelinergic system contributes to ionic homeostasis in goldfish currently remains unclear and warrants further research.

Tube Versus Trabeculectomy IRISⓇ Registry 1-Year Composite Outcome Analysis with Comparisons to the Randomized Controlled Trial.

PURPOSE: This study compared 1-year results for the composite treatment outcome from the Tube Versus Trabeculectomy (TVT) randomized controlled trial (RCT) to those from an IRISⓇ (Intelligent Research In Sight) Registry cohort of analogous eyes. DESIGN: Retrospective clinical study with comparison to an RCT. METHODS: Subjects' eyes in the IRIS Registry received either a glaucoma drainage implant (tube) or underwent trabeculectomy after a previous trabeculectomy and/or cataract extraction and had data for 1-year follow-up analyses. OUTCOME: Eyes were classified as failing if they had hypotony (intraocular pressure (IOP) ≤5 mm Hg) or inadequate IOP control (IOP >21 mm Hg or not reduced at least 20% below baseline) on 2 consecutive follow-up visits after 3 months, a reoperation for glaucoma, or no light perception vision and as successful otherwise. Failure risk was compared by treatment, demographic, and clinical variables and was compared to analogous failure risks from the TVT RCT. RESULTS: The TVT IRIS Registry cohort included 419 eyes, 236 tube eyes (56.3%) and 183 trabeculectomy eyes (43.7%). In this cohort, there was no significant failure risk difference (12.3% for tube eyes and 16.4% for trabeculectomy eyes, P = 0.231). Comparing the studies, there was a significantly greater risk of failure in the TVT IRIS Registry tube eyes than in the TVT RCT tube eyes (3.8%; P <.001). Reasons for treatment failure included reoperations for glaucoma (none in the TVT RCT at 1 year). CONCLUSIONS: Our results were different from those in the TVT RCT. Possible reasons include non-Baerveldt tubes, greater severity among tube eyes, and practice patterns that reflect real-world data, which are different than those in RCTs.

Demographic and Clinical Characteristics Associated with Minimally Invasive Glaucoma Surgery Use: An Intelligent Research in Sight (IRIS®) Registry Retrospective Cohort Analysis.

PURPOSE: Minimally invasive glaucoma surgery (MIGS) is increasingly performed at the time of cataract extraction. Understanding the demographic and clinical characteristics of patients undergoing MIGS procedures may provide insight into patient selection. This study evaluates racial-ethnic and other differences in the use of MIGS in persons with cataract and open-angle glaucoma (OAG). DESIGN: Retrospective cohort study using Intelligent Research in Sight (IRIS) Registry data. PARTICIPANTS: Patients aged ≥ 40 years with a diagnosis of OAG and no history of MIGS or cataract surgery who were undergoing cataract extraction, with or without MIGS, during 2013 to 2017 in the United States. METHODS: Multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Variables assessed include age, sex, race-ethnicity, disease severity, insurance type, census region, comorbidity, and cup-to-disc ratio (CDR). RESULTS: The odds of MIGS use was greater among patients who were aged ≥ 60 years (OR, 1.10 [95% CI, 1.05-1.16]); Black (OR, 1.11 [CI, 1.07-1.15]) compared with White; a Medicare recipient (OR, 1.12 [CI, 1.10-1.15]) versus privately insured; or in the Midwest (OR, 1.32 [CI, 1.28-1.36]) or Northeast (OR, 1.26 [CI, 1.22-1.30]) compared with the South. Having moderate rather than mild glaucoma (OR, 1.07 [CI, 1.04-1.11]) and a higher CDR (OR for 0.5 to 0.8 vs. <0.5, 1.24 [CI, 1.21-1.26]; OR for >0.8 to 1.0 vs. <0.5, 1.27 [CI, 1.23-1.32]) were also each associated with increased odds of MIGS use. Use of MIGS was less likely in women (OR, 0.96 [CI, 0.94-0.98]); patients taking 5 to 7 glaucoma medications (OR, 0.94 [CI, 0.90-0.99]) compared with 1 to 2 medications; and patients with severe, compared with mild, glaucoma (OR, 0.64 [CI, 0.61-0.67]). CONCLUSIONS: This analysis highlights the importance of capturing race-ethnicity data and other pertinent patient characteristics in electronic health records to provide insight into practice patterns. Such data can be used to assess the long-term performance of MIGS and other procedures in various patient populations.

Risk of Blindness Among Patients With Diabetes and Newly Diagnosed Diabetic Retinopathy.

OBJECTIVE: To evaluate the association between initial diabetic retinopathy (DR) severity/risk of blindness in patients with newly diagnosed DR/good vision in the U.S. RESEARCH DESIGN AND METHODS: This retrospective cohort study evaluated adult patients with good vision (20/40 or better) and newly diagnosed DR between 1 January 2013 and 31 December 2017 (index date) in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS) Registry. The primary exposure of interest was DR severity at index: mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). The main outcome measure was development of sustained blindness (SB), defined as study eyes with Snellen visual acuity readings of 20/200 or worse at two separate visits ≥3 months apart that did not improve beyond 20/100. RESULTS: Among 53,535 eligible eyes (mean follow-up 662.5 days), 678 (1.3%) eyes developed SB. Eyes with PDR at index represented 10.5% (5,629 of 53,535) of the analysis population but made up 26.5% (180 of 678) of eyes that developed SB. Kaplan-Meier analysis revealed that eyes with moderate NPDR, severe NPDR, and PDR at index were 2.6, 3.6, and 4.0 times more likely, respectively, to develop SB after 2 years of DR diagnosis versus eyes with mild DR at index. In a Cox proportional hazards model adjusted for index characteristics/development of ocular conditions during follow-up, eyes with PDR had an increased risk of developing SB versus eyes with mild NPDR at index (hazard ratio 2.26 [95% CI 2.09-2.45]). CONCLUSIONS: In this longitudinal ophthalmologic registry population involving eyes with good vision, more advanced DR at first diagnosis was a significant risk factor for developing SB.

Factors Associated With Favorable Laser Trabeculoplasty Response: IRIS Registry Analysis.

PURPOSE: We examined patients in a large clinical registry to assess factors associated with laser trabeculoplasty (LTP) responses. DESIGN: Retrospective cohort study. METHODS: StudyPopulation: LTP patients in the Intelligent Research in Sight (IRIS) Registry, 2013-2018. OBSERVATION: IRIS Registry data were extracted if the eye had a procedural code for LTP and a glaucoma diagnosis. Eyes were excluded if LTP laterality or baseline intraocular pressure (IOP) could not be determined. Following LTP, "nonresponders" were those with <20% IOP reduction after 8 weeks, while "responders" were those with ≥20% IOP reduction. MainOutcomeMeasures: Proportion of responders, odds ratios (OR) of pre-LTP factors associated with being a nonresponder. RESULTS: A total of 263,480 eyes were included, with mean age 71.4 ± 11.7 years. Mean baseline IOP was 19.1 ± 5.0 mm Hg, mean number of pre-LTP medications was 2.1 ± 1.5. Response rate was 36.9% overall and 68.8% for those with baseline IOP >24 mm Hg. Higher baseline IOP was associated with reduced odds of nonresponse (OR = 0.60, P < .0001 for a 3 mm Hg increase). Angle recession, uveitis, and aphakia increased the odds of a nonresponse (ORs 2.46, 1.50 (both P < .0001), and 1.55 (P = .0259), respectively). In nonresponders with at least 1 medication at baseline, 76.3% of eyes had fewer medications postoperatively. CONCLUSIONS: Lower baseline IOP, angle recession, uveitis, and aphakia were associated with increased odds of nonresponse. Future studies that analyze LTP responder survival and implementation lag would facilitate resource optimization in glaucoma therapy.

Ophthalmic Immune-Related Adverse Events after Anti-CTLA-4 or PD-1 Therapy Recorded in the American Academy of Ophthalmology Intelligent Research in Sight Registry.

PURPOSE: Detailed study of ophthalmic immune-related adverse events (AEs), including determination of incidence and recurrence rates, is of integral importance in cancer immunotherapy to inform management and treatment guidelines. DESIGN: Retrospective registry study. PARTICIPANTS: Patients newly diagnosed with ophthalmic immune-related AEs between January 1, 2013, and December 31, 2017, in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS®) Registry. METHODS: Data were collected from electronic health records of IRIS® Registry participating ophthalmology practices. Patients with select ophthalmic immune-related AEs were identified by International Classification of Diseases diagnosis codes. The primary exposure of interest was prior initiation of immune checkpoint inhibitors (ICIs). MAIN OUTCOME MEASURES: Incidence of ophthalmic immune-related AEs within 1 year after initiation of ICI therapy was determined. Incidence rate ratios (IRRs) were derived by comparing incidence of ophthalmic immune-related AEs after ICIs versus rates of the same ocular complications in patients not taking ICIs in the entire registry population. Rates of ophthalmic immune-related AEs in patients with a past history of ocular inflammation or other specific ophthalmic condition before initiation of ICIs were examined further. RESULTS: A total of 3123 patients who received anti-CTLA-4 or anti-programmed cell death 1 (PD-1) therapy were identified, 112 of whom demonstrated an ophthalmic immune-related AE. Incidence rates for anterior uveitis, the most common ophthalmic immune-related AE, were 8209 per 100 000 for ipilimumab (anti-CTLA-4), 2542 per 100 000 for nivolumab (anti-PD-1), 2451 per 100 000 for pembrolizumab (anti-PD-1), 5556 per 100 000 for ipilimumab plus nivolumab, and 3740 per 100 000 among all ICIs. Rates of ophthalmic immune-related AEs among patients receiving ICI therapy were higher compared with baseline rates in the general registry population (anterior uveitis IRR, 13.9; other uveitis IRR, 43.0; papilledema IRR, 38.3). Patients with a history of uveitis or other ocular inflammatory condition demonstrated high recurrence rates of ophthalmic immune-related AEs after initiating ICIs (up to 51.1%). CONCLUSIONS: For patients initiating ICI therapy, early coordination with ophthalmic subspecialist care is important because rates of ophthalmic immune-related AEs are elevated compared with ocular complication rates in the entire registry population and patients with a history of prior autoimmune ocular disease are at high risk of recurrence of ocular complications.

The Tube Versus Trabeculectomy IRIS® Registry Study: Cohort Selection and Follow-up and Comparisons to the Randomized Controlled Trial.

PURPOSE: To assess the feasibility of replicating a randomized controlled trial (RCT) with a cohort of eyes, from IRIS® Registry data, analogous to the Tube Versus Trabeculectomy (TVT) RCT cohort and compare characteristics and follow-up. DESIGN: Comparison of RCT and IRIS Registry cohorts and follow-up. METHODS: We identified a cohort of IRIS Registry eyes (2013-2017) that received either a glaucoma drainage implant (tube) or trabeculectomy after a previous trabeculectomy and/or cataract extraction; extracted clinical and demographic characteristics for baseline surgery and follow-up visits through 1 year; and compared treatment groups in the IRIS Registry cohort and this cohort to the TVT RCT cohort. RESULTS: The IRIS Registry cohort included 419 eyes: 183 (43.7%) trabeculectomy; 236 (56.3%) tube. There were significant differences between treatment groups, including race (White: trabeculectomy 61.8%, tube 44.9%; Black: trabeculectomy 20.8%, tube 35.6%; P = .003) and the percentage of follow-up visits completed (trabeculectomy 88.4%, tube 83.8%, P = .004). There were also significant differences between the TVT IRIS Registry cohort and the TVT RCT cohort in the percentage of follow-up visits completed (IRIS Registry 85.6%, RCT 96.1%, P < .001) and in the probability of having a 1-year follow-up visit (IRIS Registry 81.4%, RCT 89.2%, P = .011). CONCLUSION: The TVT IRIS Registry cohort had several significant treatment group differences at baseline, whereas there had been none in the TVT RCT cohort. Follow-up in the TVT IRIS Registry cohort was inferior to that of the TVT RCT. Some data needed to refine the selection of eyes for the cohort were not available in the IRIS Registry.

Fatherhood status in relation to prostate cancer risks in two large U.S.-based prospective cohort studies.

BACKGROUND: Despite the high incidence and mortality of prostate cancer (PCa) in the Unites States, few risk factors have been consistently linked with these PCa outcomes. Assessing proxies of reproductive factors may offer insights into PCa pathogenesis. In this study, we examined fatherhood status as a proxy of fertility in relation to total, nonaggressive, aggressive, and fatal PCa. METHODS: We examined participants of two cohorts, the NIH-AARP Diet and Health (NIH-AARP) Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals of associations between fatherhood status and number of children sired in relation to PCa incidence. RESULTS: Fatherhood status (one or more children vs. childless) was positively associated with total PCa risk in NIH-AARP or PLCO, but was not statistically significant (p = 0.06 and 0.55, respectively). Number of children sired indicated a slightly elevated risk of total PCa, but HRs were rarely significant and were of a fairly constant magnitude with no discernable trend relative to the childless referent group. Associations were similar for nonaggressive and aggressive PCa. The trend test for fatal PCa was statistically significant in NIH-AARP (ptrend  < 0.01), despite none of the individual categorical point estimates reaching this threshold. CONCLUSION: This study provides tentative evidence that fathering children is associated with a slightly increased PCa risk. Future research should strive to assess better proxies of reproductive function in relation to aggressive and fatal PCa to provide more specific evidence for this putative relationship.

Genomic and physiological mechanisms underlying skin plasticity during water to air transition in an amphibious fish.

The terrestrial radiation of vertebrates required changes in skin that resolved the dual demands of maintaining a mechanical and physiological barrier while also facilitating ion and gas transport. Using the amphibious killifish Kryptolebias marmoratus, we found that transcriptional regulation of skin morphogenesis was quickly activated upon air exposure (1 h). Rapid regulation of cell-cell adhesion complexes and pathways that regulate stratum corneum formation was consistent with barrier function and mechanical reinforcement. Unique blood vessel architecture and regulation of angiogenesis likely supported cutaneous respiration. Differences in ionoregulatory transcripts and ionocyte morphology were correlated with differences in salinity acclimation and resilience to air exposure. Evolutionary analyses reinforced the adaptive importance of these mechanisms. We conclude that rapid plasticity of barrier, respiratory and ionoregulatory functions in skin evolved to support the amphibious lifestyle of K. marmoratus; similar processes may have facilitated the terrestrial radiation of other contemporary and ancient fishes.

Fatal prostate cancer incidence trends in the United States and England by race, stage, and treatment.

BACKGROUND: Differential uptake of prostate-specific antigen testing in the US and UK has been linked to between-country differences for prostate cancer incidence. We examined stage-specific fatal prostate cancer incidence trends in the US and England, by treatment and race/ethnicity. METHODS: Using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program and Public Health England's National Cancer Registration and Analysis Service, we identified prostate cancer patients diagnosed between 1995 and 2005, aged 45-84 years. Fatal prostate cancer was defined as death attributed to the disease within 10 years of diagnosis. We used age-period-cohort models to assess trends in fatal prostate cancer incidence. RESULTS: Fatal prostate cancer incidence declined in the US by -7.5% each year and increased in England by 7.7% annually. These trends were primarily driven by locoregional disease in the US and distant disease in England. Black men in both countries had twofold to threefold higher fatal prostate cancer incidence rates, when compared with their white counterparts; however, receipt of radical prostatectomy lessened this disparity. CONCLUSIONS: We report a significant increasing rate of fatal prostate cancer incidence among English men. The black-white racial disparity appears pervasive but is attenuated among those who received radical prostatectomy in the US.

Overall and abdominal obesity and prostate cancer risk in a West African population: An analysis of the Ghana Prostate Study.

Obesity has been associated with an increased risk of advanced prostate cancer. However, most studies have been conducted among North American and European populations. Prostate cancer mortality appears elevated in West Africa, yet risk factors for prostate cancer in this region are unknown. We thus examined the relationship between obesity and prostate cancer using a case-control study conducted in Accra, Ghana in 2004 to 2012. Cases and controls were drawn from a population-based sample of 1037 men screened for prostate cancer, yielding 73 cases and 964 controls. An additional 493 incident cases were recruited from the Korle-Bu Teaching Hospital. Anthropometric measurements were taken at enrollment. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and prostate cancer, adjusting for potential confounders. The mean BMI was 25.1 kg/m2 for cases and 24.3 kg/m2 for controls. After adjustment, men with BMI ≥ 30 kg/m2 had an increased risk of prostate cancer relative to men with BMI < 25 kg/m2 (OR 1.86, 95% CI 1.11-3.13). Elevated WC (OR 1.76, 95% CI 1.24-2.51) and WHR (OR 1.46, 95% CI 0.99-2.16) were also associated with prostate cancer. Associations were not modified by smoking status and were evident for low- and high-grade disease. These findings indicate that overall and abdominal obesity are positively associated with prostate cancer among men in Ghana, implicating obesity as a potentially modifiable risk factor for prostate cancer in this region.

Claudins of sea lamprey (Petromyzon marinus) - organ-specific expression and transcriptional responses to water of varying ion content.

The role of lamprey epithelium tight junctions (TJs) in the regulation of salt and water balance is poorly understood. This study reported on claudin (Cldn) TJ protein transcripts of pre-metamorphic larval and post-metamorphic juvenile sea lamprey (Petromyzon marinus) and the transcriptional response of genes encoding Cldns to changed environmental ion levels. Transcripts encoding Cldn-3b, -4, -5, -10, -14, -18 and -19 were identified, and mRNA expression profiles revealed the organ-specific presence of cldn-5 and -14, broad expression of cldn-3b, -4, -10, -18 and -19 and spatial differences in the mRNA abundance of cldn-4, -3b and -14 along the ammocoete intestine. Expression profiles were qualitatively similar in ammocoetes and juvenile fishes. Transcript abundance of genes encoding Cldns in osmoregulatory organs (gill, kidney, intestine and skin) was subsequently investigated after exposure of ammocoetes to ion-poor water (IPW) and juveniles to hyperosmotic conditions [60% sea water (SW)]. IPW-acclimated ammocoetes increased mRNA abundance of nearly all cldns in the gill. Simultaneously, cldn-10 abundance increased in the skin, whereas cldn-4, -14 and -18 decreased in the kidney. Ammocoete cldn mRNA abundance in the intestine was altered in a region-specific manner. In contrast, cldn transcript abundance was mostly downregulated in osmoregulatory organs of juvenile fish acclimated to SW - cldn-3b, -10 and -19 in the gill; cldn-3b, -4, -10 and -19 in the skin; cldn-3b in the kidney; and cldn-3b and -14 in the intestine. Data support the idea that Cldn TJ proteins play an important role in the osmoregulatory physiology of pre- and post-metamorphic sea lamprey and that Cldn participation can occur across organs, in an organ-specific manner, as well as differ spatially within organs, which contributes to the regulation of salt and water balance in these fishes.

Effects of copper on a reconstructed freshwater rainbow trout gill epithelium: Paracellular and intracellular aspects.

The barrier properties and intracellular responses of a primary cultured trout gill epithelium (containing both mitochondria-rich and pavement cells) were examined over 24 h of copper (Cu) exposure (0, 200 and 1000 µg/L) in apical fresh water. Transepithelial resistance (TER) and mRNA abundance of tight junction proteins zonula occludens-1, occludin, cingulin, claudin-8d and -28b were examined as endpoints of barrier function and the paracellular pathway. Intracellular endpoints analyzed were Cu accumulation, Na+ content, carbonic anhydrase activity and mRNA abundance of carbonic anhydrase (ca-II) and Na+/K+ ATPase (nka α1a and nka α1b isoforms). After a brief initial drop in TER in the 1000 µg Cu/L treatment, Cu at both levels increased TER over the first 6 h of exposure but there were no differences among groups from 12 h onwards. After 24 h of Cu exposure, there were no differences in mRNA abundance of any of the tight junction proteins examined. Cu accumulation occurred at 1000 µg Cu/L (5.5-fold increase), but no depletion of Na+ content. Carbonic anhydrase activity decreased significantly (by 76%), however Cu exposure did not alter the transcript abundance of ca-II, nka α1a, or nka α1b. This study provides a first report of carbonic anhydrase sensitivity to Cu exposure in a cultured model gill epithelium. We conclude that Cu impacts the permeability of this model during the early stages of exposure and that the use of carbonic anhydrase inhibition as an endpoint of metal toxicity in this model preparation may be useful for future mechanistic investigations and environmental monitoring.

Predictors of contralateral prophylactic mastectomy in genetically high risk newly diagnosed breast cancer patients.

PURPOSE: Recent trends indicate increased use of contralateral prophylactic mastectomy (CPM) among newly diagnosed breast cancer patients, particularly those who test positive for a pathogenic variant in the BRCA1/2 genes. However, the rate of CPM among patients who test negative or choose not to be tested is surprisingly high. We aimed to identify patient predictors of CPM following breast cancer diagnosis among such patients. METHODS: As part of a randomized controlled trial of rapid genetic counseling and testing vs. usual care, breast cancer patients completed a baseline survey within 6 weeks of diagnosis and before definitive surgery. Analyses focused on patients who opted against testing (n = 136) or who received negative BRCA1/2 test results (n = 149). We used multivariable logistic regression to assess the associations between sociodemographic, clinical- and patient-reported factors with use of CPM. RESULTS: Among patients who were untested or who received negative test results, having discussed CPM with one's surgeon at the time of diagnosis predicted subsequent CPM. Patients who were not candidates for breast-conserving surgery and those with higher levels of cancer-specific intrusive thoughts were also more likely to obtain a CPM. CONCLUSION: The strongest predictors of CPM in this population were objective clinical factors and discussion with providers. However, baseline psychosocial factors were also independently related to the receipt of CPM. Thus, although CPM decisions are largely guided by relevant clinical factors, it is important to attend to psychosocial factors when counseling newly diagnosed breast cancer patients about treatment options.

C-type natriuretic peptide regulates the molecular components of the rainbow trout gill epithelium tight junction complex.

Freshwater (FW) fish experience passive paracellular loss of ions into the surrounding environment across water-exposed epithelia such as the gill. The mitigation of paracellular ion loss is thought to be regulated by proteins of the tight junction (TJ) complex and in particular, the large superfamily of claudin (cldn) TJ proteins plays an important role. Transcript and protein levels of TJ proteins in teleosts are known to be under endocrine control of several important osmoregulatory hormones and the current study was aimed at determining whether the osmoregulatory hormone, C-type natriuretic peptide (CNP), can alter paracellular permeability and TJ protein abundance in a primary cultured gill epithelium derived from rainbow trout. Natriuretic peptide receptors were detected in the cultured trout gill epithelium. It was found that (i) developing cultured gill epithelia "grown" in the presence of 10 nM CNP, and (ii) mature cultured gill epithelia exposed to 10 nM CNP for 48 h, exhibited augmented barrier properties. This occurred in association with reduced flux rates of a paracellular permeability marker (polyethylene glycol, molecular mass 400; PEG-400) and, reduced ion efflux (i.e. ion loss) when preparations were exposed to apical FW. Exposure to CNP altered mRNA abundance of cldn-3a, -5a, -6, - 8c, -20a, -25b, -28a, -32a and cgn, but differences in the transcriptional response were observed between chronic and acute CNP exposure. In contrast, chronic and acute exposure to CNP resulted in reduced cldn-10e/Cldn-10e abundance. Data suggest that CNP may play a role in regulating the molecular physiology of the TJ complex in the fish gill epithelium and contribute to the regulation of salt and water balance by influencing the paracellular permeability properties of this tissue.

A population-based study of cardiovascular disease mortality risk in US cancer patients.

AIMS: This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. METHODS AND RESULTS: The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973-2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at <35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89-3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. CONCLUSION: The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.