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Background: The objective of this economic modeling study was to compare the cost effectiveness of fully automated retinal image screening (FARIS) to the current practice of universal ophthalmologist referral for diabetic retinopathy in the United States (US) health care system. Methods: A Markov decision-analytic model was used to compare the automated versus manual screening and management pathway for diabetic patients with unknown retinopathy status. Costs (in 2021 US dollars), quality-adjusted life year (QALY) gains, and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed against a $50,000/QALY willingness-to-pay threshold. Results: FARIS was the dominant screening strategy, demonstrating cost savings of 18.8% at 5 years with equivalent net QALY gains to manual screening. Cost-effectiveness status was dependent on FARIS detection specificity, with a threshold value of 54.8%. Conclusion: Artificial intelligence-based screening represents an economically advantageous screening modality for diabetic retinopathy in the US, offering equivalent long-term utility with significant potential cost savings. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:272–280.]

Context Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular risk, especially in individuals of African descent, although the underlying mechanisms remain obscure. Lysine-specific demethylase 1 (LSD1) is a salt-sensitive epigenetic regulator associated with SSBP and aldosterone dysfunction. An LSD1 risk allele in humans is associated with SSBP and lower aldosterone levels in hypertensive individuals of African but not European descent. Heterozygous knockout LSD1 mice display SSBP and aldosterone dysregulation, but this effect is modified by age and biological sex. This might explain differences in cardiovascular risk with aging and biological sex in humans. Objective This work aims to determine if LSD1 risk allele (rs587618) carriers of African descent display a sex-by-age interaction with SSBP and aldosterone regulation. Methods We analyzed 297 individuals of African and European descent from the HyperPATH cohort. We performed multiple regression analyses for outcome variables related to SSBP and aldosterone. Results LSD1 risk allele carriers of African (but not European) descent had greater SSBP than nonrisk homozygotes. Female LSD1 risk allele carriers of African descent had greater SSBP, mainly relationship-driven by women with low estrogen (postmenopausal). There was a statistically significant LSD1 genotype-sex interaction in aldosterone response to angiotensin II stimulation in individuals aged 50 years or younger, with female carriers displaying decreased aldosterone responsiveness. Conclusion SSBP associated with LSD1 risk allele status is driven by women with a depleted estrogen state. Mechanisms related to a resistance to develop SSBP in females are uncertain but may relate to an estrogen-modulating effect on mineralocorticoid receptor (MR) activation and/or LSD1 epigenetic regulation of the MR.

Biologic sex influences the development of cardiovascular disease and modifies aldosterone (ALDO) and blood pressure (BP) phenotypes: females secrete more ALDO, and their adrenal glomerulosa cell is more sensitive to stimulation. Lysine-specific demethylase 1 (LSD1) variants in Africans and LSD1 deficiency in mice are associated with BP and/or ALDO phenotypes. This study, in 18- and 40-week-old wild type (WT) and LSD1+/− mice, was designed to determine whether (1) sex modifies ALDO biosynthetic enzymes; (2) LSD1 deficiency disrupts the effect of sex on these enzymes; (3) within each genotype, there is a positive relationship between ALDO biosynthesis (proximate phenotype), plasma ALDO (intermediate phenotype) and BP levels (distant phenotype); and (4) sex and LSD1 genotype interact on these phenotypes. In WT mice, female sex increases the expression of early enzymes in ALDO biosynthesis but not ALDO levels or systolic blood pressure (SBP). However, enzyme expressions are shifted downward in LSD1+/− females vs males, so that early enzyme levels are similar but the late enzymes are substantially lower. In both age groups, LSD1 deficiency modifies the adrenal enzyme expressions, circulating ALDO levels, and SBP in a sex-specific manner. Finally, significant sex/LSD1 genotype interactions modulate the three phenotypes in mice. In conclusion, biologic sex in mice interacts with LSD1 deficiency to modify several phenotypes: (1) proximal (ALDO biosynthetic enzymes); (2) intermediate (circulating ALDO); and (3) distant (SBP). These results provide entry to better understand the roles of biological sex and LSD1 in (1) hypertension heterogeneity and (2) providing more personalized treatment.

Context There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. Objective This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals. Methods This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes. Results Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals. Conclusion Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

Somatic activating mutations in CACNA1D can result in aldosterone producing adrenal adenomas and hypertension. Using the environmentally controlled HyperPATH cohort, we assessed whether germline mutations (variance in the CACNA1D gene) associate with blood pressure (BP), salt sensitivity of BP (SSBP) and two proximate mechanisms of SSBP--- plasma renal activity (PRA)/aldosterone (ALDO) and renal plasma flow (RPF). Participants completed a cross-over intervention of liberal and restricted Na + diets for 7 days. CACNA1D genotyping with a Multi-Ethnic Genotyping Array yielded 264 single nucleotide variants (SNVs) of which 104 met quality control. SNV rs7612148 strongly associated with systolic BP and was selected for analysis. Individuals with the SNV (n=521) were analyzed in 2 populations: 1) hypertensive, and 2) hypertensive plus normotensive. Multivariate linear regression analyses (table) identified an association with the risk allele and increased SSBP driven by a higher BP on the liberal Na + diet. Associations were also observed with reduced PRA and ALDO, and reduced RPF with increase in dietary Na + . In conclusion, we identified a novel CACNA1D SNV that associates with SSBP likely related to an impaired ability to increase RPF with increased dietary sodium intake, but not related to an increase in ALDO production.

OBJECTIVES In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine. METHODS One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of

Purpose While a return to work following trauma exposure can be therapeutic, this is not always so. As with many topics related to traumatic stress in organizations, several contingency factors complicate the effort to draw an overarching conclusion about whether returning to work is therapeutic. The purpose of this paper is to present important determinants of whether work is therapeutic or triggering for those with traumatic stress conditions. The need for contingency approaches in the study of traumatic stress in organizations is illustrated. Design/methodology/approach Literature on traumatic stress in organizations is reviewed. Findings Three of the key determinants of whether a return to work is therapeutic or triggering for traumatic stress sufferers are trauma-type contingencies, condition-type contingencies and work-setting contingencies. For instance, human-caused and task-related traumas are more likely than natural disasters to make a return-to-work triggering. Additionally, the time since developing a traumatic stress condition is inversely related to the degree of improvement in that condition through the experience of working. Moreover, managerial actions can affect how therapeutic an employee’s return to work is. Practical implications These findings suggest the challenges of reintegrating a traumatized employee to the workplace can be highly situation-specific. Careful consideration of the traumatic event suffered by each traumatic stress victim, their traumatic stress condition, and the work setting to which they would return are recommended. Social implications Promoting mental health in organizations can contribute to employers’ social performance. Originality/value Examination of the factors that complicate predicting whether work is therapeutic posttrauma demonstrates how contingency approaches can advance research on trauma in organizations.

Introduction. Physical activity (PA) can reduce blood pressure (BP) in hypertensives through possibly interacting with the renin-angiotensin-aldosterone system (RAAS). We conducted a nested-cohort analysis to determine if self-reported PA was associated with BP responsiveness to acute angiotensin converting enzyme inhibition (ACEi). Methods. Data were extracted from the HyperPATH dataset, a cohort designed to identify mechanisms of cardiometabolic risk. Hypertensives that completed a self-assessed PA questionnaire, hormonal assessments (aldosterone [ALDO]), and BP to a single dose of an ACEi (captopril, 25 mg) were included. All participants (n = 144) were studied on a controlled diet for 7 days. PA was recorded as no PA, or little, moderate, or high amounts of exercise. Analyses were adjusted for age, sex, race, and body mass index. Results. Individuals who reported high amounts of PA displayed a greater BP lowering effect from ACEi compared to those who reported moderate (−14.8 ± 8.1 vs −8.4 ± 9.9 mm Hg, P < .01) or no additional PA (−14.8 ± 8.1 vs −2.6 ± 9.9 mm Hg, P < .001). Exploratory analyses indicated high amounts of PA were associated with a reduced heart rate (54 ± 8 vs 66 ± 10 bpm, P < .001) and blunted ALDO (β = 0.44, 95% confidence interval = 0.19-0.70). Conclusions. Higher self-reported PA was associated with an augmented BP lowering effect to acute ACEi in hypertensive patients.

We have previously reported that in salt-resistant rat phenotypes brain, Gαi 2 (guanine nucleotide–binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi 2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi 2 oligodeoxynucleotide, we show that PVN-specific Gαi 2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi 2 oligodeoxynucleotide 18±4; P 2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi 2 oligodeoxynucleotide 147±3; P 2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi 2 oligodeoxynucleotide 850±27; P 2 protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P =0.041; rs4547694, P =0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi 2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency ( LSD1 +/− ) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1 +/− mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency–mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1 +/− mouse kidney tissues, aldosterone secretion from LSD1 +/− glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.

Chronic sleep restriction (CSR) has been associated with adverse effects including cognitive impairment and increased risk of diabetes and cardiovascular disease. Yet, sleep restriction therapy is an essential component of most behavioral treatments for insomnia. Moreover, little is known about the impact of CSR on sleep continuity and structure in healthy people whose need for sleep is satiated. We investigated the impact of CSR on sleep continuity and structure in nine healthy participants. They had 4 nights of sleep extension, 2 nights of post-extension sleep, 21 nights of CSR (5/5.6-hour time-in-bed), and 9 nights of recovery sleep. Compared to postextension sleep, during CSR sleep duration was reduced by 95.4 ± 21.2 min per night, Slow-Wave Activity was significantly increased, and sleep was more consolidated. During recovery, sleep duration was increased by 103.3 ± 23.8 min compared to CSR, and the CSR-induced increase in Slow-Wave Activity persisted, particularly after the 5-hour exposure. Yet, we found that sustained vigilant attention was not fully recovered even after nine nights of recovery sleep. Our results suggest that CSR improves traditional metrics of sleep quality and may have a persistent impact on sleep depth, which is consistent with the reported benefits on sleep continuity and structure of sleep restriction therapy. However, these improvements in traditional metrics of sleep quality were associated with deterioration rather than improvement in neurobehavioral performance, demonstrating that sleep duration should be included in assessments of sleep quality. These results have implications for the long-term use of sleep restriction in the behavioral treatment of insomnia. Clinical Trial Registration: Impact of Chronic Circadian Disruption vs. Chronic Sleep Restriction on Metabolism (https://clinicaltrials.gov/ct2/show/; #NCT02171273).

Salt sensitivity of blood pressure is associated with increased cardiovascular morbidity and mortality. A diplotype in the β2AR gene (rs1042713, rs1042714) and single nucleotide polymorphisms in ESR2 (rs10144225), SGK1 (rs2758151), and AGT (rs2493134) genes are all independently associated with salt sensitivity of blood pressure and all but AGT are associated with increased aldosterone levels and/or activity. We sought to determine whether individuals who carried a double hit risk phenotype—a risk allele associated with increased aldosterone secretion (either β2AR or ESR2 ) and a risk allele associated with amplification of aldosterone’s effects ( SGK1 ) would result in more significant SSBP compared with individuals homozygous for a single risk allele. Data were obtained from the Hypertension Pathotypes cohort where individuals completed 7 days of restricted sodium and liberal sodium diets. We defined 3 genetic combinations: β2AR/SGK, ESR2/SGK , and AGT/SGK. Multivariate regression analyses found a significantly higher salt sensitivity of blood pressure as the number of risk allele pairs increased in both the β2AR/SGK (β=5.46; P ESR2/SGK ( β =4.87; P 0.01). In addition, the number of risk allele pairs was associated with serum aldosterone levels for β2AR/SGK and ESR2/SGK . On the other hand, there was no association between the number of risk allele pairs with salt sensitivity of blood pressure nor aldosterone levels in the AGT/SGK combination. In conclusion, genetic combinations of β2AR/SGK1 and ESR2 / SGK1 are associated with greater salt sensitivity of blood pressure and plasma aldosterone concentrations. Hypertensive combination risk homozygotes may be candidates for mineralocorticoid receptor antagonist therapy—gene-driven, personalized medicine.

Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity, diabetes, and other cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods.We investigated the effects of recurrent circadian disruption (RCD) on glucose metabolism in C57BL/6 mice and in human participants exposed to non-24-h light-dark (LD) schedules vs. those on standard 24-h LD schedules. These LD schedules were designed to induce circadian misalignment between behaviors including rest/activity and fasting/eating with the output of the near-24-h central circadian pacemaker, while minimizing sleep loss, and were maintained for 12 weeks in mice and 3 weeks in humans. We examined interactions of these circadian-disrupted schedules compared to control 24-h schedules with a lower-fat diet (LFD, 13% in mouse and 25-27% in humans) and high-fat diet (HFD, 45% in mouse and 45-50% in humans). We also used young vs. older mice to determine whether they would respond differently to RCD.When combined with a HFD, we found that RCD caused significant weight gain in mice and increased body fat in humans, and significantly impaired glucose tolerance and insulin sensitivity in both mice and humans, but this did not occur when RCD was combined with a LFD. This effect was similar in both young and older mice.These results in both humans and a model organism indicate that circadian disruption has an adverse effect on metabolism among individuals eating a high-fat Western-style diet, even in the absence of significant sleep loss, and suggest that reducing dietary fat may protect against the metabolic consequences of a lifestyle (such as shift work) that involves chronic circadian disruption.

The SPRINT (Systolic Blood Pressure Intervention Trial) demonstrated reduced cardiovascular outcomes. We evaluated diabetes mellitus incidence in this randomized trial that compared intensive blood pressure strategy (systolic blood pressure 1 g/d, heart failure, dementia, or stroke. Postrandomization exclusions included participants missing blood glucose or ≥126 mg/dL (6.99 mmol/L) or on hypoglycemics. The outcome was incident diabetes mellitus: fasting blood glucose ≥126 mg/dL (6.99 mmol/L), diabetes mellitus self-report, or new use of hypoglycemics. The secondary outcome was impaired fasting glucose (100–125 mg/dL [5.55–6.94 mmol/L]) among those with normoglycemia ( Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01206062.

The circadian system, ubiquitous across species, generates ~24-h rhythms in virtually all biological processes and allows them to anticipate and adapt to the 24-h day/night cycle, thus ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular events, while controlled laboratory studies demonstrate a circadian influence on key markers of cardiovascular function and risk. Furthermore, circadian misalignment, typically experienced by shift workers, and by individuals who experience late eating, jet lag, or circadian rhythm sleep-wake disturbances, increases cardiovascular risk factors. Therefore, understanding the mechanisms by which the circadian system regulates cardiovascular function, and which of those are affected by circadian disruption, may help to develop intervention strategies to mitigate cardiovascular risk.

There are conflicting data on whether variations of physiologic cortisol levels associated with cardiovascular risk. We hypothesize that prior discordant findings are related to problems associated with varying sample size, techniques for assessing cardiovascular risk and failure to adequately account for environmental factors. To address these issues, we utilized a large sample size, selected the Framingham risk score to compute cardiovascular risk and performed the study in a highly controlled setting. We had two main objectives: determine whether higher, yet physiologic, cortisol levels associated with increased cardiovascular risk and determine whether caveolin-1 (rs926198) risk allele carriers associated with increased cardiovascular risk. This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol. Data collection included fasting blood samples, blood pressure measurements and a 24-h urine-free cortisol collection. Five hundred seventeen of these participants also completed caveolin-1 genotyping. Subjects were classified as belonging to either the low-mode or high-mode urine-free cortisol groups, based on the bimodal distribution of urine-free cortisol. In multivariate analysis, Framingham risk score was statistically higher in the high-mode cortisol group (10.22 (mean) ± 0.43 (s.e.m.)) compared to the low-mode cortisol group (7.73 ± 0.34), P P = 0.034. Overall, the estimated effect on Framingham risk score of carrying the caveolin-1 risk allele was 1.33 ± 0.61, P = 0.029. Both urinary cortisol and caveolin-1 risk allele status are independent predictors of Framingham risk score.

PURPOSE OF REVIEW Lateral orbital wall decompression is one of many well established techniques available to surgeons in management of patients with clinically significant thyroid eye disease (TED). Several different surgical approaches have been described in the literature and are reviewed herein. RECENT FINDINGS Lateral orbital wall decompression remains a popular technique for surgical management of TED, with a recent American Society of Ophthalmic Plastic and Reconstructive Surgery survey showing that 22.6% of respondents preferred a single-wall procedure, with 36.8% of that subset preferring lateral wall decompression alone. Surgical techniques for lateral orbital wall decompression differ based on several steps, such as the incisional approach, whether to take an ab-interno versus ab-externo approach, and whether to remove orbital fat to achieve further decompression. In addition, technological advances have produced an array of tools available to the orbital surgeon to achieve efficient and accurate bone removal. SUMMARY Lateral orbital wall decompression for TED, despite being an older technique, remains a popular and well established procedure for orbital decompression. Though no randomized controlled clinical trial supports one decompression technique over another for TED, lateral orbital wall decompression offers many benefits such as its ease of access and visualization of the orbital space.

Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular morbidity. A diplotype on the beta 2 adrenergic receptor (β2AR) gene (rs1042713, rs1042714)—associated with increased aldosterone (ALDO)—and a polymorphism in the serum-and-glucocorticoid-inducible kinase 1 (SGK1) gene (rs2758151)—an ALDO target that increases sodium reabsorption—are each associated with SSBP. We hypothesized that SSBP will be increased in homozygotes for both β2AR and SGK1 (Combo) when compared to non-risk homozygotes and homozygotes in either gene alone. The HyperPATH database includes individuals who completed 7 days of both restricted and liberal sodium diets to determine systolic SSBP. We conducted a gene association study in 329 individuals: 42 were homozygotes for Combo; 242 were homozygotes for β2AR or SGK1; and 45 were non-carriers. Multivariate regression analyses (adjusted for age, sex, BMI, race, hypertension) found a significantly higher SSBP in the Combo homozygotes when compared to non-carriers and homozygotes for either β2AR or SGK1(p Figure 1.

Statin use is associated with lower aldosterone levels. We hypothesized that caveolin-1 may be important for the uptake of statins into the adrenal gland and would affect statin’s aldosterone-lowering effects. The aim of this study was to test whether the caveolin-1 risk allele (rs926198) would affect aldosterone levels associated with statin use. The Hypertensive Pathotype database includes healthy and hypertensive individuals who have undergone assessment of adrenal hormones. Individuals were studied off antihypertensive medications but were maintained on statins if prescribed by their personal physician. Adrenal hormones were measured at baseline and after 1 hour of angiotensin II stimulation on both high- and low-sodium diets. A mixed-model repeated-measures analysis was employed with a priori selected covariates of age, sex, body mass index, and protocol (low versus high sodium, baseline versus angiotensin II stimulated aldosterone). A total of 250 individuals were included in the study; 31 individuals were taking statins (12.4%) and 219 were not. Among statin users, carrying a caveolin-1 risk allele resulted in a 25% (95% CI, 1–43.2) lower aldosterone level ( P =0.04). However, among nonstatin users, carrying a caveolin-1 risk allele resulted in no significant effect on aldosterone levels ( P =0.38). Additionally, the interaction between caveolin-1 risk allele and statin use on aldosterone levels was significant ( P =0.03). These findings suggest caveolin-1 risk allele carrying individuals are likely to receive the most benefit from statin’s aldosterone-lowering properties; however, due to the observational nature of this study, these findings need further investigation.

Purpose With the recent rise of teleophthalmology due to coronavirus disease, we are in need of accurate and reliable methods of checking visual acuity remotely. We compare the visual acuity as measured by the GoCheck Kids application, HOTV with the amblyopia treatment study (ATS), and our clinic protocol. Design This is a prospective, comparison of visual acuity assessment methods. Methods Established patients (aged 3-18) in the practice of a single pediatric ophthalmologist were eligible. Visual acuity was measured by: 1) GoCheck Kids mobile application (by patient’s family member), 2) HOTV-ATS (by study personnel), and 3) regular clinic protocol (by ophthalmic technician). To assess agreement between measures of acuity, intraclass correlations with 95% confidence intervals were computed. Results Fifty-three children participated. The mean difference between GoCheck Kids and HOTV-ATS acuities (0.094) was significantly different (p, Highlights • Teleophthalmology is part of our practices due to coronavirus disease (COVID-19) • Visual acuity can be checked at home with paper charts or devices • GoCheck Kids has a modest correlation of visual acuity compared to the chart screen • GoCheck Kids has a fair correlation of visual acuity compared to HOTV-ATS

Background: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. Methods: Patients with a daytime ambulatory BP ≥135/85 mm Hg and Results: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group ( P =0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P =0.010 and 1.4±1.5 versus 2.0±1.8, P =0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (−18.1±12.2 versus −15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: −4.3 mm Hg, 95% confidence interval, −7.9 to −0.6, P =0.024). There were no major adverse events in either group through 6 months. Conclusions: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02649426.

The risk for developing heparin-induced thrombocytopenia in healthy individuals is thought to be low, but monitoring recommendations remain controversial. Therefore, a retrospective cohort study was conducted to identify the incidence of thrombocytopenic events in a healthy research population exposed and re-exposed to continuous intravenous (IV) unfractionated heparin. The Division of Sleep Medicine and the Centre for Clinical Investigations at Brigham and Women's Hospital, Boston, Massachusetts, United States, instituted a standardized platelet monitoring procedure for all research protocols that involved heparin to detect platelet count decreases. Protocol-related frequent blood sampling required use of continuous IV unfractionated heparin infusion (5,000 unit/L in 0.45% saline at 40 mL/h) to maintain line patency over extended periods of IV access. From the years 2009 to 2012, a total of 273 healthy volunteers enrolled in Sleep Medicine research protocols met study criteria as having been exposed and/or re-exposed to continuously infused intravenous heparin for at least 4 hours. The mean continuous heparin exposure time was 88 ± 82 SD hours with a total of 397 heparin exposure and re-exposure events. Platelet count measurements were obtained on 629 occasions, representing a range from 2 to 9 draws per participant. No platelet count decrease of more than 50% was detected. There were no detected adverse bleeding or thrombotic events. In this retrospective study of healthy volunteers involved in a rigorously applied inpatient platelet monitoring protocol, heparin exposure and re-exposure did not lower platelet concentration and, therefore, does not appear to be associated with increased risk of HIT in this population.

BACKGROUND Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms. METHODS We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/−). RESULTS The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN–SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/− mice. No significant associations were observed with other volume regulated systems. CONCLUSIONS These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention.

OBJECTIVE To determine whether the effects of intensive ( RESEARCH DESIGN AND METHODS This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose RESULTS Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively (P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia (P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05). CONCLUSIONS In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia.

Introduction Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity and cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods. Here we used a forced desynchrony protocol to investigate the effect of 3 weeks of recurrent circadian disruption (RCD) with minimal sleep loss on glucose metabolism in humans on a lower or higher fat diet (LFD and HFD, respectively). Methods Six healthy adults (38-69yrs; 3f) participated in a 37-day inpatient protocol with LFD (25–27% fat) and 15.67-hr fasting duration, or HFD (45–50% fat) and 13-hr fasting duration. The protocol included three weeks of RCD consisting of 28-hr “days” with 11.67-hr sleep opportunities (=10hrs/24hr). Glucose and insulin responses to a standardized breakfast were conducted at baseline, at an aligned circadian phase after 2–3 weeks of exposure to RCD, and after 1 week of recovery. Frequent blood samples were assayed for glucose and insulin; the Area-Under-Curve was calculated from start of breakfast through postprandial minute 180. Results Total Sleep Time was similar in Baseline and RCD in both groups. Participants on the LFD showed no change in glucose AUC during RCD compared to Baseline. Insulin AUC was lower during RCD (p=0.0269) and Recovery (p=0.0443) than Baseline. In contrast, participants on the HFD showed a significant increase in glucose AUC during RCD compared to Baseline (p Conclusion RCD (in the absence of sleep loss) led to impaired glucose tolerance when combined with HFD, but not when combined with LFD. These results suggest that LFD may be part of healthy strategies for people experiencing RCD. Support Study supported by P01AG009975 and conducted in the Brigham and Women’s Hospital Center for Clinical Investigation, part of Harvard Clinical and Translational Science Center supported by UL1TR001102. Authors supported by a fellowship from the Finnish Cultural Foundation (KMZ); T32HL007901 and F32HL143893 (RKY); T32HL007901 and F32AG051325 (NV); K24HL105664 (EBK); R01HL118601 (FAJLS).

Daily rhythms in several physiological processes are important for cardiometabolic health. The lipid panel is used clinically to assess cardiovascular disease risk, but previous attempts to demonstrate circadian variation in lipids have failed to uncouple the endogenous circadian rhythm from the effects of meals and wake duration. Changes in basal lipid levels and dampening of circadian rhythms have been reported with aging, but it is unknown whether aging is also associated with changes in the rhythmic variation of lipids. We measured fasting lipid panels (triglycerides, total cholesterol, high‐density lipoprotein, and low‐density lipoprotein) in blood at wake time in 21 healthy adults using a specialized laboratory protocol that uncouples sleep–wake and activity‐related effects from the endogenous circadian rhythm. Young and older adults exhibited endogenous circadian variations in fasting triglycerides, with both groups peaking in the early biological morning. Young adults also exhibited significant circadian rhythmicity in total cholesterol and low‐density lipoprotein, while older adults did not exhibit circadian rhythmicity in any other lipids. These results reveal that triglyceride metabolism may be regulated by the central circadian pacemaker. Moreover, our findings may have clinical implications in assessing cardiovascular risk in shift workers and younger adults, since routine measurement of morning/fasting lipids may not fully and reliably assess triglyceride‐ and other lipid‐related biomarkers of cardiovascular disease risk in these groups., Daily rhythms in several physiological processes are important for cardiometabolic health. Young and older adults exhibited endogenous circadian variations in fasting triglycerides, with both groups peaking in the early biological morning. These results reveal that triglyceride metabolism may be regulated by the central circadian pacemaker, and may have clinical implications in assessing cardiovascular risk in shift workers and younger adults.

We have previously reported that in salt resistant rat phenotypes brain guanine nucleotide-binding protein alpha inhibiting activity polypeptide 2 (Gαi(2)) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi(2) proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi(2) oligodeoxynucleotide (ODN), we show PVN specific Gαi(2) proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] SCR ODN 41±3 vs. Gαi(2) ODN 18±4, P

Context Complex relationships between aldosterone and calcium homeostasis have been proposed. Objective To disentangle the influence of aldosterone and intravascular volume on calcium physiology. Design Patient-oriented and epidemiology studies. Setting Clinical research center and nationwide cohorts. Participants/Interventions Patient-oriented study (n = 18): Participants were evaluated after completing a sodium-restricted (RES) diet to contract intravascular volume and after a liberalized-sodium (LIB) diet to expand intravascular volume. Cross-sectional studies (n = 3755): the association between 24h urinary sodium and calcium excretion and risk for kidney stones was assessed. Results Patient-oriented study: compared to a RES-diet, a LIB-diet suppressed renin activity (LIB: 0.3 [0.1, 0.4] vs. RES: 3.1 [1.7, 5.3] ng/mL/h; P Conclusions High dietary sodium intake suppresses aldosterone, decreases serum calcium, and increases calciuria and the risk for developing kidney stones. Our findings help disentangle the influences of volume from aldosterone on calcium homeostasis and provide support for the recommendation to restrict dietary sodium for kidney stone prevention.

Background The Dietary Approaches to Stop Hypertension (DASH) diet is widely recommended to lower blood pressure, but its mechanisms of action are unclear. Lines of evidence suggest an interaction with the renin-angiotensin-aldosterone system (RAAS). Objective We conducted a randomized, controlled, cross-over feeding trial to test RAAS-related mechanisms underlying the DASH diet in patients with isolated systolic hypertension. Methods Participants entered a 1-wk run-in period on a control (CON) diet and then consumed the DASH or CON diets for 4 wk each in randomized sequence. Calorie content was controlled to maintain weight, and sodium intake was set at 3 g daily. After each diet, participants had hormonal and hemodynamic assessments obtained at baseline, in response to RAAS inhibition with captopril (CAP) 25 mg, and to graded angiotensin II (AngII) infusions (1 ng/kg and 3 ng/kg × 45 min). Primary outcomes were mean arterial pressure (MAP) and renal blood flow (RBF), and secondary outcomes were diastolic function, pulse wave velocity (PWV), plasma renin activity (PRA), and aldosterone (ALDO) responses by diet. Results In total, 44 (19 female) participants completed the study. DASH + CAP significantly lowered MAP compared with CON + CAP (83 ± 11 mmHg compared with 88 ± 14 mmHg, P

Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/-) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/- mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/- mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels.

Context: There is conflicting data on whether variations of physiologic cortisol levels associate with cardiovascular (CV) risk. Objective: We sought to reconcile prior discordant findings through utilization of a large sample size and selection of Framingham risk score to assess cardiovascular risk. An additional objective was to assess the relationship between caveolin-1 (CAV1) risk allele, cortisol levels, and CV risk given that CAV1 risk allele carriers have been associated with increased CV risk. Design & Participants: This was a cross-sectional study of 574 non-diabetic individuals who completed a common protocol that controlled for environmental factors. Data collection included fasting blood samples, blood pressure measurements, and a 24-hour urine free cortisol (UFC) collection. 517 of these participants also completed CAV1 genotyping. Main Outcome Measure: Subjects were classified as belonging to either the low-mode or high-mode urine cortisol groups, based on the bimodal distribution of UFC. Framingham risk score was selected as the main outcome measure to assess composite cardiovascular risk. Results: Framingham risk score was statistically higher in the high-mode cortisol group (10.22 ± 5.12) compared to the low-mode cortisol group (7.73 ± 7.08), p-value < 0.001. Framingham risk score was also statistically higher in the CAV1 risk allele carriers (8.91 ± 6.51) compared to CAV1 non-risk allele carriers (7.59 ± 6.88), p-value 0.034. Overall, the estimated effect of the risk allele was 1.33 ± 0.61, p-value 0.029. Conclusions: Higher, yet physiologic, levels of urinary cortisol are associated with increased cardiovascular risk.

Introduction Sleep loss negatively impacts many aspects of neurobehavioral performance, including sustained attention and reaction times. However, the time course of recovery from chronic sleep restriction (CSR) is not well understood. To explore this, we assessed the effects of 3 weeks of CSR followed by 1 week of recovery on psychomotor vigilance task (PVT) performance in healthy adults. Methods 8 healthy adults (27–71; 4f) participated in a 37-day inpatient study. The study consisted of 6 baseline (BL) days with 8–16 h time-in-bed, followed by 3 weeks of CSR (5-5.6h time-in-bed at night), and 1 week of recovery (RC; 8-10h time-in-bed). Sustained attention was assessed by 10-minute visual PVTs administered every 2h starting ~5h after wake (~4/day). Linear and generalized linear mixed models were used to compare average reaction times (RT) and number of lapses, respectively, from the last 3 days of baseline, CSR, and recovery. Results Average RT was almost twice as long at the end of CSR compared to baseline (p Conclusion One week of recovery sleep of 8-10 h/night following 3 weeks of chronic sleep restriction was insufficient for full recovery of sustained attention as assessed by PVT reaction time and number of lapses. This suggests that chronic sleep restriction has consequences on neurobehavioral performance that do not fully dissipate within one week. Support Study supported by P01AG009975 and conducted in the Brigham and Women’s Hospital Center for Clinical Investigation, part of Harvard Clinical and Translational Science Center supported by UL1TR001102. KMZ supported by a fellowship from the Finnish Cultural Foundation. RKY supported by T32HL007901 and F32HL143893. NV supported by T32HL007901 and F32AG051325.

Human risk allele carriers of lysine-specific demethylase 1 (LSD1) and LSD1-deficient mice have salt-sensitive hypertension for unclear reasons. We hypothesized that LSD1 deficiency causes dysregulation of aldosterone’s response to salt intake resulting in increased cardiovascular risk factors (blood pressure and microalbumin). Furthermore, we determined the effect of biological sex on these potential abnormalities. To test our hypotheses, LSD1 male and female heterozygote-knockout (LSD1+/−) and WT mice were assigned to two age groups: 18 weeks and 36 weeks. Plasma aldosterone levels and aldosterone production from zona glomerulosa cells studied ex vivo were greater in both male and female LSD1+/− mice consuming a liberal salt diet as compared to WT mice consuming the same diet. However, salt-sensitive blood pressure elevation and increased microalbuminuria were only observed in male LSD1+/− mice. These data suggest that LSD1 interacts with aldosterone’s secretory response to salt intake. Lack of LSD1 causes inappropriate aldosterone production on a liberal salt diet; males appear to be more sensitive to this aldosterone increase as males, but not females, develop salt sensitivity of blood pressure and increased microalbuminuria. The mechanism responsible for the cardiovascular protective effect in females is uncertain but may be related to estrogen modulating the effect of mineralocorticoid receptor activation.

Summary There is emerging evidence that circadian misalignment may alter energy expenditure, leading to obesity risk among those with irregular schedules [ 1 , 2 , 3 , 4 , 5 ]. It has been reported that energy expenditure is affected by the timing of sleep, exercise, and meals [ 6 ]. However, it is unclear whether the circadian system also modulates energy expenditure, independent of behavioral state and food intake. Here, we used a forced desynchrony protocol to examine whether fasted resting energy expenditure (REE) varies with circadian phase in seven participants. This protocol allowed us to uncouple sleep-wake and activity-related effects from the endogenous circadian rhythm, demonstrating that REE varies by circadian phase. REE is lowest at circadian phase ∼0°, corresponding to the endogenous core body temperature (CBT) nadir in the late biological night, and highest at circadian phase ∼180° in the biological afternoon and evening. Furthermore, we found that respiratory quotient (RQ), reflecting macronutrient utilization, also varies by circadian phase. RQ is lowest at circadian phase ∼240° and highest at circadian phase ∼60°, which corresponds to biological morning. This is the first characterization of a circadian profile in fasted resting energy expenditure and fasted respiratory quotient (with rhythmic profiles in both carbohydrate and lipid oxidation), decoupled from effects of activity, sleep-wake cycle, and diet in humans. The rhythm in energy expenditure and macronutrient metabolism may contribute to greater weight gain in shift workers and others with irregular schedules.

The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared with publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, whereas UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC.

The relationship between biological sex and aldosterone on blood pressure (BP) is unclear. We hypothesized that sex would modify the interaction between aldosterone and vascular responses to salt intake and angiotensin II (AngII). To test this hypothesis, in 1592 subjects from the well-controlled Hypertensive Pathotype cohort, we compared responses of women and men to chronic (BP and aldosterone levels in response to dietary salt) and acute (BP, renal plasma flow, and aldosterone responses to AngII infusion) manipulations. Women had a 30% higher salt sensitivity of BP than men ( P P P =0.003) between sex and aldosterone on BP response to AngII. Women also had a greater ( P P P P P

Background: Prior studies suggest that vitamin D therapy may decrease cardiovascular disease risk in type 2 diabetes (T2DM) by lowering renin-angiotensin system (RAS) activity. However, randomized human intervention studies to evaluate the effect of vitamin D receptor (VDR) agonists on RAS activity are lacking. Objective: The objective of this article is to investigate the effect of direct VDR activation with calcitriol on circulating RAS activity and vascular hemodynamics in T2DM. Methods: A randomized, double-blinded, and placebo-controlled study wherein 18 participants with well-controlled T2DM without chronic kidney disease (CKD) were administered calcitriol or placebo for three weeks was conducted. Outcome measures included plasma renin activity (PRA), serum and urinary aldosterone, mean arterial pressure (MAP) before and after an infusion of angiotensin II, and renal plasma flow (RPF) via para-aminohippurate clearance. Results: Despite an increase in 1,25(OH)2D with calcitriol administration (45.4 to 61.8 pg/ml, p = 0.03) and no change with placebo, there were no significant differences in PRA, serum or urinary aldosterone, baseline and angiotensin II-stimulated MAP, or basal and angiotensin II-stimulated RPF between interventions. Conclusion: In this randomized and placebo-controlled study in participants with T2DM without CKD, calcitriol therapy to raise 1,25(OH)2D levels, when compared with placebo, did not significantly change circulating RAS activity or vascular hemodynamics.