Citations

Due to frequent abnormal breathing events and their effects on sleep architecture, patients with obstructive sleep apnea (OSA) exhibit decreased amounts of slow wave sleep (SWS). Reduced SWS has been linked to hypertension in community-based studies. We sought to investigate whether SWS percentage modifies the association between OSA and prevalent hypertension. We studied 7107 patients with OSA and 1118 primary snorers who underwent in-laboratory polysomnography. Patients were classified into quartiles of percent SWS. Hypertension was defined based either on clinic blood pressure measures or on physician diagnosis. Multivariable logistic regression model showed a significant interaction effect of OSA and SWS on prevalent hypertension ( P =0.002). Decreased SWS was associated with higher odds for hypertension in OSA but not in primary snoring, with patients with OSA exhibiting <0.1% SWS (OR, 1.44 [95% CI, 1.21–1.70]; P =0.001) and those with 0.1% to 4.8% SWS (OR, 1.20 [95% CI, 1.03–1.40]; P =0.02) being more likely to have hypertension compared with those with >11.1% SWS. In analysis stratified by OSA severity, significant associations between percent SWS and blood pressure emerged only in moderate and severe OSA. Effect modifications by sex ( P =0.040) and age ( P =0.007) were also only evident in OSA, indicating that decreased SWS was associated with hypertension only in men and in patients <60 years old. Decreased SWS is associated with a dose-dependent increase in odds of prevalent hypertension in patients with OSA. The effects of SWS are likely to be modulated by OSA severity. SWS may be implicated in the heightened risk of cardiovascular diseases exhibited by patients with OSA.

Abstract Hypoxia‐induced extracellular matrix (ECM) deposition is an important cause of renal fibrosis that is triggered by unknown mechanisms. Human epididymis secretory protein 4 (HE4) is a newly discovered key molecule that causes ECM deposition. We used the unilateral ureteral obstruction (UUO) mouse model to investigate the expression and mechanisms of HE4 in the pathogenesis of renal fibrosis. Results were confirmed in the HK2 cell line and in human donors of kidney tissue with chronic kidney disease. Hypoxia significantly increased HE4 in renal tubular epithelial cells. HE4 overexpression activated the NF‐κB pathway through the NF‐κB transcription‐activating group P65 by phosphorylation and nuclear translocation. NF‐κB upregulated tissue inhibitor metalloproteinases 1, which may inhibit ECM degradation through inhibition of matrix metallopeptidase 2 activity. Silencing HE4 inhibited hypoxia‐induced ECM deposition and alleviated fibrosis in UUO mice in vivo and blocked NF‐κB activation in vitro. Expression of HE4 in the tubulointerstitium was positively correlated with tubulointerstitial fibrosis in tissue samples from patients with chronic kidney disease. Our results suggest that hypoxia induces renal fibrosis by upregulating HE4 and activating the HIF‐1α/HE4/NF‐κB signaling pathway. Uncovering the molecular mechanisms and function of HE4 overexpression in hypoxia‐induced renal fibrosis will provide important insights into understanding renal fibrosis and antifibrotic strategies.

AbstractObjectiveTo conduct a systematic literature review of spinal cord stimulation (SCS) for pain.DesignGrade the evidence for SCS.MethodsAn international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year’s duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsSCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT).ConclusionsHigh-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.

PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized.METHODSWe analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.RESULTSWe found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.CONCLUSIONThese results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Abstract Background Coronary microvascular inflammation is hypothesized to play a fundamental role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). No study has directly evaluated both endothelium-dependent and independent coronary microvascular function in HFpEF. Methods and results Consecutive patients with HFpEF undergoing invasive coronary physiologic testing and echocardiography were examined. Endothelial function was quantified by the increase in coronary blood flow in response to intracoronary infusion of acetylcholine (10−6–10−4 mol/L) using a Doppler flow wire with quantitative angiography. Endothelium-independent coronary microvascular function was assessed by the hyperaemic increase in coronary flow reserve in response to adenosine infusion. Among 162 HFpEF patients (67% women), coronary microvascular function was abnormal in 117 (72%). Isolated endothelium-dependent microvascular dysfunction was present in 47 patients (29%), isolated endothelium-independent microvascular dysfunction in 53 patients (33%), and combined microvascular dysfunction in 17 patients (10%). The presence of coronary microvascular dysfunction was not identifiable from medical co-morbidities or other clinical characteristics. As compared to patients with normal endothelium-independent function, HFpEF patients with endothelium-independent coronary microvascular dysfunction displayed lower diastolic relaxation velocities (7.0 ± 1.8 vs. 8.4 ± 2.9 cm/s, P = 0.002) and higher estimated filling pressures (E/e’ 13.1 ± 4.1 vs. 9.6 ± 3.4, P &lt; 0.001). There were no relationships between left ventricular structure, function, or haemodynamics and endothelium-dependent coronary vasodilatation. Endothelium-independent microvascular dysfunction was associated with increased mortality. Conclusions Coronary microvascular dysfunction is common in patients with HFpEF and is caused equally by endothelium-dependent and independent mechanisms, but the presence of microvascular dysfunction cannot be identified from clinical markers and co-morbidities alone. Patients with HFpEF and endothelium-independent microvascular dysfunction display worse diastolic dysfunction and outcomes.

OBJECTIVE The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort. METHODS An institutional review board–approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis. RESULTS A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2–84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm 3 . The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm 3 , and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS. CONCLUSIONS This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.

Background: Mechanical injury in the conduction system requiring permanent pacemaker (PPM) associated with transcatheter aortic valve replacement (TAVR) procedure is a common complication. The objective of this study was to use ambulatory monitor BodyGuardian to assess late occurrence of atrioventricular block (AVB) after TAVR. Methods: This prospective study evaluated 365 patients who underwent TAVR at Mayo Clinic, Rochester, Minnesota between June 2016 and August 2017. Patients who received PPM for bradycardia after TAVR before discharge were considered as the PPM group. Those not requiring PPM received a BodyGuardian system (BodyGuardian group) for 30 days of continuous monitoring. Primary end point was Mobitz II or third-degree atrioventricular block (II/III AVB) at 30-day follow-up. Results: Of 365 patients, 74 who had a PPM or an implantable cardioverter-defibrillator before TAVR and 94 who were enrolled in other studies were excluded. Of 197 patients enrolled in the study, 70 (35.5%) received PPM and 127 had BodyGuardian before the hospital dismissal. Eleven of 127 (8.6%) BodyGuardian group required PPM within 30 days after TAVR for late occurrence of symptomatic bradycardia. In total, 33 of 197 (16.7%) patients developed II/III AVB (24 before and 9 after discharge). Thirty-four patients had preexisting right bundle branch block. Of them, 16 (47%) developed II/III AVB. Of 53 patients who developed new left bundle branch block after TAVR, 14% progressed to II/III AVB within 30 days. Conclusions: In patients without a standard post-TAVR pacing indication, yet a potential risk to develop AVB, a strategy of 30-day monitoring identifies additional patients who require permanent pacing.

Abstract Background: Lung cancer kills more people than any other cancer in the United States. In addition to environmental factors, lung cancer has genetic risk factors as well, though the genetic etiology is still not well understood. We have performed whole exome sequencing on 262 individuals from 28 extended families with a family history of lung cancer. Methods: Parametric genetic linkage analysis was performed on these samples using two distinct analyses—the lung cancer only (LCO) analysis, where only patients with lung cancer were coded as affected, and the all aggregated cancers (AAC) analysis, where other cancers seen in the pedigree were coded as affected. Results: The AAC analysis yielded a genome-wide significant result at rs61943670 in POLR3B at 12q23.3. POLR3B has been implicated somatically in lung cancer, but this germline finding is novel and is a significant expression quantitative trait locus in lung tissue. Interesting genome-wide suggestive haplotypes were also found within individual families, particularly near SSPO at 7p36.1 in one family and a large linked haplotype spanning 4q21.3-28.3 in a different family. The 4q haplotype contains potential causal rare variants in DSPP at 4q22.1 and PTPN13 at 4q21.3. Conclusions: Regions on 12q, 7p, and 4q are linked to increased cancer risk in highly aggregated lung cancer families, 12q across families and 7p and 4q within a single family. POLR3B, SSPO, DSPP, and PTPN13 are currently the best candidate genes. Impact: Functional work on these genes is planned for future studies and if confirmed would lead to potential biomarkers for risk in cancer.