Search

IMPORTANCE: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. OBJECTIVE: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. INTERVENTION: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. MAIN OUTCOMES AND MEASURES: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. RESULTS: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, −20.4; 95% CI, −34.1 to −6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). CONCLUSIONS AND RELEVANCE: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03281499

I. Introduction 511 II. The Evolution of CDCs in NYC Affordable Housing 513 A. CDC 1G--Pioneers and Activists 514 B. CDC 2G--Scrappy and Sophisticated 515 C. CDC 3G--Rise of the [...]

IMPORTANCE: Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence. OBJECTIVE: To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins. DESIGN, SETTING, AND PARTICIPANTS: The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023. MAIN OUTCOMES AND MEASURES: Main outcomes were risk factors for local recurrence. RESULTS: A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KITmutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N= 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing–based assay. ctDNA was detected in 280/362 (77%) samples with KITmutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KITexon 11 + 13/14 mutations (ripretinib, n= 21; sunitinib, n= 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KITexon 11 + 17/18 mutations (ripretinib, n= 27; sunitinib, n= 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KITexon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4–6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p< 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p= 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p< 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

IMPORTANCE: Oral cavity cancer often requires multidisciplinary management, subjecting patients to complex therapeutic trajectories. Prolonged treatment intervals in oral cavity cancer have been associated with poor oncological outcomes, but there has yet to be a study investigating treatment times in Canada. OBJECTIVE: To report treatment delays for patients with oral cavity cancer in Canada and evaluate the outcomes of treatment delays on overall survival. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study was performed at 8 Canadian academic centers from 2005 to 2019. Participants were patients with oral cavity cancer who underwent surgery and adjuvant radiation therapy. Analysis was performed in January 2023. MAIN OUTCOMES AND MEASURES: Treatment intervals evaluated were surgery to initiation of postoperative radiation therapy interval (S-PORT) and radiation therapy interval (RTI). The exposure variables were prolonged intervals, respectively defined as index S-PORT greater than 42 days and RTI greater than 46 days. Patient demographics, Charlson Comorbidity Index, smoking status, alcohol status, and cancer staging were also considered. Univariate (log rank and Kaplan-Meier) and multivariate (Cox regression) analyses were performed to determine associations with overall survival (OS). RESULTS: Overall, 1368 patients were included; median (IQR) age at diagnosis was 61 (54-70) years, and 896 (65%) were men. Median (IQR) S-PORT was 56 (46-68) days, with 1093 (80%) patients waiting greater than 42 days, and median (IQR) RTI was 43 (41-47) days, with 353 (26%) patients having treatment time interval greater than 46 days. There were variations in treatment time intervals between institutions for S-PORT (institution with longest vs shortest median S-PORT, 64 days vs 48 days; η2 = 0.023) and RTI (institution with longest vs shortest median RTI, 44 days vs 40 days; η2 = 0.022). Median follow-up was 34 months. The 3-year OS was 68%. In univariate analysis, patients with prolonged S-PORT had worse survival at 3 years (66% vs 77%; odds ratio 1.75; 95% CI, 1.27-2.42), whereas prolonged RTI (67% vs 69%; odds ratio 1.06; 95% CI, 0.81-1.38) was not associated with OS. Other factors associated with OS were age, Charlson Comorbidity Index, alcohol status, T category, N category, and institution. In the multivariate model, prolonged S-PORT remained independently associated with OS (hazard ratio, 1.39; 95% CI, 1.07-1.80). CONCLUSIONS AND RELEVANCE: In this multicenter cohort study of patients with oral cavity cancer requiring multimodal therapy, initiation of radiation therapy within 42 days from surgery was associated with improved survival. However, in Canada, only a minority completed S-PORT within the recommended time, whereas most had an appropriate RTI. An interinstitution variation existed in terms of treatment time intervals. Institutions should aim to identify reasons for delays in their respective centers, and efforts and resources should be directed toward achieving timely completion of S-PORT.

IMPORTANCE: Fear is commonly experienced by individuals newly diagnosed with papillary thyroid cancer (PTC). OBJECTIVE: To explore the association between gender and fears of low-risk PTC disease progression, as well as its potential surgical treatment. DESIGN, SETTING, AND PARTICIPANTS: This single-center prospective cohort study was conducted at a tertiary care referral hospital in Toronto, Canada, and enrolled patients with untreated small low risk PTC (&lt;2 cm in maximal diameter) that was confined to the thyroid. All patients had a surgical consultation. Study participants were enrolled between May 2016 and February 2021. Data analysis was performed from December 16, 2022, to May 8, 2023. EXPOSURES: Gender was self-reported by patients with low-risk PTC who were offered the choice of thyroidectomy or active surveillance. Baseline data were collected prior to the patient deciding on disease management. MAIN OUTCOMES AND MEASURES: Baseline patient questionnaires included the Fear of Progression–Short Form and Surgical Fear (referring to thyroidectomy) questionnaires. The fears of women and men were compared after adjustment for age. Decision-related variables, including Decision Self-Efficacy, and the ultimate treatment decisions were also compared between genders. RESULTS: The study included 153 women (mean [SD] age, 50.7 [15.0] years) and 47 men (mean [SD] age, 56.3 [13.8] years). There were no significant differences in primary tumor size, marital status, education, parental status, or employment status between the women and men. After adjustment for age, there was no significant difference observed in the level of fear of disease progression between men and women. However, women reported greater surgical fear compared with men. There was no meaningful difference observed between women and men with respect to decision self-efficacy or the ultimate treatment choice. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with low-risk PTC, women reported a higher level of surgical fear but not fear of the disease compared with men (after adjustment for age). Women and men were similarly confident and satisfied with their disease management choice. Furthermore, the decisions of women and men were generally not significantly different. The context of gender may contribute to the emotional experience of being diagnosed with thyroid cancer and its treatment perception.

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1Lassociates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

About 5600 Canadians (1) and more than 56 000 Americans (2) are estimated to have received a diagnosis of thyroid cancer in 2012, and both countries have seen recent dramatic [...]

IMPORTANCE: While several studies have documented a link between socioeconomic status and survival in head and neck cancer, nearly all have used ecologic, community-based measures. Studies using more granular patient-level data are lacking. OBJECTIVE: To determine the association of baseline annual household income with financial toxicity, health utility, and survival. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort of adult patients with head and neck cancer treated at a tertiary cancer center in Toronto, Ontario, between September 17, 2015, and December 19, 2019. Data analysis was performed from April to December 2021. EXPOSURES: Annual household income at time of diagnosis. MAIN OUTCOME AND MEASURES: The primary outcome of interest was disease-free survival. Secondary outcomes included subjective financial toxicity, measured using the Financial Index of Toxicity (FIT) tool, and health utility, measured using the Health Utilities Index Mark 3. Cox proportional hazards models were used to estimate the association between household income and survival. Income was regressed onto log-transformed FIT scores using linear models. The association between income and health utility was explored using generalized linear models. Generalized estimating equations were used to account for patient-level clustering. RESULTS: There were 555 patients (mean [SD] age, 62.7 [10.7] years; 109 [20%] women and 446 [80%] men) included in this cohort. Two-year disease-free survival was worse for patients in the bottom income quartile (&lt;$30 000: 67%; 95% CI, 58%-78%) compared with the top quartile (≥$90 000: 88%; 95% CI, 83%-93%). In risk-adjusted models, patients in the bottom income quartile had inferior disease-free survival (adjusted hazard ratio, 2.13; 95% CI, 1.22-3.71) and overall survival (adjusted hazard ratio, 2.01; 95% CI, 0.94-4.29), when compared with patients in the highest quartile. The average FIT score was 22.6 in the lowest income quartile vs 11.7 in the highest quartile. In adjusted analysis, low-income patients had 12-month FIT scores that were, on average, 134% higher (worse) (95% CI, 16%-253%) than high-income patients. Similarly, health utility scores were, on average, 0.104 points lower (95% CI, 0.026-0.182) for low-income patients in adjusted analysis. CONCLUSIONS AND RELEVANCE: In this cohort study, patients with head and neck cancer with a household income less than CAD$30 000 experienced worse financial toxicity, health status, and disease-free survival. Significant disparities exist for Ontario’s patients with head and neck cancer.

Supplemental Digital Content is Available in the Text.

Abstract The present research involving the Vermont State Police Peer Support Program was undertaken in order to examine membership utilization of the program and its relationship to the existence of [...]

The compliance issues for mutual fund managers under Securities and Exchange Commission's new rules, following breach of fiduciary duties with investment plans, are presented.

On July 20, 2004, the Securities and Exchange Commission (the 'SEC') published for comment proposed new rule 203(b)(3)-2 under the Investment Advisers Act of 1940 (the 'Act'), which would require [...]

Monitoring of glycemic status, as performed by patients and health care providers, is considered a cornerstone of diabetes care. Results of monitoring are used to assess the efficacy of therapy [...]

A study is conducted to investigate cancer survival in New South Wales by geographic remoteness. The conclusion sates that access to screening or early diagnosis probably contributes to the variation in cancer survival and remoteness of residence in NSW, but persistence after adjustment for stage suggests that treatment variation is also important.

Bruton’s tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11has completed phase 1 trials as a topical agent, and 12is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.

The goal of stratified medicine is to identify subgroups of patients with similar disease mechanisms and specific responses to treatments. To prepare for stratified clinical trials, genome-wide genetic analysis should occur across clinical areas to identify undiagnosed genetic diseases and new genetic causes of disease.

IMPORTANCE: Patient-derived xenografts (PDXs) offer the opportunity to identify patients with oral cavity squamous cell carcinoma (OSCC) who are at risk for recurrence and optimize clinical decision-making. OBJECTIVE: To develop and validate a prediction score for locoregional failure (LRF) and distant metastases (DM) in OSCC that incorporates PDX engraftment in addition to known clinicopathological risk factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, PDX models were generated from patients with OSCC treated with curative intent at Princess Margaret Cancer Centre (Toronto, Canada) between 2006 and 2018. The cohort included 288 patients (aged ≥18 years) with a new diagnosis of nonmetastatic (M0) OSCC whose tumor samples were available for engraftment under the skin of xenograft mice. Patients were scored as a nonengrafter if PDX formation did not occur within 6 months. Data analysis was performed between August 2006 and May 2018. INTERVENTIONS: All patients received up-front curative-intent surgery followed by either observation or postoperative radiation with or without concurrent chemotherapy based on institutional guidelines. MAIN OUTCOMES AND MEASURES: Main outcomes were LRF, DM, and overall survival (OS). Multivariable analysis (MVA) was used to identify predictors of LRF and DM. Factors retained in the final MVA were used to construct a prediction score and classify patients into risk groups. RESULTS: Overall, 288 patients (mean [SD] age at diagnosis, 63.3 [12.3] years; 112 [39%] women and 176 [61%] men) with OSCC were analyzed. The MVA identified pT3-4, pathologic extranodal extension, and engraftment as predictors of LRF and DM. Patients whose tumors engrafted (n = 198) were more likely to develop LRF (hazard ratio [HR], 1.98; 95% CI, 1.24-3.18) and DM (HR, 2.64; 95% CI, 1.21-5.75) compared with nonengrafters. A prediction score based on the aforementioned variables identified patients at high risk and low risk for LRF (43.5% vs 26.5%), DM (38.2% vs 8.4%), and inferior OS (34% vs 66%) at 5 years. Additionally, rapid engraftment was shown to be similarly prognostic, with rapid engrafters demonstrating higher rates of relapse and poor OS. CONCLUSIONS: In this cohort study, a prediction score using OSCC PDX engraftment, in conjunction with pT3-4 and pathologic extranodal extension, was associated with improved prognostic utility of existing clinical models and predicted patients at risk for LRF, DM, and poor survival.

IMPORTANCE: Primary hyperparathyroidism (pHPT) is a common endocrine disorder with many diagnostic and treatment challenges. Despite high-quality guidelines, care is variable, and there is low adherence to evidence-based treatment pathways. OBJECTIVE: To develop quality indicators (QIs) to evaluate the diagnosis and treatment of pHPT that could measure, improve, and optimize quality of care and outcomes for patients with this disease. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study used a guideline-based approach to develop QIs that were ranked by a Canadian 9-member expert panel of 3 endocrinologists, 3 otolaryngologists, and 3 endocrine surgeons. Data were analyzed between September 2020 and May 2021. MAIN OUTCOMES AND MEASURES: Candidate indicators (CIs) were extracted from published primary hyperparathyroidism guidelines and summarized with supporting evidence. The 9-member expert panel rated each CI on the validity, reliability, and feasibility of measurement. Final QIs were selected from CIs using the modified RAND–University of California, Los Angeles appropriateness methodology. All panelists were then asked to rank the top 5 QIs for primary, endocrine, and surgical care. RESULTS: Forty QIs were identified and evaluated by the expert panel. After 2 rounds of evaluations and discussion, a total of 18 QIs were selected as appropriate measures of high-quality care. The top 5 QIs for primary, endocrine, and surgical care were selected following panelist rankings. CONCLUSIONS AND RELEVANCE: This quality improvement study proposes 18 QIs for the diagnosis and management of pHPT. Furthermore, the top 5 QIs applicable to physicians commonly treating pHPT, including general physicians, internists, endocrinologists, otolaryngologists, and surgeons, are included. These QIs not only assess the quality of care to guide the process of improvement, but also can assess the implementation of evidence-based guideline recommendations. Using these indicators in clinical practice and health system registries can improve quality and cost-effectiveness of care for patients with pHPT.

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N= 190), schizoaffective disorder (N= 49), or other conditions involving psychosis (N= 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N= 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families.

This study evaluated predictors of cardiac rehabilitation (CR) utilization in a nationwide cohort of acute myocardial infarction (AMI) patients age ≥75 yr. Traditional risk factors (eg, education and coronary intervention) as well as novel factors (eg, functional and sensory impairments) were important drivers of CR use among older adults with AMI.

This study assessed whether painful diabetic neuropathy is associated with abnormal sympathetic nervous function in the affected limbs. Nine patients with diabetes (four men, five women; age 61 ± 7 years) and painful peripheral neuropathy of the feet, but without evidence of generalized autonomic neuropathy, underwent intravenous infusion of tritiated norepinephrine (NE) and sampling of arterial and venous blood in both feet and in one arm to quantify the rate of entry of NE into the local venous plasma (NE spillover). In the same patients, positron emission tomography (PET) scanning after intravenous injection of the sympathoneural imaging agent 6-[sup.18]F]fluorodopamine was used to visualize sympathetic innervation and after intravenous [[sup.13]N]ammonia to visualize local perfusion. The results were compared with those in the feet of normal volunteers and in an unaffected foot of patients with unilateral complex regional pain syndrome (CRPS). In addition, neurochemical results obtained in painful diabetic neuropathy were compared with those obtained in diabetic control patients with painless neuropathy and diabetic control patients without neuropathy. Local arteriovenous difference in plasma NE levels (ΔN[E.sub.AV]) and NE spillover in the arms did not differ across the groups. However, ΔN[E.sub.AV] in the feet was significantly less in the group with painful diabetic neuropathy than in the control groups. Also NE spillover in the feet tended to be lower in painful neuropathy. ΔN[E.sub.AV] of diabetic control patients without neuropathy (n = 6) resembled values in the control groups without diabetes, whereas patients with painless diabetic neuropathy (n = 6) had evidence suggesting partial loss of sympathetic innervation. PET scanning revealed decreased flow-corrected 6-[[sup.15]F]fluorodopamine-derived radioactivity in patients with painful diabetic neuropathy, compared with values in normal volunteers and patients with CRPS. The results provide neurochemical and neuroimaging evidence for regionally selective sympathetic denervation in the painful feet of patients with diabetic neuropathy., Peripheral somatosensory polyneuropathy constitutes a classic long-term complication of both type 1 and type 2 diabetes. The symptoms vary widely and can include pain that ranges from mild to intractable [...]

The term dysautonomia refers to a change in autonomic nervous system function that adversely affects health. The changes range from transient, occasional episodes of neurally mediated hypotension to progressive neurodegenerative diseases; from disorders in which altered autonomic function plays a primary pathophysiologic role to disorders in which it worsens an independent pathologic state; and from mechanistically straightforward to mysterious and controversial entities. In chronic autonomic failure (pure autonomic failure, multiple system atrophy, or autonomic failure in Parkinson disease), orthostatic hypotension reflects sympathetic neurocirculatory failure from sympathetic denervation or deranged reflexive regulation of sympathetic outflows. Chronic orthostatic intolerance associated with postural tachycardia can arise from cardiac sympathetic activation after 'patchy' autonomic impairment or blood volume depletion or, as highlighted in this discussion, from a primary abnormality that augments delivery of the sympathetic neurotransmitter norepinephrine to its receptors in the heart. Increased sympathetic nerve traffic to the heart and kidneys seems to occur as essential hypertension develops. Acute panic can evoke coronary spasm that is associated with sympathoneural and adrenomedullary excitation. In congestive heart failure, compensatory cardiac sympathetic activation may chronically worsen myocardial function, which rationalizes treatment with beta-adrenoceptor blockers. A high frequency of positive results on tilt-table testing has confirmed an association between the chronic fatigue syndrome and orthostatic intolerance; however, treatment with the salt-retaining steroid fludrocortisone, which is usually beneficial in primary chronic autonomic failure, does not seem to be beneficial in the chronic fatigue syndrome. Dysautonomias are an important subject in clinical neurocardiology.

Background: Multiple laboratory tests are used in the diagnosis and management of patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these assays varies substantially. [...]

OBJECTIVE -- To define the relationship between [HbA.sub.1c] and plasma glucose (PG) levels in patients with type 1 diabetes using data from the Diabetes Control and Complications Trial (DCCT). RESEARCH [...]

ABSTRACT Background. We assessed the results of peripheral vascular surgery in patients with end-stage renal disease (ESRD) who were being treated with peritoneal dialysis. Methods. Sixty-seven ESRD patients on peritoneal [...]

Background: In Parkinson disease, orthostatic hypotension can result from L-dopa treatment or from sympathetic neurocirculatory failure. The latter is detected by abnormal blood pressure responses to the Valsalva maneuver and can be associated with loss of functional cardiac sympathetic nerve terminals. Objective: To determine the frequency of cardiac sympathetic denervation in Parkinson disease, with or without sympathetic neurocirculatory failure, and its association with disease duration, severity, and L-dopa treatment. Design: Intergroup comparisons in resting patients. Setting: National Institutes of Health Clinical Center, Bethesda, Maryland. Patients: 29 patients with Parkinson disease (9 with sympathetic neurocirculatory failure, 10 who had stopped receiving or had never been treated with L-dopa), 24 patients with multiple-system atrophy (17 with sympathetic neurocirculatory failure, 8 receiving L-dopa), 7 patients with pure autonomic failure, 33 controls with episodic or persistent orthostatic intolerance without sympathetic neurocirculatory failure, and 19 normal volunteers. Measurements: Beat-to-beat blood pressure responses to the Valsalva maneuver, interventricular septal 6-[(super 18)F]fluorodopamine-derived radioactivity, cardiac extraction fraction of [(super 3)H]norepinephrine, appearance rate of nompinephrine in coronary sinus plasma (cardiac norepinephrine spillover) and venous-arterial differences in levels of dihydroxyphenylglycol (DHPG) and endogenous L-dopa. Results: Of the 29 patients with Parkinson disease, 9 with sympathetic neurocirculatory failure and 11 without had low septal 6-[(super 18)F]fluorodopamine-derived radioactivity (2861 +/- 453 Bq/mL per MBq/kg and 5217 +/- 525 Bq/mL per MBq/kg, respectively). All 6 patients with Parkinson disease and decreased 6-[(super 18)F]fluorodopamine-derived radioactivity who underwent right-heart catheterization had a decreased cardiac extraction fraction of [(super 3)H]norepinephrine and virtually no cardiac norepinephrine spillover or venous-arterial increments in plasma levels of DHPG and L-dopa. Sympathetic neurocirculatory failure and decreased 6-[(super 18)F]fluomdopamine-derived radioactivity were unrelated to disease duration, disease severity, or L-dopa treatment. Conclusions: Many patients with Parkinson disease - including all those with sympathetic neurocirculatory failure - have evidence of cardiac sympathetic denervation. This suggests that loss of catecholamine innervation in Parkinson disease occurs in the nigrostriatal system in the brain and in the sympathetic nervous system in the heart.

IMPORTANCE: Pharyngocutaneous fistula (PCF) results in an inflammatory reaction, but its association with the rate of locoregional and distant control, disease-free survival, and overall survival in laryngeal cancer remains uncertain. OBJECTIVE: To determine if pharyngocutaneous fistula after salvage laryngectomy is associated with locoregional and distant control, disease-free survival, and/or overall survival. DESIGN, SETTING, AND PARTICIPANTS: A multicenter collaborative retrospective cohort study conducted at 5 centers in Canada and the US of 550 patients who underwent salvage laryngectomy for recurrent laryngeal cancer from January 1, 2000, to December 31, 2014. The median follow-up time was 5.7 years (range, 0-18 years). MAIN OUTCOMES AND MEASURES: Outcomes examined included locoregional and distant control, disease-free survival, and overall survival. Fine and Gray competing risk regression and Cox-proportional hazard regression models were used for outcomes. Competing risks and the Kaplan-Meier methods were used to estimate outcomes at 3 years and 5 years. RESULTS: In all, 550 patients (mean [SD] age, 64 [10.4] years; men, 465 [85%]) met inclusion criteria. Pharyngocutaneous fistula occurred in 127 patients (23%). The difference in locoregional control between the group of patients with PCF (75%) and the non–PCF (72%) group was 3% (95% CI, −6% to 12%). The difference in overall survival between the group with PCF (44%) and the non–PCF group (52%) was 8% (95% CI, −2% to 20%). The difference in disease-free survival between PCF and non–PCF groups was 6% (95% CI, −4% to 16%). In the multivariable model, patients with PCF were at a 2-fold higher rate of distant metastases (hazard ratio, 2.00; 95% CI, 1.22 to 3.27). Distant control was reduced in those with PCF, a 13% (95% CI, 3% to 21%) difference in 5-year distant control. CONCLUSIONS AND RELEVANCE: This multicenter retrospective cohort study found that development of PCF after salvage laryngectomy is associated with an increased risk for the development of distant metastases.

Quoting the Greatest: I greatly enjoyed reading Rob Fletcher's 'My Favorite Inspiring Muhammad Ali Quote' featuring the late champion's opinion of the word impossible, including the observation that 'Impossible is [...]

Recent large-scale epidemiological studies demonstrate that blood concentrations of immunoreactive insulin predict the development of NIDDM and IDDM and are associated with the risk of several degenerative diseases, such as [...]

Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11variants and document the nature of the variants.