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The study of parental lifespan has emerged as an innovative tool to advance aging biology and our understanding of the genetic architecture of human longevity and aging‐associated diseases. Here, we leveraged summary statistics of a genome‐wide association study including over one million parental lifespans to identify genetically regulated genes from the Genotype‐Tissue Expression project. Through a combination of multi‐tissue transcriptome‐wide association analyses and genetic colocalization, we identified novel genes that may be associated with parental lifespan. Mendelian randomization (MR) analyses also identified circulating proteins and metabolites causally associated with parental lifespan and chronic diseases offering new drug repositioning opportunities such as those targeting apolipoprotein‐B‐containing lipoproteins. Liver expression of HP, the gene encoding haptoglobin, and plasma haptoglobin levels were causally linked with parental lifespan. Phenome‐wide MR analyses were used to map genetically regulated genes, proteins and metabolites with other human traits as well as the disease‐related phenome in the FinnGen cohorts (n = 135,638). Altogether, this study identified new candidate genes, circulating proteins and metabolites that may influence human aging as well as potential therapeutic targets for chronic diseases that warrant further investigation., Schematic overview of the analytical framework used to identify novel biological determinants of lifespan and potential drug targets for aging‐associated diseases using genome‐wide association study summary statistics of >1 million parental lifespans.

Loss of sacsin, a large 520 kDa multidomain protein, causes autosomal recessive spastic ataxia of the Charlevoix-Saguenay, one of the most common childhood-onset recessive ataxias. A prominent feature is abnormal bundling of neurofilaments in many neuronal populations. This study shows the direct involvement of sacsin domains in regulating intermediate filament assembly and dynamics and identifies important domains for alleviating neurofilament bundles in neurons lacking sacsin. Peptides encoding sacsin internal repeat (SIRPT) 1, J-domains, and ubiquitin-like domain modified neurofilament assembly in vivo. The domains with chaperone homology, the SIRPT and the J-domain, had opposite effects, promoting and preventing filament assembly, respectively. In cultured Sacs-/- motor neurons, both the SIRPT1 and J-domain resolved preexisting neurofilament bundles. Increasing expression of heat shock proteins also resolved neurofilament bundles, indicating that this endogenous chaperone system can compensate to some extent for sacsin deficiency.-Gentil, B. J., Lai, G.-T., Menade, M., Lariviere, R., Minotti, S., Gehring, K., Chapple, J.-P., Brais, B., Durham, H. D. Sacsin, mutated in the ataxia ARSACS, regulates intermediate filament assembly and dynamics.

Targeting atherogenic lipoprotein levels with statins remains the current cornerstone of atherosclerotic cardiovascular disease (ACVD) management. In patients at high ACVD risk who cannot achieve the desired low-density lipoprotein (LDL) cholesterol target, the addition of compounds such as ezetimibe and proprotein subtilisin/kexin type-9 (PCSK9) inhibitors incrementally lowers cardiovascular risk. New glucose-lowering drugs such as glucacon-like peptide-1 receptor (GLP1R) agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors were also shown to improve cardiometabolic risk factors and provide cardiovascular benefits in patients with type 2 diabetes. Our objective is to review the role of these agents in the management of patients at high ACVD risk and introduce new and (re)-emerging drugs targeting atherogenic lipoproteins such as LDL (inclisiran, bempedoic acid, etc.), remnant-like particles (fibrates, volanesorsen, and angiopoietin-like protein-3 (ANGPTL3) inhibitors), and lipoprotein(a) (AKCEA-APO[A]LRX ). The potential role of drugs targeting inflammation (canakinumab, methotrexate, and colchicine) in ACVD risk prevention/management will also be discussed.

The urgent nature of head and neck cancer referrals often results in overbooked schedules, access delays, and patient, physician, and staff dissatisfaction. The goal of this study is to examine how incorporation of associate providers (APs) into a head and neck tumor clinic (HNTC) can improve access.Scheduling data for the Dartmouth-Hitchcock HNTC 2 years prior (January 2011 to December 2012) and 2 years subsequent (January 2013 to December 2014) to program initiation were abstracted, including number of new patients seen per month, third available for new and established patients, overbooked hours, surgeon productivity, and patient satisfaction scores.New patients seen per month increased from 44 ± 4 to 60 ± 5 (P.001). Third available for new patients decreased from 56 ± 4 to 27 ± 2 days and from 43 ± 3 to 35 ± 2 days for follow-ups (P.001). Overbooked hours decreased from 14.7 ± 3.1 to 8.6 ± 1.7 hours (P.001). Surgeon productivity remained stable (109% ± 11% vs 113% ± 6%, P = .56). Patient satisfaction in seeing APs versus surgeons was comparable (94 ± 2 vs 94 ± 3, P = .79).Incorporation of APs into the HNTC increases the number of new patients seen by the surgeon, decreases wait times for all appointments, and decreases overbooking while maintaining patient satisfaction and surgeon productivity.AP incorporation significantly improves access to head and neck surgical services. With improved access, new cancer patients could start treatment sooner, potentially affecting outcome.

Background We present a fold-over technique for total and subtotal glossectomy reconstruction utilizing the ALT flap with the goal of increasing soft tissue bulk. Methods Retrospective review of total and subtotal glossectomy patients undergoing ALT fold-over flap reconstruction from January 2007 to December 2012. Results Eight patients fit inclusion criteria. Average length of follow-up was 35 months. There were no flap failures. At last follow-up, no patients were tracheostomy dependent. Six out of 8 patients (75%) did not require a g-tube and were able to maintain their weight. Speech intelligibility was good in 6/8 patients (75%). Conclusions The ALT fold-over flap technique provides sufficient bulk to allow decannulation and airway protection as well as PO intake in most patients. Given the minimal donor site morbidity, it is our technique of choice for total and subtotal glossectomy defects. © 2016 Wiley Periodicals, Inc. Microsurgery, 2016.

The aim of the study was to understand the effect of a long-term metal exposure (110 years) on sediment microbial communities. Two freshwater sites, Ferin and MetalEurop, differing by one order of magnitude in metal levels (MetalEurop: 3218 mg Zn kg(-1) ; 913 mg Pb kg(-1) ) were compared by shotgun metaproteogenomics. A total of 69-118 Mpb of DNA and 943-1241 proteins were obtained. PhymmBL analysis of the DNA sequences indicated that the phylogenetic profile was similar in both stations and that β-Proteobacteria were dominant. However, subtle but significant changes were observed for some bacteria: e.g. Pseudomonas (+0.4%), Leptothrix (-0.4%), Thiobacillus (+0.36%) and Acidovorax (+0.48%). Using the stamp software, the two communities were found to be functionally very similar. However, significant genetic differences (10(-6)

Autotaxin (ATX), an adipose tissue‐derived lysophospholipase, has been involved in the pathophysiology of cardiometabolic diseases. The impact of bariatric surgery on circulating ATX levels is unknown. We examined the short‐ (24 h, 5 days) and longer‐term (6 and 12 months) impact of bariatric surgery; as well as the short‐term effect of caloric restriction (CR) on plasma ATX levels in patients with severe obesity. We measured ATX levels in 69 men and women (mean age: 41 ± 11 years, body mass index: 49.8 ± 7.1 kg/m2), before and after biliopancreatic diversion with duodenal switch surgery (BPD‐DS) as well as in a control group (patients with severe obesity without surgery; n = 34). We also measured ATX levels in seven patients with severe obesity and type 2 diabetes who underwent a 3‐day CR protocol before their BPD‐DS. At baseline, ATX levels were positively associated with body mass index, fat mass, insulin resistance (HOMA‐IR) as well as insulin and leptin levels and negatively with fat‐free mass. ATX concentrations decreased 26.2% at 24 h after BPD‐DS (342.9 ± 152.3 pg/mL to 253.2 ± 68.9 pg/mL, P

Intermediate filaments serve important structural roles, but other cellular functions are increasingly recognized. This study demonstrated normal function of the low-molecular-weight neurofilament protein (NFL) in mitochondrial dynamics and disruption in Charcot-Marie-Tooth disease (CMT) due to mutations in the Nefl gene. In motor neurons of spinal cord cultured from Nefl-knockout mice, mitochondrial length and the rate of fusion were decreased concomitant with increased motility. These parameters were normalized after expression of NFL(wt) on the Nefl(-/-) background, but not by overexpression of the profusion protein, mitofusin 2 (MFN2). The effects of CMT-causing NFL mutants bore similarities to and differences from Nefl knockout. In the early phase of toxicity before disruption of the neurofilament network, NFL(Q333P) and NFL(P8R) integrated into neurofilaments and had effects on mitochondria similar to those with Nefl knockout. The reduction of fusion rate by NFL(Q333P) was partly due to interference with the function of the profusion protein MFN2, which is mutated in CMT2A, functionally linking these forms of CMT. In the later phase of toxicity, mitochondria essentially stopped moving in neurons expressing NFL mutants, probably a consequence of cytoskeletal disruption. Overall, the data point to important functions of neurofilaments in mitochondrial dynamics as well as primary involvement in CMT2E/1F.

P>Background Although the total to high-density lipoprotein cholesterol ratio (TC/HDL-C) has been used for decades to identify individuals at risk for coronary heart disease (CHD), apolipoprotein-based (apolipoprotein B/apolipoprotein A-I [apoB/apoA-I]) and nuclear magnetic resonance spectroscopy (NMR)-based lipoprotein concentrations (low-density lipoprotein(NMR)/high-density lipoprotein(NMR) [LDLNMR/HDLNMR]) may also be useful for CHD risk stratification. Materials and methods In a case-control study conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study population, 870 individuals who developed CHD during a 6-year follow-up were matched to 1659 controls on the basis of gender, age and enrolment time. LDLNMR and HDLNMR were measured by proton NMR spectroscopy. Results After adjusting for traditional CHD risk factors, men in the top quintile of the various lipoprotein ratios proved to be at increased CHD risk (OR = 2 center dot 59 [95% IC, 1 center dot 76-3 center dot 83] for TC/HDL-C ratio, 2 center dot 59 [1 center dot 75-3 center dot 83] for apoB/apoA-I ratio and 2 center dot 78 [1 center dot 86-4 center dot 17] for LDLNMR/HDLNMR ratio) compared with men in the bottom quintile. Similar associations were observed in women (OR = 2 center dot 86 [1 center dot 71-4 center dot 80] for TC/HDL-C ratio, 2 center dot 94 [1 center dot 74-4 center dot 97] for apoB/apoA-I ratio and 2 center dot 03 [1 center dot 21-3 center dot 43] for LDLNMR/HDLNMR ratio). Compared with participants with only one component of the metabolic syndrome, those who had five had an increased TC/HDL-C ratio (73 center dot 0% and 80 center dot 4% in men and women respectively), apoB/apoA-I ratio (58 center dot 0% and 62 center dot 9% in men and women respectively) and for LDLNMR/HDLNMR ratio (52 center dot 6% and 54 center dot 1% in men and women respectively). Conclusion In this European study population, the TC/HDL-C, apoB/apoA-I and LDLNMR/HDLNMR ratios were similarly associated with components of the metabolic syndrome and CHD risk

Program Description:Human papillomavirus (HPV)–related oropharyngeal cancer is now recognized as a clinically distinct entity, and data describing the nature of the epidemic, optimal treatment strategies, and survival outcomes are rapidly developing. Our patients are asking pertinent questions about HPV transmission, the role of vaccination, and monitoring recommendations. This miniseminar will update practitioners on the accuracy of testing, how to counsel patients and families regarding the nature of HPV infection (risk and transmissibility), vaccination, the management of benign lesions, and surveillance. This panel will appeal broadly to trainees, general otolaryngologists, and head and neck surgical oncologists.Educational Objectives:(1) Advise patients and partners regarding HPV infection and transmission. (2) List the Centers for Disease Control and Prevention recommendations for HPV vaccination. (3) Develop a surveillance plan for patients with HPV and their families.

Program Description: Neck dissection continues to be an integral part of surgical treatment of head and neck squamous cell carcinoma (HNSCC). The operation has evolved significantly since first des...

From its earliest beginnings dated to 200BC by Nicander of Colophon, hirudotherapy has been a long-established medical treatment. In cases of tissue-threatening venous congestion, where outflow obstruction leads to microcirculatory collapse and tissue ischemia, hirudotherapy can effectively reverse venous stasis while the microcirculation reestablishes itself. Derganc has been widely credited for the original use of hirudotherapy in flap salvage. Hirudin, among other anticoagulative substrates found in leech saliva, inhibits platelet aggregation and increases tissue permeability; both necessary therapeutic effects to counteract erythrocyte extravasation and the procoagulative micro-environment seen with venous congestion. Hirudotherapy is not without the risk of complications however, the most substantive of which being infection and blood loss. Standard protocols for coverage of common bacterial pathogens found in leech saliva include the use of quinolones, aminoglycosides, third-generation cephalosporins or sulfa drugs. Daily hemagrams and coagulation studies are also indicated to assure blood loss is well controlled.

ObjectivesIn a prior communication, we showed that ischemic rat groin flaps exposed to the free radical scavenger N-2 mercaptopropionylglycine (MPG) at the time of arterial and venous occlusion had a higher rate of survival than untreated flaps. In this study, the objective is to test the efficacy and timing of administration of MPG in salvaging rat groin flaps subjected to venous occlusion alone.MethodsRandomized controlled trial. Main outcome is mean percentage of flap survival at 7 days. 30 mature Sprague-Dawley rats were randomized to 3 groups based on timing of treatment with MPG: 1- flap raised, no MPG, no venous occlusion (sham group); 2- flap raised, no MPG, 10-hour period of venous occlusion (control group); 3- flap raised, MPG after 10 hours venous occlusion (post-reperfusion group).ResultsThere was no statistical difference noted in mean survival of venous occluded flaps when comparing the control and post-reperfusion groups, after 7 days. Specifically, the mean flap survival in the control gro...