Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR.

Background: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation. Methods: This study uses genetic tools (transgenic C. elegans , RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions. Results: We use the C. elegans system to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging in C. elegans . Enhanced resilience to protein unfolding stress requires neuronal expression of cbp-1 . Conclusion: Low translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.

Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis in C. elegans.

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer's disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide ( flp ) genes and the neuroprotective growth factor progranulin gene prgn-1 under dietary restriction in C. elegans . Here, we tested the effects of flp-5 , flp-14 , flp-15 and pgrn-1 on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression of pgrn-1 and flp genes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression of flp-14 in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of the eat-2 gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown of pgrn-1 or flp genes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown of pgrn-1 and flp genes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targeting flp-14 increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi of pgrn-1 decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show that pgrn-1 , flp-5 , flp-14 , and flp-15 do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1ß, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound 14, which displayed nanomolar reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic profiles and synergistic antitumor activity when administered in combination with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents.

Successful kinetic impact into an asteroid for planetary defence.

Although no known asteroid poses a threat to Earth for at least the next century, the catalogue of near-Earth asteroids is incomplete for objects whose impacts would produce regional devastation1,2. Several approaches have been proposed to potentially prevent an asteroid impact with Earth by deflecting or disrupting an asteroid1-3. A test of kinetic impact technology was identified as the highest-priority space mission related to asteroid mitigation1. NASA's Double Asteroid Redirection Test (DART) mission is a full-scale test of kinetic impact technology. The mission's target asteroid was Dimorphos, the secondary member of the S-type binary near-Earth asteroid (65803) Didymos. This binary asteroid system was chosen to enable ground-based telescopes to quantify the asteroid deflection caused by the impact of the DART spacecraft4. Although past missions have utilized impactors to investigate the properties of small bodies5,6, those earlier missions were not intended to deflect their targets and did not achieve measurable deflections. Here we report the DART spacecraft's autonomous kinetic impact into Dimorphos and reconstruct the impact event, including the timeline leading to impact, the location and nature of the DART impact site, and the size and shape of Dimorphos. The successful impact of the DART spacecraft with Dimorphos and the resulting change in the orbit of Dimorphos7 demonstrates that kinetic impactor technology is a viable technique to potentially defend Earth if necessary.

The integrated stress response protects against ER stress but is not required for altered translation and lifespan from dietary restriction in Caenorhabditis elegans.

The highly conserved integrated stress response (ISR) reduces and redirects mRNA translation in response to certain forms of stress and nutrient limitation. It is activated when kinases phosphorylate a key residue in the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). General Control Nonderepressible-2 (GCN2) is activated to phosphorylate eIF2α by the presence of uncharged tRNA associated with nutrient scarcity, while protein kinase R-like ER kinase-1 (PERK) is activated during the ER unfolded protein response (UPRER). Here, we investigated the role of the ISR during nutrient limitation and ER stress with respect to changes in protein synthesis, translationally driven mRNA turnover, and survival in Caenorhabditis elegans. We found that, while GCN2 phosphorylates eIF2α when nutrients are restricted, the ability to phosphorylate eIF2α is not required for changes in translation, nonsense-mediated decay, or lifespan associated with dietary restriction (DR). Interestingly, loss of both GCN2 and PERK abolishes increased lifespan associated with dietary restriction, indicating the possibility of other substrates for these kinases. The ISR was not dispensable under ER stress conditions, as demonstrated by the requirement for PERK and eIF2α phosphorylation for decreased translation and wild type-like survival. Taken together, results indicate that the ISR is critical for ER stress and that other translation regulatory mechanisms are sufficient for increased lifespan under dietary restriction.

Olfactory flow in the sea catfish, Ariopsis felis (L.): Origin, regulation, and resampling.

The olfactory epithelium of the sea catfish, Ariopsis felis, is found on a pinnate array of lamellae (the olfactory rosette) housed within a nasal chamber. The nasal anatomy of A. felis suggests an ability to capture external water currents. We prepared models from X-ray micro-computed tomography scans of two preserved specimens of A. felis. We then used dye visualisation and computational fluid dynamics to show that an external current induced a flow of water through a) the nasal chamber and b) the sensory channels of the olfactory rosette. The factors responsible for inducing flow through the nasal chamber are common to fishes from two other orders. The dye visualisation experiments, together with observations of sea catfishes in vivo, indicate that flow through the nasal chamber is regulated by a mobile nasal flap. The position of the nasal flap - elevated (significant flow) or depressed (reduced flow) - is controlled by the sea catfish's movements. Flow in the sensory channels of the olfactory rosette can pass through either a single channel or, via multiple pathways, up to four consecutive channels. Flow through consecutive sensory channels (olfactory resampling) is more extensive at lower Reynolds numbers (200 and 300, equivalent to swimming speeds of 0.5-1.0 total lengths s-1), coinciding with the mean swimming speed of the sea catfishes observed in vivo (0.6 total lengths s-1). Olfactory resampling may also occur, via a vortex, within single sensory channels. In conclusion, olfactory flow in the sea catfish is regulated and thoroughly sampled by novel mechanisms.

Safety risk management for low molecular weight process-related impurities in monoclonal antibody therapeutics: Categorization, risk assessment, testing strategy, and process development with leveraging clearance potential.

Process-related impurities (PRIs) derived from manufacturing process should be minimized in final drug product. ICH Q3A provides a regulatory road map for PRIs but excludes biologic drugs like monoclonal antibodies (mAbs) that contain biological PRIs (e.g. host cell proteins and DNA) and low molecular weight (LMW) PRIs (e.g., fermentation media components and downstream chemical reagents). Risks from the former PRIs are typically addressed by routine tests to meet regulatory expectations, while a similar routine-testing strategy is unrealistic and unnecessary for LMW PRIs, and thus a risk-assessment-guided testing strategy is often utilized. In this report, we discuss a safety risk management strategy including categorization, risk assessment, testing strategy, and its integrations with other CMC development activities, as well as downstream clearance potentials. The clearance data from 28 mAbs successfully addressed safety concerns but did not fully reveal the process clearance potentials. Therefore, we carried out studies with 13 commonly seen LMW PRIs in a typical downstream process for mAbs. Generally, Protein A chromatography and cation exchange chromatography operating in bind-and-elute mode showed excellent clearances with greater than 1,000- and 100-fold clearance, respectively. The diafiltration step had better clearance (greater than 100-fold) for the positively and neutrally charged LMW PRIs than for the negatively charged or hydrophobic PRIs. We propose that a typical mAb downstream process provides an overall clearance of 5,000-fold. Additionally, the determined sieving coefficients will facilitate diafiltration process development. This report helps establish effective safety risk management and downstream process design with robust clearance for LMW PRIs.

Characteristics and outcomes of patients with COVID-19 at a district general hospital in Surrey, UK.

BACKGROUND: This retrospective cohort study aims to define the clinical findings and outcomes of every patient admitted to a district general hospital in Surrey with COVID-19 in March 2020, providing a snapshot of the first wave of infection in the UK. This study is the first detailed insight into the impact of frailty markers on patient outcomes and provides the infection rate among healthcare workers. METHODS: Data were obtained from medical records. Outcome measures were level of oxygen therapy, discharge and death. Patients were followed up until 21 April 2020. RESULTS: 108 patients were included. 34 (31%) died in hospital or were discharged for palliative care. 43% of patients aged over 65 died. The commonest comorbidities were hypertension (49; 45%) and diabetes (25; 23%). Patients who died were older (mean difference ±SEM, 13.76±3.12 years; p<0.0001) with a higher NEWS2 score (median 6, IQR 2.5-7.5 vs median 2, IQR 2-6) and worse renal function (median differences: urea 2.7 mmol/L, p<0.01; creatinine 4 µmol/L, p<0.05; eGFR 14 mL/min, p<0.05) on admission compared with survivors. Frailty markers were identified as risk factors for death. Clinical Frailty Scale (CFS) was higher in patients over 65 who died than in survivors (median 5, IQR 4-6 vs 3.5, IQR 2-5; p<0.01). Troponin and creatine kinase levels were higher in patients who died than in those who recovered (p<0.0001). Lymphopenia was common (median 0.8, IQR 0.6-1.2; p<0.005). Every patient with heart failure died (8). 26 (24%) were treated with continuous positive airway pressure (CPAP; median 3 days, IQR 2-7.3) and 9 (8%) were intubated (median 14 days, IQR 7-21). All patients who died after discharge (4; 6%) were care home residents. 276 of 699 hospital staff tested were positive for COVID-19. CONCLUSIONS: This study identifies older patients with frailty as being particularly vulnerable and reinforces government policy to protect this group at all costs.

Changing multiple health behaviors in cancer survivors: smoking and exercise.

Research regarding cross-behavioral relationships between the cognitive mechanisms motivating health behavior change is lacking for cancer survivors. This study investigated these relationships to inform the development of multiple health behavior change (MHBC) interventions for this at-risk population. Eligible participants included cancer survivors attending an intake appointment for smoking cessation services. This cross-sectional survey study assessed participants' self-efficacy and motivation (stage of change) for smoking cessation and exercise, as well as self-reported health behaviors. Analyses evaluated cross-behavioral associations between cognitive mechanisms and their relationships with smoking and exercise behaviors. Seventy-six participants completed the survey questionnaire. The correlation between self-efficacy scores for smoking cessation and exercise was statistically significant (r = .45, 95% CI [.09, .67]), as were correlations between self-efficacy and reported levels of exercise ((r = .44, 95% CI [.20, .65]) strenuous); ((r = .36, 95% CI [.12, .59]) moderate), exercise self-efficacy and smoking behavior (r = -.27, 95% CI [-.46, -.05]), and smoking self-efficacy and smoking behavior (r = -0.41, 95% CI [-.61, -.18]). For cancer survivors, associations between exercise self-efficacy and smoking cessation self-efficacy may offer an opportunity to leverage MHBC; specifically, this positive association may facilitate exercise intervention in survivors seeking smoking cessation services..

Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance.

Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.

Long-term Outcomes of Ossiculoplasty With and Without an Intact Malleus.

OBJECTIVE: To compare long-term hearing outcomes following ossiculoplasty with cartilage tympanoplasty with (M) and without (M) the malleus present. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: One twenty-six patients (18-88 yr of age) undergoing ossiculoplasty with tympanoplasty or tympanomastoidectomy using cartilage tympanic membrane grafts from 1998 to 2012 with at least 5 years of documented postoperative follow-up. MAIN OUTCOME MEASURES: Short-term hearing results (pure-tone average air-bone gap [PTA-ABG] measured between 60 d and 1 yr after surgery), long-term hearing results (PTA-ABG measured ≥5 yr after surgery), Ossiculoplasty Outcome Parameter Staging (OOPS) index, and complications. RESULTS: There were 46 patients in the M group and 80 in the M group. Preoperative PTA-ABG was 23.8 dB for M and 34.5 dB for M (p = 0.00001). Short-term postoperative PTA-ABG was 19.3 dB for M and 18.5 dB for M (p = 0.727). Long-term postoperative PTA-ABG was 18.2 dB for M and 19.6 dB for M (p = 0.500). The OOPS index was 4.11 and 6.41 for M and M, respectively, (p = 0.00001). Thirteen patients (10.3%) experienced complications. CONCLUSION: Our data suggest that the malleus is not statistically significant with regard to its impact on final audiometric outcome following ossiculoplasty. This has implications in our clinic, particularly in our use of the OOPS index as a prognostic tool, and will likely lead to its revision. These data may further support the coupling theory of acoustic gain and weaken the catenary lever theory.

Evaluation of Intraoperative Testing During Cochlear Implantation From a Time and Cost Perspective: A Single-Center Experience in the United States.

OBJECTIVE: To measure the time spent performing intraoperative testing during cochlear implantation (CI) and determine the impact on hospital charges. STUDY DESIGN: Prospective study. SETTING: Tertiary referral hospital. PATIENTS: Twenty-two children (7 mo-18 yr) who underwent a total of 22 consecutive primary and/or revision CIs by a single surgeon from December 2016 to July 2017. INTERVENTION: The time spent performing intraoperative testing, including evoked compound action potentials (ECAP) and electrical impedances (EI), was recorded for each case. The audiologist performing the testing was unaware of the time measurement and subsequent evaluations with regard to cost data. Billing information was used to determine if the testing contributed to increased operative charges to the patient. OUTCOME MEASURES: Whether intraoperative testing had an impact on operative charges to the patient. RESULTS: The average time spent in testing (ECAPs/EIs in all cases) was 6.7 minutes (range, 2-26 min). No correlation was found between testing time and preoperative computed tomography findings, the audiologist performing testing, or the electrode type used (p > 0.05). Based on billing data, including time spent in the operating room (OR), 5/22 (23%) cases incurred greater charges than if intraoperative testing had not been performed. CONCLUSION: Our data suggest that intraoperative testing increases time in the OR and can contribute to increased hospital charges for CI patients. By using testing selectively, costs incurred by patients and hospitals may be reduced. This is of interest in a healthcare environment that is increasingly focused on cost, quality, and outcomes.

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge. OBJECTIVE: To assess the feasibility of recruiting patients, collecting data and delivering EPR to patients with AECOPD to evaluate EPR compared with usual care. DESIGN: Parallel-group, pilot 2 × 2 factorial randomised trial with nested qualitative research and an economic analysis. SETTING: Two acute hospital NHS trusts. Recruitment was carried out from September 2015 to April 2016 and follow-up was completed in July 2016. PARTICIPANTS: Eligible patients were those aged ≥ 35 years who were admitted with AECOPD, who were non-acidotic and who maintained their blood oxygen saturation level (SpO2) within a prescribed range. Exclusions included the presence of comorbidities that affected the ability to undertake the interventions. INTERVENTIONS: (1) Hospital EPR: muscle training delivered at the patient's hospital bed using a cycle ergometer and (2) home EPR: a pulmonary rehabilitation programme delivered in the patient's home. Both interventions were delivered by trained physiotherapists. Participants were allocated on a 1 : 1 : 1 : 1 ratio to (1) hospital EPR (n = 14), (2) home EPR (n = 15), (3) hospital EPR and home EPR (n = 14) and (4) control (n = 15). Outcome assessors were blind to treatment allocation; it was not possible to blind patients. MAIN OUTCOME MEASURES: Feasibility of recruiting 76 participants in 7 months at two centres; intervention delivery; views on intervention/research acceptability; clinical outcomes including the 6-minute walk distance (6WMD); and costs. Semistructured interviews with participants (n = 27) and research health professionals (n = 11), optimisation assessments and an economic analysis were also undertaken. RESULTS: Over 7 months 449 patients were screened, of whom most were not eligible for the trial or felt too ill/declined entry. In total, 58 participants (76%) of the target 76 participants were recruited to the trial. The primary clinical outcome (6MWD) was difficult to collect (hospital EPR, n = 5; home EPR, n = 6; hospital EPR and home EPR, n = 5; control, n = 5). Hospital EPR was difficult to deliver over 5 days because of patient discharge/staff availability, with 34.1% of the scheduled sessions delivered compared with 78.3% of the home EPR sessions. Serious adverse events were experienced by 26 participants (45%), none of which was related to the interventions. Interviewed participants generally found both interventions to be acceptable. Home EPR had a higher rate of acceptability, mainly because patients felt too unwell when in hospital to undergo hospital EPR. Physiotherapists generally found the interventions to be acceptable and valued them but found delivery difficult because of staffing issues. The health economic analysis results suggest that there would be value in conducting a larger trial to assess the cost-effectiveness of the hospital EPR and hospital EPR plus home EPR trial arms and collect more information to inform the hospital cost and quality-adjusted life-year parameters, which were shown to be key drivers of the model. CONCLUSIONS: A full-scale randomised controlled trial using this protocol would not be feasible. Recruitment and delivery of the hospital EPR intervention was difficult. The data obtained can be used to design a full-scale trial of home EPR. Because of the small sample and large confidence intervals, this study should not be used to inform clinical practice. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18634494. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 11. See the NIHR Journals Library website for further project information.

Trends in Intraoperative Testing During Cochlear Implantation.

OBJECTIVE: No consensus guidelines exist regarding intraoperative testing during cochlear implantation and wide variation in practice habits exists. The objective of this observational study was to survey otologists/neurotologists to understand practice habits and overall opinion of usefulness of intraoperative testing. STUDY DESIGN: Cross-sectional survey. SETTING: A web-based survey was sent to 194 practicing Otologists/Neurotologists. MAIN OUTCOME MEASURES: Questions included practice setting and experience, habits with respect to electrodes used, intraoperative testing modalities used, overall opinion of intraoperative testing, and practice habits in various scenarios. RESULTS: Thirty-nine of 194 (20%) completed the survey. For routine patients, ECAPs and EIs were most commonly used together (38%) while 33% do not perform testing at all. Eighty-nine percent note that testing "rarely" or "never" changes management. Fifty-one percent marked the most important reason for testing is the reassurance provided to the family and/or the surgeon. CONCLUSION: Intraoperative testing habits and opinions regarding testing during cochlear implantation vary widely among otologic surgeons. The majority of surgeons use testing but many think there is minimal benefit and that surgical decision-making is rarely impacted. The importance of testing may change as electrodes continue to evolve.

Adverse events and safety issues associated with physical activity and exercise for adults with osteoporosis and osteopenia: A systematic review of observational studies and an updated review of interventional studies.

OBJECTIVES: We conducted a systematic review to identify adverse effects of physical activity and/or exercise for adults with osteoporosis/osteopenia. We synthesised evidence from observational studies, and updated three previously published systematic reviews. METHODS: We searched MEDLINE, EMBASE, CINAHL, Web of Science, grey literature and reference lists of relevant studies. Selection criteria were: (1) observational studies in patients with osteoporosis/osteopenia; and (2) in accordance with the criteria used in the previous reviews. A narrative synthesis was conducted for the observational data. Random effects meta-analysis was undertaken for the review updates. RESULTS: For the observational synthesis 14 studies were included. The majority of studies reported no adverse events, reduced incidence/improvement, or no significant change after physical activity or exercise. Activities that involved spinal flexion (certain yoga moves and sit-ups) were associated with a greater risk of vertebral fractures but these events were rare. For the update of reviews, 57 additional studies were identified. Exercise was generally associated with a greater number of minor adverse events including mild muscle/joint pain. Serious adverse events were rare and could not be attributed to the intervention. CONCLUSION: Patients with osteoporosis/osteopenia can safely participate in structured exercise programmes, whether at home or in supervised facilities. Systematic review registration for observational studies: PROSPERO 2017: CRD42017070551.

Long-term Complications and Surgical Failures After Ossiculoplasty.

OBJECTIVE: To study long-term complications after ossiculoplasty. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care referral center otology practice. PATIENTS: One hundred ninety-five patients (18-88 yr of age) undergoing ossiculoplasty with tympanoplasty or tympanomastoidectomy using cartilage tympanic membrane grafts, retrograde mastoidectomy with canal wall reconstruction, or mastoid obliteration techniques between July 1998 and July 2012. The studied patients all had at least 3 years of clinical follow-up. OUTCOME MEASURES: Incidence of long-term complications, including need for revision surgery, need for secondary ventilation tube placement, recurrence of conductive hearing loss (and related etiologies), recurrent cholesteatoma, and delayed graft failure (recurrent tympanic membrane perforation). RESULTS: Long-term complications were observed in 10.3% (20/195) of patients. 8.2% (16/195) required revision surgery, 10.2% (17/195) required secondary ventilation tube placement, 3.6% (7/195) experienced recurrence of conductive hearing loss, 4.1% (8/195) had delayed failure of tympanic membrane graft, and 1.5% (3/195) had recurrence of cholesteatoma. Recurrence of conductive hearing loss was caused by the displacement of prosthesis in 3 of 7 patients and extensive scar tissue formation without prosthesis displacement in 4 of 7 patients. Seventy-two percent obtained a postoperative pure-tone average - air-bone gap  < 20 dB. Forty-eight percent (93/195) obtained a hearing result worse than expected based on the ossiculoplasty outcome parameter staging index. CONCLUSION: Long-term complications are a significant consideration in all the patients undergoing ossiculoplasty. Our data suggest that tobacco smoking, Eustachian tube dysfunction, and an unexpectedly poor hearing result on the first postoperative audiogram are all important risk factors for the development of significant complications.

Comparison of Internet and Telephone Interventions for Weight Loss Among Cancer Survivors: Randomized Controlled Trial and Feasibility Study.

BACKGROUND: Weight loss interventions have been successfully delivered via several modalities, but recent research has focused on more disseminable and sustainable means such as telephone- or Internet-based platforms. OBJECTIVE: The aim of this study was to compare an Internet-delivered weight loss intervention to a comparable telephone-delivered weight loss intervention. METHODS: This randomized pilot study examined the effects of 6-month telephone- and Internet-delivered social cognitive theory-based weight loss interventions among 37 cancer survivors. Measures of body composition, physical activity, diet, and physical performance were the outcomes of interest. RESULTS: Participants in the telephone intervention (n=13) showed greater decreases in waist circumference (-0.75 cm for telephone vs -0.09 cm for Internet, P=.03) than the Internet condition (n=24), and several other outcomes trended in the same direction. Measures of engagement (eg, number of telephone sessions completed and number of log-ins) suggest differences between groups which may account for the difference in outcomes. CONCLUSIONS: Cancer survivors in the telephone group evidenced better health outcomes than the Internet group. Group differences may be due to higher engagement in the telephone group. Incorporating a telephone-based component into existing weight loss programs for cancer survivors may help enhance the reach of the intervention while minimizing costs. More research is needed on how to combine Internet and telephone weight loss intervention components so as to maximize engagement and outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01311856; https://clinicaltrials.gov/ct2/show/NCT01311856 (Archived by WebCite at http://www.webcitation.org/6tKdklShY).