Citations

Objective This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD). Design Systematic review and meta-analysis. Data sources PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017). Eligibility criteria The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language. Data analysis We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study. Results Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95% CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24 hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95% CI: 1.2 to 2.5; I 2 : 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95% CI: 1.3 to 3.6; I 2 : 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95% CI: 1.2 to 1.7; I 2 : 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14 mg vs 18.9±13.0 mg; mean difference: 2.8; 95% CI: 0.4 to 5.3; I 2 : 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status. Conclusion Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose.

Significance The energy-producing organelle mitochondrion contains its own compact genome, which is separate from the nuclear genome. In nearly all mammals, this mitochondrial genome is inherited exclusively from the mother, and transmission of paternal mitochondria or mitochondrial DNA (mtDNA) has not been convincingly demonstrated in humans. In this paper, we have uncovered multiple instances of biparental inheritance of mtDNA spanning three unrelated multiple generation families, a result confirmed by independent sequencing across multiple unrelated laboratories with different methodologies. Surprisingly, this pattern of inheritance appears to be determined in an autosomal dominantlike manner. This paper profoundly alters a widespread belief about mitochondrial inheritance and potentially opens a novel field in mitochondrial medicine.

Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13–2.42), and among white (OR 1.33, 95% CI: 1.02–1.75), but not African American, participants ( p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

Background: Increasing evidence points to intracranial atherosclerosis as a risk factor not only for stroke but also for dementia, but whether it is linked to Alzheimer’s disease-specific pathology itself is less understood. In the community-based Atherosclerosis Risk in Communities (ARIC) study, we evaluated the cross-sectional association between intracranial atherosclerosis and cerebral amyloid deposition, in nondemented participants. Methods: In 2011-2014, a subset of participants from the ARIC Neurocognitive Study underwent both a brain MRI, including high-resolution vessel wall imaging, and florbetapir PET, as a marker of amyloid deposition. We analyzed the association between elevated amyloid (defined as a global cortical florbetapir standardized uptake value ratio (SUVR)>1.2) and intracranial arterial plaque presence, frequency, and extent of stenosis, with adjustment for demographic and vascular risk factors. We tested effect modification by APOE ε4 genotype. Results: In 300 participants (mean age of 76y, 44% African-American, 56% female, 31% carriers of at least one APOE ε4 allele), intracranial plaque was found in 105 (35%) participants. Mean SUVR was higher in individuals with vs without plaque (1.34 ± 0.29 vs 1.27 ± 0.23, p=0.03). In adjusted models, plaque presence was not associated significantly with elevated SUVR in the total sample, nor was number of plaques. Associations between plaque presence and extent were generally stronger in APOE ε4 carriers than noncarriers (p<0.05 for interaction for some plaque features; see Table). Conclusions: Although intracranial arterial plaque or stenosis was not definitively associated with brain amyloid in this sample of nondemented older adults, associations with brain amyloid appeared stronger in carriers of an APOE ε4 allele, consistent with studies demonstrating a similar relationship as that seen with other more traditionally measured vascular risk factors.

TPS2618 Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.

e16555 Background: The ProtecT trial underscores the importance of treatment in men with prostate cancer and life expectancies > 10 years and the validity of radiation therapy (RT). RT can be given with photons or protons (PT). To address the controversy of which is better, clinical outcomes of photon-based intensity modulated RT (IMRT) and PT cohorts from 2 institutions were directly compared. Methods: Under respective IRB approvals, data from 2 cohorts were analyzed. The first was 301 men treated with ultrasound image guided IMRT from 2000-05 to 75.6 Gy in 42 fractions. The second was 1214 men treated with fiducial image guided PT from 2006-10 to 78 CGE in 39 fractions. Median age and followup were 74 y and 7.2 y for IMRT and 66 y and 5.6 y for PT. Hormone therapy (ADT) was used with IMRT and PT, respectively, in 3% and 7% of low-risk patients, 25% and 9.9% of intermediate-risk, and 91% and 57.8% of high-risk. Comparative endpoints were age-stratified 5-year (5Y) survival (OS), ≥ grade 3 gastrointestinal (GI) and urologic (GU) toxicity, and 5Y freedom from biochemical progression (FFBP). Results: There was a lower prevalence of GI (1.3% vs 0.1%, p = 0.0065) and GU (4.3% vs 0.1%, p < 0.0001) toxicity at last follow-up in the PT group. In the IMRT and PT cohorts, OS rates were 90.8% and 88.7% in men ≥75 (p = 0.4083). In men < 75, OS rates were 91.6% and 97.5% in the IMRT and PT low-risk patients (p = 0.003), 92.1% and 95.5% in the IMRT and PT intermediate-risk (p = 0.0535), and 92.0% and 90.0% (p = 0.4975) in the IMRT and PT high-risk. In the IMRT and PT cohorts, respectively, FFBP rates were 92.2% and 98.9% for low-risk patients (p < 0.0001), 87.3% and 94.5% for intermediate-risk patients(p = 0.0226), and 80.3% and 74.4% for high-risk patients (p = 0.5154). Conclusions: In this retrospective comparison of outcomes in cohorts of men treated with IMRT and PT for prostate cancer, FFBP rates were better with PT for men with low- and intermediate-risk disease and similar in men with high-risk disease despite longer and more frequent use of ADT in the IMRT cohort. This study underscores the difficulty of comparing retrospective series, with differences noted in age, RT dose, and ADT use between cohorts. However, the magnitude of improvement with PT is intriguing and warrants prospective testing.