Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.

The three human SNM1 metallo-ß-lactamase fold nucleases (SNM1A-C) play key roles in DNA damage repair and in maintaining telomere integrity. Genetic studies indicate that they are attractive targets for cancer treatment and to potentiate chemo- and radiation-therapy. A high-throughput screen for SNM1A inhibitors identified diverse pharmacophores, some of which were shown by crystallography to coordinate to the di-metal ion centre at the SNM1A active site. Structure and turnover assay-guided optimization enabled the identification of potent quinazoline-hydroxamic acid containing inhibitors, which bind in a manner where the hydroxamic acid displaces the hydrolytic water and the quinazoline ring occupies a substrate nucleobase binding site. Cellular assays reveal that SNM1A inhibitors cause sensitisation to, and defects in the resolution of, cisplatin-induced DNA damage, validating the tractability of MBL fold nucleases as cancer drug targets.

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

National recruitment system for pre-registration pharmacist trainees in England and Wales: context, process and outcomes.

In England and Wales, a new National Recruitment Scheme (NRS) for pre-registration pharmacists was introduced in 2017. The NRS replaced the traditional method of employer-led recruitment or the national recruitment system previously limited to some hospital training programmes. NRS uses assessment methodology involving Multiple-Mini Interviews, Situational Judgement Tests and numeracy skills in ranking and appointing candidates to their preferred training providers through a centralised procedure. This commentary will describe the background, assessment methodology, outcomes of preliminary evaluations and priority research areas for the future in the context of the NRS.

Cognitive Function in a Sleep Clinic Cohort of Patients with Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is associated with an increased risk of mild cognitive impairment (MCI) within the general population. However, MCI risk in sleep-clinic populations of patients with OSA is poorly characterized.Objectives: To determine the prevalence of MCI in a sleep-clinic population of patients with OSA and which patients are at the greatest risk for this complication.Methods: Adults (n = 1,084) referred to three academic sleep centers for suspected OSA who had home sleep apnea testing or in-laboratory polysomnography were recruited. Patients completed sleep and medical history questionnaires, the Montreal Cognitive Assessment Test (MoCA) of global cognition, the Rey Auditory Verbal Learning Test of memory, and the Wechsler Adult Intelligence Scale-Fourth Edition Digit-Symbol Coding (DSC) subtest of information processing speed.Results: A MoCA score <26 (range 0-30) was operationally defined as MCI. MCI was present in 47.9% of our entire patient cohort, increasing to >55.3% in patients with moderate and severe OSA. Patients with a MoCA <26 were predominantly older males with more severe OSA, hypoxemia, and vascular comorbidities. Moderate and severe OSA were independently associated with >70% higher odds for MCI compared with patients with no OSA (P = 0.003). Memory and information processing speed was lower than age-matched normal values (P < 0.001), with lower MoCA and DSC scores associated with a higher oxygen desaturation index and nocturnal hypoxemia.Conclusions: Cognitive impairment is highly prevalent in patients referred to sleep clinics for suspected OSA, occurring predominantly in older males with moderate to severe OSA and concurrent vascular comorbidities. Moderate to severe OSA is an independent risk factor for MCI.

The Advisory Committee on Immunization Practices' Ethical Principles for Allocating Initial Supplies of COVID-19 Vaccine - United States, 2020.

To reduce the spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) and its associated impacts on health and society, COVID-19 vaccines are essential. The U.S. government is working to produce and deliver safe and effective COVID-19 vaccines for the entire U.S. population. The Advisory Committee on Immunization Practices (ACIP)* has broadly outlined its approach for developing recommendations for the use of each COVID-19 vaccine authorized or approved by the Food and Drug Administration (FDA) for Emergency Use Authorization or licensure (1). ACIP's recommendation process includes an explicit and transparent evidence-based method for assessing a vaccine's safety and efficacy as well as consideration of other factors, including implementation (2). Because the initial supply of vaccine will likely be limited, ACIP will also recommend which groups should receive the earliest allocations of vaccine. The ACIP COVID-19 Vaccines Work Group and consultants with expertise in ethics and health equity considered external expert committee reports and published literature and deliberated the ethical issues associated with COVID-19 vaccine allocation decisions. The purpose of this report is to describe the four ethical principles that will assist ACIP in formulating recommendations for the allocation of COVID-19 vaccine while supply is limited, in addition to scientific data and implementation feasibility: 1) maximize benefits and minimize harms; 2) promote justice; 3) mitigate health inequities; and 4) promote transparency. These principles can also aid state, tribal, local, and territorial public health authorities as they develop vaccine implementation strategies within their own communities based on ACIP recommendations.

Interventions to improve spontaneous adverse drug reaction reporting by healthcare professionals and patients: systematic review and meta-analysis.

INTRODUCTION: The aim of this study was to evaluate the effectiveness of interventions used for improving ADR reporting by patients and healthcare professionals. AREAS COVERED: A systematic review of literature was conducted by searching Medline, Embase and Cochrane Central Register of Controlled of Trials. Meta-analysis of randomized controlled trials (RCTs; n = 5) was conducted to estimate the pooled risk ratio for the effectiveness of interventions on ADR reporting rates. Data from observational studies were synthesized using narrative synthesis approach. EXPERT OPINION: A total of 28 studies were included. All except one study targeted healthcare professionals using educational, technological, policy, financial and/or mixed interventions. The results showed that financial and face-to-face educational interventions improved quality and quantity of ADR reporting when compared with interventions not involving face-to-face interactions. However, the quality of studies was generally low. Meta-analysis showed a statistically significant 3.5-fold overall increase in reporting of ADRs [RR 3.53; 95% CI (1.77,7.06)] in the intervention group compared to the control. There was a lack of consideration of theory and sustainability in the design of the interventions. There is a need to develop and test theory-based interventions and target patient reporting. More research needs to be conducted in the low- and middle-income countries.

Multimorbidity and emergency department visits by a homeless population: a database study in specialist general practice.

BACKGROUND: Estimating healthcare needs of the homeless is associated with challenges in identifying the eligible population. AIM: To explore the demographic characteristics, disease prevalence, multimorbidity, and emergency department visits of the homeless population. DESIGN AND SETTING: EMIS electronic database of patient medical records and Quality and Outcomes Framework (QOF) data of all 928 patients registered with a major specialist homeless primary healthcare centre based in the West Midlands in England, from the period of October 2016 to 11 October 2017. METHOD: Prevalence data on 21 health conditions, multimorbidity, and visits to emergency departments were explored and compared with the general population datasets. RESULTS: Most homeless people identified were male (89.5%), with a mean age of 38.3 (SD = 11.5) years, and of white British origin (22.1%). Prevalence of substance (13.5%) and alcohol dependence (21.3%), hepatitis C (6.3%), and multimorbidity (21.3%) were markedly higher than in the general population. A third (32.5%) had visited the emergency department in the preceding 12 months. Emergency department visits were associated with a patient history of substance (odds ratio [OR] = 2.69) and alcohol dependence (OR = 3.14). CONCLUSION: A high prevalence of substance and alcohol dependence, and hepatitis C, exists among the homeless population. Their emergency department visit rate is 60 times that of the general population and the extent of multimorbidity, despite their lower mean age, is comparable with that of 60-69-year-olds in the general population. Because of multimorbidity, homeless people are at risk of fragmentation of care. Diversification of services under one roof, preventive services, and multidisciplinary care are imperative.

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer.

Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin. Metformin is prescribed globally to improve insulin sensitivity, including in those individuals with Type 2 Diabetes Mellitus (DM2). We demonstrate the effectiveness of metformin in resensitizing MDR breast cancer cell lines to their original treatment, and provide evidence that metformin may function through a mechanism involving post-translational histone modifications via an indirect histone deacetylase inhibitor (HDACi) activity. We find that metformin, at low physiological concentrations, reduces the expression of multiple classic protein markers of MDR in vitro and in preliminary in vivo models. Our demonstration that metformin can prevent MDR development and resensitize MDR cells to chemotherapy in vitro, provides important medical relevance towards metformin's potential clinical use against MDR cancers.

Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study.

AIM: To determine the short-term biochemical effects and clinical tolerability of intermittent fasting (IF) in adults with type 2 diabetes mellitus (T2DM). METHODS: We describe a three-phase observational study (baseline 2 wk, intervention 2 wk, follow-up 2 wk) designed to determine the clinical, biochemical, and tolerability of IF in community-dwelling volunteer adults with T2DM. Biochemical, anthropometric, and physical activity measurements (using the Yale Physical Activity Survey) were taken at the end of each phase. Participants reported morning, afternoon and evening self-monitored blood glucose (SMBG) and fasting duration on a daily basis throughout all study stages, in addition to completing a remote food photography diary three times within each study phase. Fasting blood samples were collected on the final days of each study phase. RESULTS: At baseline, the ten participants had a confirmed diagnosis of T2DM and were all taking metformin, and on average were obese [mean body mass index (BMI) 36.90 kg/m2]. We report here that a short-term period of IF in a small group of individuals with T2DM led to significant group decreases in weight (-1.395 kg, P = 0.009), BMI (-0.517, P = 0.013), and at-target morning glucose (SMBG). Although not a study requirement, all participants preferentially chose eating hours starting in the midafternoon. There was a significant increase (P < 0.001) in daily hours fasted in the IF phase (+5.22 h), although few attained the 18-20 h fasting goal (mean 16.82 ± 1.18). The increased fasting duration improved at-goal (< 7.0 mmol/L) morning SMBG to 34.1%, from a baseline of 13.8%. Ordinal Logistic Regression models revealed a positive relationship between the increase in hours fasted and fasting glucose reaching target values (χ2 likelihood ratio = 8.36, P = 0.004) but not for afternoon or evening SMBG (all P > 0.1). Postprandial SMBGs were also improved during the IF phase, with 60.5% readings below 9.05 mmol/L, compared to 52.6% at baseline, and with less glucose variation. Neither insulin resistance (HOMA-IR), nor inflammatory markers (C-reactive protein) normalized during the IF phase. IF led to an overall spontaneous decrease in caloric intake as measured by food photography (Remote Food Photography Method). The data demonstrated discernable trends during IF for lower energy, carbohydrate, and fat intake when compared to baseline. Physical activity, collected by a standardized measurement tool (Yale Physical Activity Survey), increased during the intervention phase and subsequently decreased in the follow-up phase. IF was well tolerated in the majority of individuals with 6/10 participants stating they would continue with the IF regimen after the completion of the study, in a full or modified capacity (i.e., every other day or reduced fasting hours). CONCLUSION: The results from this pilot study indicate that short-term daily IF may be a safe, tolerable, dietary intervention in T2DM patients that may improve key outcomes including body weight, fasting glucose and postprandial variability. These findings should be viewed as exploratory, and a larger, longer study is necessary to corroborate these findings.

Subjective and objective findings in patients with true dehiscence versus thin bone over the superior semicircular canal.

OBJECTIVE: To compare subjective and objective findings between patients with true dehiscence versus thin bone over the superior semicircular canal (SSC). STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: All patients from our institution with true dehiscence or thin bone over the SSC on computed tomography temporal bone (oblique view) from 2007 to 2013. MAIN OUTCOME MEASURES: Subjective test: Dizziness Handicap Inventory (DHI). Objective tests: Infrared video eye recording with varying stimuli (Tulio, Fistula, and Vibration); vestibular evoked myogenic potential (VEMP); electrocochleography; videonystagmography; pure-tone audiometry (i.e., air-bone gap). RESULTS: Fifty-four patients (64 ears) were reviewed. Thirty-nine patients (47 ears) had true dehiscence of the SSC on temporal bone computed tomography. Fifteen patients (17 ears) had thin bone over the SSC. There was no statistical difference in DHI scores for patients with true dehiscence versus those with thin bone over the SSC. Only cervical VEMP and air-bone gap via pure-tone audiometry revealed a significant difference between the two groups. The remaining vestibular assessments did not demonstrate any difference. No significant correlations were revealed between DHI and objective test findings across and within the two groups. CONCLUSION: Among the objective tests, cervical VEMP and pure-tone audiometry are the only tools to distinguish between true dehiscence and thin bone over the SSC. DHI does not differentiate between these two groups. Furthermore, no correlation exists between DHI and any objective finding. Further investigation is necessary to develop a validated subjective symptom index of patients with SSC syndrome.

Feedback-mediated dynamics in a model of coupled nephrons with compliant thick ascending limbs.

The tubuloglomerular feedback (TGF) system in the kidney, a key regulator of glomerular filtration rate, has been shown in physiologic experiments in rats to mediate oscillations in thick ascending limb (TAL) tubular fluid pressure, flow, and NaCl concentration. In spontaneously hypertensive rats, TGF-mediated flow oscillations may be highly irregular. We conducted a bifurcation analysis of a mathematical model of nephrons that are coupled through their TGF systems; the TALs of these nephrons are assumed to have compliant tubular walls. A characteristic equation was derived for a model of two coupled nephrons. Analysis of that characteristic equation has revealed a number of parameter regions having the potential for differing stable dynamic states. Numerical solutions of the full equations for two model nephrons exhibit a variety of behaviors in these regions. Also, model results suggest that the stability of the TGF system is reduced by the compliance of TAL walls and by internephron coupling; as a result, the likelihood of the emergence of sustained oscillations in tubular fluid pressure and flow is increased. Based on information provided by the characteristic equation, we identified parameters with which the model predicts irregular tubular flow oscillations that exhibit a degree of complexity that may help explain the emergence of irregular oscillations in spontaneously hypertensive rats.

Diagnostic and interventional sialendoscopy: a preliminary experience.

OBJECTIVES/HYPOTHESIS: To review our preliminary experience with diagnostic and therapeutic sialendoscopy for the management of non-neoplastic disorders of the salivary gland. STUDY DESIGN: Retrospective chart review. METHODS: Thirty-three consecutive patients undergoing 36 sialendoscopy procedures performed at a tertiary medical center from July 2008 to July 2010 were included. RESULTS: The mean age of presentation was 43 years (range, 7-74 years), and 61% of patients were male. Indications included sialolithiasis (47%; 17 of 36), recurrent sialadenitis (44%, 16 of 36), and Sjögren's syndrome (8%; three of 36). Successful endoscopy was performed in 97% (35 of 36). A papillotomy for access was necessary in 25% (nine of 36). In patients with sialolithiasis (n = 17), the mean size of the stones was 7.3 mm (range, 1-20 mm). Complete stone removal was achieved in 76% (13 of 17) of cases. Endoscopic stone removal was possible in 29% (five of 17), and a combined approach technique was required in 47% (eight of 17). Seventy-two percent (26 of 36) of patients had complete resolution of symptoms after sialendoscopy, with 19% (seven of 36) having partial resolution of symptoms. Patients with partial improvement of symptoms had a mean duration of improvement of 4.7 months. The overall complication rate was 22% (eight of 36). The major and minor complication rates were 3% (one of 36) and 19% (seven of 36), respectively. CONCLUSIONS: Sialendoscopy is safe and effective in managing non-neoplastic salivary gland disorders with low rates of major complications. Knowledge of options to navigate the rate-limiting steps, like dilation of the papilla and careful case selection, are key to successful outcomes.

Pathological use of electronic media: case studies and commentary.

Since its formal introduction barely a dozen years ago, internet addiction (IA) has been both increasingly researched and much debated. The majority of studies have been conducted on large populations through internet surveys, with the most popular instrument for assessing IA being the Internet Addiction Test (IAT). However, both the large scale anonymous survey approach and the design and application of the IAT yield limited clinical insights. IA and the recently proposed more encompassing term of Pathological Use of Electronic Media (PUEM) require more exquisite understanding for essential and timely incorporation into DSM-5 nosology. This study presents four cases modifying the IAT for application within a structured individual interview. The findings are discussed in regard to both the clinical benefit of the procedure and considerations of PUEM for its role in DSM-5.

Percutaneous common iliac artery aneurysm repair - a case report.

Endovascular repair of common iliac artery aneurysms has become the preferred form of treatment, provided the appropriate anatomy for endovascular repair exists. The Zenith abdominal aortic aneurysm graft converter (Cook Medical Inc, USA), by virtue of its design, appears to be the ideal device for such a repair. A case to illustrate the same is presented.

Hepatic resection for recurrent metastatic ovarian cancer.

BACKGROUND: The role for liver resection in metastatic ovarian cancer has not been defined. The aim of the current study was to investigate the validity of hepatic resection as a treatment option in metastatic ovarian cancer. METHODS: Retrospective review of a single institution's experience of patients undergoing hepatic resection for metastatic ovarian cancer from 1998-2006. RESULTS: Ten patients underwent resection for metastatic ovarian cancer. Primary tumor type included serous cystadenocarcinoma (n = 8), granulosa cell (n = 1), and yolk sac (n = 1). Median disease-free interval was 48 months. Liver resections included trisegmentectomy (n = 4), lobectomy (n = 4), and bisegmentectomy(n = 1). Additional surgeries included diaphragm resection (n = 60), bowel resection, (n = 30), and adrenalectomy (n = 10). The median overall survival following liver resection was 33 months. CONCLUSION: Liver resection for metastatic ovarian cancer is safe and is associated with long-term survival in some patients. Larger analysis may lead to the identification of prognostic factors associated with improved outcomes.