Antimicrobial Stewardship Training for Infectious Diseases Fellows: Program Directors Identify a Curriculum Need

A needs assessment survey of infectious diseases (ID) training program directors identified gaps in educational resources for training and evaluating ID fellows in antimicrobial stewardship. An Infectious Diseases Society of America-sponsored core curriculum was developed to address that need

Reflections on Seminole Rock: The Past, Present, and Future of Deference to Agency Regulatory Interpretations

Seminole Rock (or Auer) deference has captured the attention of scholars, policymakers, and the judiciary. That is why Notice & Comment, the blog of the Yale Journal on Regulation and the American Bar Association’s Section of Administrative Law & Regulatory Practice, hosted an online symposium from September 12 to September 23, 2016 on the subject. This symposium contains over 20 contributions addressing different aspects of Seminole Rock deference. Topics include: History of Seminole Rock Empirical Examinations of Seminole Rock Understanding Seminole Rock Within Agencies Understanding Seminole Rock as Applied to Tax, Environmental Law, and Criminal Sentencing Why Seminole Rock Matters Should the Supreme Court Overrule Seminole Rock? Would Overruling Seminole Rock Have Unintended Consequences? What Might the Supreme Court Do? What Might Congress Do? The Future of Seminole Roc

SmCL3, a Gastrodermal Cysteine Protease of the Human Blood Fluke Schistosoma mansoni

Parasitic infection caused by blood flukes of the genus Schistosoma is a major global health problem. More than 200 million people are infected. Identifying and characterizing the constituent enzymes of the parasite's biochemical pathways should reveal opportunities for developing new therapies (i.e., vaccines, drugs). Schistosomes feed on host blood, and a number of proteolytic enzymes (proteases) contribute to this process. We have identified and characterized a new protease, SmCL3 (for Schistosoma mansoni cathepsin L3), that is found within the gut tissue of the parasite. We have employed various biochemical and molecular biological methods and sequence similarity analyses to characterize SmCL3 and obtain insights into its possible functions in the parasite, as well as its evolutionary position among cathepsin L proteases in general. SmCL3 hydrolyzes major host blood proteins (serum albumin and hemoglobin) and is expressed in parasite life stages infecting the mammalian host. Enzyme substrate specificity detected by positional scanning-synthetic combinatorial library was confirmed by molecular modeling. A sequence analysis placed SmCL3 to the cluster of other cathepsins L in accordance with previous phylogenetic analyses

Evaluation of the Infectious Diseases Society of America’s Core Antimicrobial Stewardship Curriculum for Infectious Diseases Fellows

Background Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact. Methods ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows’ knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation (“pre-curriculum”) and compared to first-year fellows who complete the curriculum the following year (“post-curriculum”). Results Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a “formal” curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows’ confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning. Conclusions Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors

Impact of serum sodium concentrations, and effect modifiers on mortality in the Irish Health System

Abstract Background Abnormalities of serum sodium are associated with increased mortality risk in hospitalised patients, but it is unclear whether, and to what extent other factors influence this relationship. We investigated the impact of dysnatraemia on total and cause-specific mortality in the Irish health system while exploring the concurrent impact of age, kidney function and designated clinical work-based settings. Methods A retrospective cohort study of 32,666 participants was conducted using data from the National Kidney Disease Surveillance System. Hyponatraemia was defined as  145 mmol/L with normal range 135–145 mmol/L. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR’s) and 95% Confidence Intervals (CIs) while penalised spline models further examined patterns of risk. Results There were 5,114 deaths (15.7%) over a median follow up of 5.5 years. Dysnatraemia was present in 8.5% of patients overall. In multivariable analysis, both baseline and time-dependent serum sodium concentrations exhibited a U-shaped association with mortality. Hyponatremia was significantly associated with increased risk for cardiovascular [HR 1.38 (1.18–1.61)], malignant [HR: 2.49 (2.23–2.78)] and non-cardiovascular/non-malignant causes of death [1.36 (1.17–1.58)], while hypernatremia was significantly associated with cardiovascular [HR: 2.16 (1.58–2.96)] and non-cardiovascular/ non-malignant deaths respectively [HR: 3.60 (2.87–4.52)]. The sodium-mortality relationship was significantly influenced by age, level of kidney function and the clinical setting at baseline (P < 0.001). For hyponatraemia, relative mortality risks were significantly higher for younger patients (interaction term P < 0.001), for patients with better kidney function, and for patients attending general practice [HR 2.70 (2.15–3.36)] than other clinical settings. For hypernatraemia, age and kidney function remained significant effect modifiers, with patients attending outpatient departments experiencing the greatest risk [HR 9.84 (4.88–18.62)] than patients who attended other clinical locations. Optimal serum sodium thresholds for mortality varied by level of kidney function with a flattening of mortality curve observed for patients with poorer kidney function. Conclusion Serum sodium concentrations outside the standard normal range adversly impact mortality and are associated with specific causes of death. The thresholds at which these risks appear to vary by age, level of kidney function, and are modified in specific clinical settings within the health system

Impact of serum sodium concentrations, and effect modifers on mortality in the Irish Health System

Background Abnormalities of serum sodium are associated with increased mortality risk in hospitalised patients, but it is unclear whether, and to what extent other factors infuence this relationship. We investigated the impact of dysnatraemia on total and cause-specifc mortality in the Irish health system while exploring the concurrent impact of age, kidney function and designated clinical work-based settings. Methods A retrospective cohort study of 32,666 participants was conducted using data from the National Kidney Disease Surveillance System. Hyponatraemia was defned as145 mmol/L with normal range 135–145 mmol/L. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR’s) and 95% Confdence Intervals (CIs) while penalised spline models further examined patterns of risk. Results There were 5,114 deaths (15.7%) over a median follow up of 5.5 years. Dysnatraemia was present in 8.5% of patients overall. In multivariable analysis, both baseline and time-dependent serum sodium concentrations exhibited a U-shaped association with mortality. Hyponatremia was signifcantly associated with increased risk for cardiovascular [HR 1.38 (1.18–1.61)], malignant [HR: 2.49 (2.23–2.78)] and non-cardiovascular/non-malignant causes of death [1.36 (1.17–1.58)], while hypernatremia was signifcantly associated with cardiovascular [HR: 2.16 (1.58–2.96)] and non-cardiovascular/ non-malignant deaths respectively [HR: 3.60 (2.87–4.52)]. The sodium-mortality relationship was signifcantly infuenced by age, level of kidney function and the clinical setting at baseline (P Conclusion Serum sodium concentrations outside the standard normal range adversly impact mortality and are associated with specifc causes of death. The thresholds at which these risks appear to vary by age, level of kidney function, and are modifed in specifc clinical settings within the health system.</p

Sexual Behavior Patterns and PrEP Dosing Preferences in a large sample of North American Men who have Sex with Men

Pre-exposure prophylaxis (PrEP), taken as a single daily co-formulated pill containing tenofovir-emtricitabine, is a promising intervention to reduce the likelihood of HIV acquisition in at-risk individuals, including men who have sex with men (MSM). Little is known about the acceptability of less than daily, intermittent PrEP (iPrEP) regimens. We conducted an online survey of North American MSM to characterize their sexual frequency and planning behaviors and correlate these with PrEP dosing preferences. Of the 3,217 respondents who completed the survey, 46% reported engaging in unplanned condomless anal intercourse (CAI) at least once in the prior 3 months and 8% reported engaging in CAI more than once per week. In multivariable analysis, reporting unplanned CAI was associated with lower educational level, identifying as homosexual/gay as compared to bisexual, being in a monogamous relationship, having a higher self-perceived risk of HIV acquisition, higher income, engaging in CAI more than five times in the last 3 months, and not having visited a healthcare provider in the previous year. Frequent CAI (>1×/week) was associated with being younger, identifying as homosexual/gay as compared to bisexual, being in a monogamous relationship, and having a higher self-perceived risk of HIV. Having had only planned sex over the last 3 months was associated with a preference for event-based PrEP, while having frequent or unplanned CAI was associated with a preference for daily or time-driven PrEP regimens, respectively. Our findings suggest that preferences for different PrEP regimens are associated with the sexual frequency and planning behaviors of potential users

Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy

SummaryExpansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA