Geisinger Commonwealth School of Medicine

INTRODUCTION: The role of lipophilicity in drug discovery and design is a critical one. Lipophilicity is a key physicochemical property that plays a crucial role in determining ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and the overall suitability of drug candidates. There is increasing evidence to suggest that control of physicochemical properties such as lipophilicity, within a defined optimal range, can improve compound quality and the likelihood of therapeutic success. AREAS COVERED: This review focuses on understanding lipophilicity, techniques used to measure lipophilicity, and summarizes the importance of lipophilicity in drug discovery and development, including a discussion of its impact on individual ADMET parameters as well as its overall influence on the drug discovery and design process, specifically within the past 15 years. EXPERT OPINION: A current review of the literature reveals a continued reliance on the synthesis of novel structures with increased potency, rather than a focus on maintaining optimal physicochemical properties associated with ADMET throughout drug optimization. Particular attention to the optimum region of lipophilicity, as well as monitoring of lipophilic efficiency indices, may contribute significantly to the overall quality of candidate drugs at different stages of discovery.

A narrative review was conducted to examine the current state of the utilisation of telemedicine amid the current COVID-19 pandemic and to evaluate the benefits of continuing telemedicine usage in the future. A literature review was performed for articles related to telemedicine. Databases including PubMed, Google Scholar, Cochrane Library and Ovid MEDLINE were searched. Three reviewers independently performed article selection based on relevance to our topic. We included all articles between 1990 and 2020 related to telemedicine using the following keywords: 'telemedicine', 'telehealth', 'policy', 'COVID-19', 'regulation', 'rural', 'physical examination', 'future'. A total of 60 articles were identified, and through careful selection we narrowed the final number of articles to 42 based on relevance to our topic. Telemedicine has been rapidly evolving over the past several decades. Issues with regulation and reimbursement have prevented its full immersion into the healthcare system. During the current pandemic, Centers for Medicare and Medicaid services have expanded access to telemedicine services. The advantages of telemedicine moving forward include its cost-effectiveness, ability to extend access to specialty services and its potential to help mitigate the looming physician shortage. Disadvantages include lack of available technological resources in certain parts of the country, issues with security of patient data, and challenges in performing the traditional patient examination. It is critically important that changes are made to fully immerse telemedicine services into the healthcare landscape in order to be prepared for future pandemics as well as to reap the benefits of this service in the future.

A variety of organisms, such as bacteria, fungi, and plants, produce secondary metabolites, also known as natural products. Natural products have been a prolific source and an inspiration for numerous medical agents with widely divergent chemical structures and biological activities, including antimicrobial, immunosuppressive, anticancer, and anti-inflammatory activities, many of which have been developed as treatments and have potential therapeutic applications for human diseases. Aside from natural products, the recent development of recombinant DNA technology has sparked the development of a wide array of biopharmaceutical products, such as recombinant proteins, offering significant advances in treating a broad spectrum of medical illnesses and conditions. Herein, we will introduce the structures and diverse biological activities of natural products and recombinant proteins that have been exploited as valuable molecules in medicine, agriculture and insect control. In addition, we will explore past and ongoing efforts along with achievements in the development of robust and promising microorganisms as cell factories to produce biologically active molecules. Furthermore, we will review multi-disciplinary and comprehensive engineering approaches directed at improving yields of microbial production of natural products and proteins and generating novel molecules. Throughout this article, we will suggest ways in which microbial-derived biologically active molecular entities and their analogs could continue to inspire the development of new therapeutic agents in academia and industry.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host⁻microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon. High-fat diets increase secondary BAs, such as deoxycholic acid (DCA) and lithocholic acid (LCA), which are risk factors for colonic inflammation and cancer. In contrast, increased dietary fiber intake is associated with anti-inflammatory and anticancer effects. These effects may be due to the increased production of the SCFAs acetate, propionate, and butyrate during dietary fiber fermentation in the colon. Elucidation of the molecular events by which secondary BAs and SCFAs regulate colonic cell proliferation and inflammation will lead to a better understanding of the anticancer potential of dietary fiber in the context of high-fat diet-related colon cancer. This article reviews the current knowledge concerning the effects of secondary BAs and SCFAs on the proliferation of colon epithelial cells, inflammation, cancer, and the associated microbiome.

Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources.

BACKGROUND: Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human. RESULTS: The confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS) and the stabilization of microtubules. We also showed Akt/GSK-3beta signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3beta - mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery. CONCLUSION: Our results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.

BACKGROUND: Radial artery occlusion (RAO) may occur posttransradial intervention and limits the radial artery as a future access site, thus precluding its use as an arterial conduit. In this study, we investigate the incidence and factors influencing the RAO in the current literature. METHODS AND RESULTS: We searched MEDLINE and EMBASE for studies of RAO in transradial access. Relevant studies were identified and data were extracted. Data were synthesized by meta-analysis, quantitative pooling, graphical representation, or by narrative synthesis. A total of 66 studies with 31 345 participants were included in the analysis. Incident RAO ranged between <1% and 33% and varied with timing of assessment of radial artery patency (incidence of RAO within 24 hours was 7.7%, which decreased to 5.5% at >1 week follow-up). The most efficacious measure in reducing RAO was higher dose of heparin, because lower doses of heparin were associated with increased RAO (risk ratio 0.36, 95% CI 0.17-0.76), whereas shorter compression times also reduced RAO (risk ratio 0.28, 95% CI 0.05-1.50). Several factors were found to be associated with RAO including age, sex, sheath size, and diameter of radial artery, but these factors were not consistent across all studies. CONCLUSIONS: RAO is a common complication of transradial access. Maintenance of radial patency should be an integral part of all procedures undertaken through the radial approach. High-dose heparin along with shorter compression times and patent hemostasis is recommended in reducing RAO.

AIMS: X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. METHODS AND RESULTS: We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P < 0.001). Major bleeding occurred in six patients (0.6%) in the rivaroxaban group and four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). CONCLUSION: Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov; TRIAL REGISTRATION NUMBER: NCT01674647.

In response to growing U.S. interest, the Society for Coronary Angiography and Interventions recently formed a Transradial Committee whose purpose is to examine the utility, utilization, and training considerations related to transradial access for percutaneous coronary and peripheral procedures. With international partnership, the committee has composed a comprehensive overview of this subject presented here-with.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

More than 27% of the U.S. workforce now reports having an ability to alter their daily starting and ending times of work. Yet, provision of flexibility in the timing of work is not keeping pace with demand. Moreover, there is much disparity in access to schedule flexibility by workers' demographic, work, and job characteristics. Probit estimation finds that the probability that a worker has such flexibility is reduced by being female, non-White, and less educated. The likelihood is increased by being self-employed, in college, married, part-time, in certain occupations and industries, and working 50 or more hours per week. Flexibility is reduced for those working a standard day shift or 40-hour workweek. Workers thus sacrifice either leisure time or income to gain better access to flexibility in the scheduling of work, or they endure the costs of job mobility. Public policy should focus on delivering more flexible schedules to the excluded 73%.

Few patients read their doctors' notes, despite having the legal right to do so. As information technology makes medical records more accessible and society calls for greater transparency, patients' interest in reading their doctors' notes may increase. Inviting patients to review these notes could improve understanding of their health, foster productive communication, stimulate shared decision making, and ultimately lead to better outcomes. Yet, easy access to doctors' notes could have negative consequences, such as confusing or worrying patients and complicating rather than improving patient-doctor communication. To gain evidence about the feasibility, benefits, and harms of providing patients ready access to electronic doctors' notes, a team of physicians and nurses have embarked on a demonstration and evaluation of a project called OpenNotes. The authors describe the intervention and share what they learned from conversations with doctors and patients during the planning stages. The team anticipates that "open notes" will spread and suggests that over time, if drafted collaboratively and signed by both doctors and patients, they might evolve to become contracts for care.

BACKGROUND: Small RNAs complex with proteins to mediate a variety of functions in animals and plants. Some small RNAs, particularly miRNAs, circulate in mammalian blood and may carry out a signaling function by entering target cells and modulating gene expression. The subject of this study is a set of circulating 30-33 nt RNAs that are processed derivatives of the 5' ends of a small subset of tRNA genes, and closely resemble cellular tRNA derivatives (tRFs, tiRNAs, half-tRNAs, 5' tRNA halves) previously shown to inhibit translation initiation in response to stress in cultured cells. RESULTS: In sequencing small RNAs extracted from mouse serum, we identified abundant 5' tRNA halves derived from a small subset of tRNAs, implying that they are produced by tRNA type-specific biogenesis and/or release. The 5' tRNA halves are not in exosomes or microvesicles, but circulate as particles of 100-300 kDa. The size of these particles suggest that the 5' tRNA halves are a component of a macromolecular complex; this is supported by the loss of 5' tRNA halves from serum or plasma treated with EDTA, a chelating agent, but their retention in plasma anticoagulated with heparin or citrate. A survey of somatic tissues reveals that 5' tRNA halves are concentrated within blood cells and hematopoietic tissues, but scant in other tissues, suggesting that they may be produced by blood cells. Serum levels of specific subtypes of 5' tRNA halves change markedly with age, either up or down, and these changes can be prevented by calorie restriction. CONCLUSIONS: We demonstrate that 5' tRNA halves circulate in the blood in a stable form, most likely as part of a nucleoprotein complex, and their serum levels are subject to regulation by age and calorie restriction. They may be produced by blood cells, but their cellular targets are not yet known. The characteristics of these circulating molecules, and their known function in suppression of translation initiation, suggest that they are a novel form of signaling molecule.

Although Staphylococcus aureus osteomyelitis is considered to be incurable, the major bacterial reservoir in live cortical bone has remained unknown. In addition to biofilm bacteria on necrotic tissue and implants, studies have implicated intracellular infection of osteoblasts and osteocytes as a mechanism of chronic osteomyelitis. Thus, we performed the first systematic transmission electron microscopy (TEM) studies to formally define major reservoirs of S. aureus in chronically infected mouse (Balb/c J) long bone tissue. Although rare, evidence of colonized osteoblasts was found. In contrast, we readily observed S. aureus within canaliculi of live cortical bone, which existed as chains of individual cocci and submicron rod-shaped bacteria leading to biofilm formation in osteocyte lacunae. As these observations do not conform to the expectations of S. aureus as non-motile cocci 1.0 to 1.5 μm in diameter, we also performed immunoelectron microscopy (IEM) following in vivo BrdU labeling to assess the role of bacterial proliferation in canalicular invasion. The results suggest that the deformed bacteria: (1) enter canaliculi via asymmetric binary fission; and (2) migrate toward osteocyte lacunae via proliferation at the leading edge. Additional in vitro studies confirmed S. aureus migration through a 0.5-μm porous membrane. Collectively, these findings define a novel mechanism of bone infection, and provide possible new insight as to why S. aureus implant-related infections of bone tissue are so challenging to treat. © 2016 American Society for Bone and Mineral Research.

IMPORTANCE: Although outcomes in patients with ST-segment elevation myocardial infarction (STEMI) have improved in the past 2 decades, a sex disparity exists in survival, with women having higher mortality than men. OBJECTIVE: To conduct a meta-analysis of observational studies that examined differences in mortality by sex in patients with STEMI treated with primary percutaneous coronary intervention (PPCI). DATA SOURCES: MEDLINE, EMBASE, Cochrane central, and electronic databases were searched for relevant studies in all languages and without time restriction. STUDY SELECTION: Studies were included if (1) they studied patients who presented with STEMI, (2) primary percutaneous coronary intervention (PPCI) was the treatment for STEMI, (3) PPCI was performed within 12 hours of symptom onset, and (4) sex-specific in-hospital and/or 1-year mortality were reported. DATA EXTRACTION AND SYNTHESIS: Two investigators independently reviewed retrieved citations and assessed eligibility. Discrepancies were resolved by consensus. Quality of included studies was assessed using Newcastle-Ottawa Quality Assessment Scale for cohort studies. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: Sex-specific in-hospital and 1-year all-cause mortality. Risk ratios (RRs) of mortality were used for these 2 time points, if reported. RESULTS: Of the 149 studies identified, 35 met inclusion criteria, representing 18 555 women and 49 981 men. In the unadjusted analyses, women were at a higher risk for in-hospital (RR, 1.93; 95% CI, 1.75-2.14 [P < .001, I2 = 14%]) and 1-year all-cause mortality (RR, 1.58; 95% CI, 1.36-1.84 [P < .001, I2 = 51%]) compared with men. However, when adjusted RRs were used, the association between women and higher risk of all-cause mortality was attenuated but still significantly elevated for in-hospital mortality (RR, 1.48; 95% CI, 1.07-2.05 [P = .02, I2 = 56%]), but the higher risk for 1-year mortality in women was no longer significant (RR, 0.90; 95% CI, 0.69-1.17 [P = .42, I2 = 58%]). CONCLUSIONS AND RELEVANCE: An increased mortality in women with STEMI treated with PPCI was detected in this large meta-analysis but is likely confounded by baseline cardiovascular risk factors and the differences in clinical profile of male and female patients with STEMI. Intensive cardiovascular risk modification efforts in women may help to reduce this sex disparity.

The estrogen receptor (ER) mediates most of the biological effects of estrogens at the level of gene regulation by interacting through its site-specific DNA and with other coregulatory proteins. In recent years, new information regarding the dynamic structural nature of ER has emerged. The physiological effects of estrogen are manifested through ER's two isoforms, ER(α) and ER(β). These two isoforms (ER(α) and ER(β)) display distinct regions of sequence homology. The three-dimensional structures of the DNA-binding domain (DBD) and ligand-binding domain (LBD) have been solved, whereas no three-dimensional natively folded structure for the ER N-terminal domain (NTD) is available to date. However, insights about the structural and functional correlations regarding the ER NTD have recently emerged. In this paper, we discuss the knowledge about the structural characteristics of the ER in general and how the structural features of the two isoforms differ, and its subsequent role in gene regulation.

Selective estrogen receptor modulators (SERMs) are a diverse group of nonsteroidal compounds that function as agonists or antagonists for estrogen receptors (ERs) in a target gene-specific and tissue-specific fashion. SERM specificity involves tissue-specific expression of ER subtypes, differential expression of co-regulatory proteins in various tissues, and varying ER conformational changes induced by ligand binding. To date, the major clinical applications of SERMs are their use in the prevention and treatment of breast cancer, the prevention of osteoporosis, and the maintenance of beneficial serum lipid profiles in postmenopausal women. However, SERMs have also been found to promote adverse effects, including thromboembolic events and, in some cases, carcinogenesis, that have proven to be obstacles in their clinical utility. In this review, we discuss the mechanisms of SERM tissue specificity and highlight the therapeutic application of well-known and emergent SERMs.

NMDA receptors (NMDARs) are critical mediators of activity-dependent synaptic plasticity, but the differential roles of NR2A- versus NR2B-containing NMDARs have been controversial. Here, we investigate the roles of NR2A and NR2B in long-term potentiation (LTP) in organotypic hippocampal slice cultures using RNA interference (RNAi) and overexpression, to complement pharmacological approaches. In young slices, when NR2B is the predominant subunit expressed, LTP is blocked by the NR2B-selective antagonist Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol]. As slices mature and NR2A expression rises, activation of NR2B receptors became no longer necessary for LTP induction. LTP was blocked, however, by RNAi knockdown of NR2B, and this was rescued by coexpression of an RNAi-resistant NR2B (NR2B*) cDNA. Interestingly, a chimeric NR2B subunit in which the C-terminal cytoplasmic tail was replaced by that of NR2A failed to rescue LTP, whereas the reverse chimera, NR2A channel with NR2B tail, was able to restore LTP. Thus, expression of NR2B with its intact cytoplasmic tail is required for LTP induction, at an age when channel activity of NR2B-NMDARs is not required for LTP. Overexpression of wild-type NR2A failed to rescue LTP in neurons transfected with the NR2B-RNAi construct, despite restoring NMDA-EPSC amplitude to a similar level as NR2B*. Surprisingly, an NR2A construct lacking its entire C-terminal cytoplasmic tail regained its ability to restore LTP. Together, these data suggest that the NR2B subunit plays a critical role for LTP, presumably by recruiting relevant molecules important for LTP via its cytoplasmic tail. In contrast, NR2A is not essential for LTP, and its cytoplasmic tail seems to carry inhibitory factors for LTP.

Delivering food to nutritionally vulnerable patients is important for addressing these patients' social determinants of health. However, it is not known whether food delivery programs can reduce the use of costly health services and decrease medical spending among these patients. We sought to determine whether home delivery of either medically tailored meals or nontailored food reduces the use of selected health care services and medical spending in a sample of adults dually eligible for Medicare and Medicaid. Compared with matched nonparticipants, participants had fewer emergency department visits in both the medically tailored meal program and the nontailored food program. Participants in the medically tailored meal program also had fewer inpatient admissions and lower medical spending. Participation in the nontailored food program was not associated with fewer inpatient admissions but was associated with lower medical spending. These findings suggest the potential for meal delivery programs to reduce the use of costly health care and decrease spending for vulnerable patients.