Reducing the vicissitudes of heterologous prochiral substrate catalysis by alcohol dehydrogenases through machine learning algorithms.

Alcohol dehydrogenases (ADHs) are popular catalysts for synthesizing chiral synthons a vital step for active pharmaceutical intermediate (API) production. They are grouped into three superfamilies namely, medium-chain (MDRs), short-chain dehydrogenase/reductases (SDRs), and iron-containing alcohol dehydrogenases. The former two are used extensively for producing various chiral synthons. Many studies screen multiple enzymes or engineer a specific enzyme for catalyzing a substrate of interest. These processes are resource-intensive and intricate. The current study attempts to decipher the ability to match different ADHs with their ideal substrates using machine learning algorithms. We explore the catalysis of 284 antibacterial ketone intermediates, against MDRs and SDRs to demonstrate a unique pattern of activity. To facilitate machine learning we curated a dataset comprising 33 features, encompassing 4 descriptors for each compound. Subsequently, an ensemble of machine learning techniques viz. Partial Least Squares (PLS) regression, k-Nearest Neighbors (kNN) regression, and Support Vector Machine (SVM) regression, was harnessed. Moreover, the assimilation of Principal Component Analysis (PCA) augmented precision and accuracy, thereby refining and demarcating diverse compound classes. As such, this classification is useful for discerning substrates amenable to diverse alcohol dehydrogenases, thereby mitigating the reliance on high-throughput screening or engineering in identifying the optimal enzyme for specific substrate.

"I've been really happy since I got that letter!": Longitudinal patient perspectives on lung cancer screening communication.

OBJECTIVE: Experts recommend structured shared decision making when discussing lung cancer screening (LCS) and reporting low-dose computed tomography (LDCT) results. We examined patients' reactions to pre- and post-LDCT results communication processes at three medical centers in the US with established LCS programs. METHODS: Multicenter, qualitative, longitudinal study of patients considering and receiving LCS using data from semi-structured interviews guided by a patient-centered communication model using conventional content analysis. We conducted 61 interviews among 32 patients (sixteen of whom had a nodule on their LDCT) at one month and 12 months after an initial LCS decision making interaction. RESULTS: Participants were mostly satisfied with LCS communication processes pre- and post-LDCT even though guideline concordant shared decision making was rare. Most participants reported no more than mild distress even if the LDCT detected a pulmonary nodule, felt relief after getting the results, and reported the perceived benefits of LCS outweighed their distress. Nearly all participants were satisfied with recommended follow-up plans. They reported that they trusted their clinicians and health care system to provide appropriate care and recommendations. They did not appear to regret their decision since almost all participants planned to get their next LDCT. However, they were at risk of non-adherence to follow-up recommendations since they often relied on the health care system to ensure they received timely follow-up. CONCLUSIONS: Despite receiving guideline discordant decision-making communication, patients seem very satisfied, rarely experience severe distress, and have low decisional regret after LCS decision making and receiving the results of their LDCT.

Electro-Oxidation Reaction of Methanol over La2-xSrxNi1-y(Mn/Fe/Co)yO4+δ Ruddlesden-Popper Oxides.

Solution combustion-synthesized Ruddlesden-Popper oxides La1.4Sr0.6Ni0.9(Mn/Fe/Co)0.1O4+δ were explored for the methanol electro-oxidation reaction. With optimal doping of Sr2+ in the A site and Co2+ in the B site, Ni3+ with t2g6 dx2-y21 configuration in La1.4Sr0.6Ni0.9Co0.1O4+δ exhibited a tetragonal distortion with compression in axial bonds and elongation in equatorial bonds. This structural modification fostered an augmented overlap of dz2 orbitals with axial O 2p orbitals, leading to a heightened density of states at the Fermi level. Consequently, this facilitated not only elevated electrical conductivity but also a noteworthy reduction in the charge transfer resistance. These effects collectively contributed to the exceptional methanol oxidation activity of La1.4Sr0.6Ni0.9Co0.1O4+δ, as evidenced by an impressive current density of 21.4 mA cm-2 and retention of 95% of initial current density even after 10 h of prolonged reaction. The presence of Ni3+ further played a pivotal role in the creation of NiOOH, a crucial intermediate species, facilitated by the presence of surface oxygen vacancies. These factors synergistically enabled efficient methanol oxidation. In summary, our present study not only yields substantial insights but also paves the way for a novel avenue to fine-tune the activity of Ruddlesden-Popper oxides for the successful electro-oxidation of methanol.

A curated list of targeted optimized promiscuous ketoreductases (TOP-K).

Enzymes are either specific or promiscuous catalysts in nature. The latter is portrayed by protein families like CYP450Es, Aldo-ketoreductases and short/medium-chain dehydrogenases which participate in detoxification or secondary metabolite production. However, enzymes are evolutionarily 'blind' to an ever-increasing synthetic substrate library. Industries and laboratories have circumvented this by high-throughput screening or site-specific engineering to synthesize the product of interest. However, this paradigm entails cost and time-intensive one-enzyme, one-substrate catalysis model. One of the superfamilies regularly used for chiral alcohol synthesis are short-chain dehydrogenases/reductases (SDRs). Our objective is to determine a superset of promiscuous SDRs that can catalyze multiple ketones. They are typically classified into shorter 'Classical' and longer 'Extended' type ketoreductases. However, current analysis of modelled SDRs reveals a length-independent conserved N-terminus Rossmann-fold and a variable substrate-binding C-terminus substrate-binding region for both categories. The latter is recognized to influence the enzyme's flexibility and substrate promiscuity and we hypothesize these properties are directly linked with each other. We tested this by catalyzing ketone intermediates with the essential and specific enzyme: FabG_E, as well as non-essential SDRs such as UcpA and IdnO. The experimental results confirmed this biochemical-biophysical association, making it an interesting filter for ascertaining promiscuous enzymes. Hence, we created a dataset of physicochemical properties derived from the protein sequences and employed machine learning algorithms to examine potential candidates. This resulted in 24 targeted optimized ketoreductases (TOP-K) from 81 014 members. The experimental validation of select TOP-Ks demonstrated the correlation between the C-terminal lid-loop structure, enzyme flexibility and turnover rate on pro-pharmaceutical substrates.

The conundrum of bacteria-specific antibiotics.

There is a continual debate on the pros and cons of broad-spectrum versus pathogen-specific antibiotics. The unmet need for a solution for antimicrobial resistance (AMR) has put this argument into sharper focus. A shortage of clinically differentiated antibiotics in late-stage clinical development coupled with the global unmet need in the face of the AMR onslaught has exacerbated the treatment options of drug-resistant bacterial infections. An added dimension to this problem is the current understanding of dysbiosis caused by antibiotics, often leading to negative fallout in immunocompromised patients. We attempt to deconstruct the nuances of this debate from an antibiotics discovery and a clinical standpoint.

Increased odds for COVID-19 infection among individuals with periodontal disease.

OBJECTIVES: Periodontal disease has been linked to multiple systemic conditions, but the relationship with COVID-19 still needs to be elucidated. We hypothesized that periodontal disease may be associated with COVID-19 infection. MATERIALS AND METHODS: This study utilized cross-sectional data to establish the strength of the association between periodontal disease and COVID-19 infection. The University of Florida Health Center's i2b2 patient's registry was used to generate patient counts through ICD-10 diagnostic codes. Univariate descriptive statistics of the patient population and logistic regression to estimate odds ratios of associations between periodontal disease and COVID-19 infection were used for analysis. RESULTS: Patients with periodontal disease were 4.4 times more likely to be positively diagnosed with COVID-19 than patients without PD. Associations remained similar and robust (P value < 0.0001) after adjustment for age (OR = 4.34; 95% CI, 3.68-5.09), gender (OR = 4.46; 95% CI, 3.79-5.23), and smoking status (OR = 4.77; 95% CI, 4.04-5.59). Associations were smaller but remained robust (P value < 0.0001) after adjusting for race (OR = 2.83; 95% CI, 2.40-3.32), obesity (OR = 2.53; 95% CI, 2.14-2.98), diabetes (OR = 3.32; 95% CI, 2.81-3.90), and cardiovascular disease (OR = 2.68; 95% CI, 2.27-3.14). CONCLUSIONS: Periodontal disease is significantly associated with increased odds for COVID-19 infection. CLINICAL RELEVANCE: With the caveat of a cross-sectional study design, these results suggest that periodontal disease may increase the odds for COVID-19 infection.

BSAC Vanguard Series: The future of drug development and the tension between access and excess.

There is a crying need for a new broad-spectrum antibiotic. The global unmet need has energized governments and researchers alike. We may soon have the next antibiotics coming to the aid of patients after a drought of over half a century. However, we need to traverse a complex causeway between access to new antibiotics and their overuse. In an ICU setting where time is premium, identifying the causative organism and its resistance pattern in the time window is often impossible; physicians may be forced to prescribe the latest antibiotics. This practice in the long term may give rise to a rapid spread of resistance among microbes. There is an urgent need to do a cost-benefit analysis of easy access and use of the new antibiotics.

Assessing the Financial Sustainability of High-Fidelity and Virtual Reality Simulation for Nursing Education: A Retrospective Case Analysis.

To stimulate classroom discussion and collaboration amid the COVID-19 pandemic, increasingly creative pedological methods for nursing education are necessary. Traditionally, high-fidelity simulation has been the standard for nursing education, but the use of virtual reality simulation is increasing. One of the major evaluative measures of simulation clinical training is the cost associated with each modality. In this retrospective case analysis, budget impact analysis methods were employed to compare high-fidelity simulation with virtual reality simulation. The components of each simulation pedagogy were compared in categorized cost buckets. Overall, virtual reality simulation education was determined to require 22% less time than high-fidelity simulation education. The cost associated with the virtual reality simulation was found to be 40% less expensive than the high-fidelity simulation. Our results demonstrate that virtual reality simulation is a financially advantageous, resource conscious pedagogical option for nursing education.

A Randomized Controlled Trial of an Integrated Alcohol Reduction Intervention in Patients With Hepatitis C Infection.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) and alcohol use are patient risk factors for accelerated fibrosis progression, yet few randomized controlled trials have tested clinic-based alcohol interventions. APPROACH AND RESULTS: A total of 181 patients with HCV and qualifying alcohol screener scores at three liver center settings were randomly assigned to the following: (1) medical provider-delivered Screening, Brief Intervention, and Referral to Treatment (SBIRT), including motivational interviewing counseling and referral out for alcohol treatment (SBIRT-only), or (2) SBIRT plus 6 months of integrated colocated alcohol therapy (SBIRT + Alcohol Treatment). The timeline followback method was used to assess alcohol use at baseline and 3, 6, and 12 months. Coprimary outcomes were alcohol abstinence at 6 months and heavy drinking days between 6 and 12 months. Secondary outcomes included grams of alcohol consumed per week at 6 months. Mean therapy hours across 6 months were 8.8 for SBIRT-only and 10.1 for SBIRT + Alcohol Treatment participants. The proportion of participants exhibiting full alcohol abstinence increased from baseline to 3, 6, and 12 months in both treatment arms, but no significant differences were found between arms (baseline to 6 months, 7.1% to 20.5% for SBIRT-only; 4.2% to 23.3% for SBIRT + Alcohol Treatment; P = 0.70). Proportions of participants with any heavy drinking days decreased in both groups at 6 months but did not significantly differ between the SBIRT-only (87.5% to 26.7%) and SBIRT + Alcohol Treatment (85.7% to 42.1%) arms (P = 0.30). Although both arms reduced average grams of alcohol consumed per week from baseline to 6 and 12 months, between-treatment effects were not significant. CONCLUSIONS: Patients with current or prior HCV infection will engage in alcohol treatment when encouraged by liver medical providers. Liver clinics should consider implementing provider-delivered SBIRT and tailored alcohol treatment referrals as part of the standard of care.

A Comparison of Web-Based Cancer Risk Calculators That Inform Shared Decision-making for Lung Cancer Screening.

INTRODUCTION: To align patient preferences and understanding with harm-benefit perception, the Centers for Medicare & Medicaid Services (CMS) mandates that providers engage patients in a collaborative shared decision-making (SDM) visit before LDCT. Nonetheless, patients and providers often turn instead to the web for help making decisions. Several web-based lung cancer risk calculators (LCRCs) provide risk predictions and screening recommendations; however, the accuracy, consistency, and subsequent user interpretation of these predictions between LCRCs is ambiguous. We conducted a systematic review to assess this variability. DESIGN: Through a systematic Internet search, we identified 10 publicly available LCRCs and categorized their input variables: demographic factors, cancer history, smoking status, and personal/environmental factors. To assess variance in LCRC risk prediction outputs, we developed 16 hypothetical patients along a risk continuum, illustrated by randomly assigned input variables, and individually compared them to each LCRC against the empirically validated "gold-standard" PLCO risk model in order to evaluate the accuracy of the LCRCs within identical time-windows. RESULTS: From the inclusion criteria, 11 calculators were initially identified. The analyzed calculators also vary in output characteristics and risk depiction for hypothetical patients. There were 13 total instances across ten hypothetical patients in which the sample standard error exceeded the mean risk percentage across all general samples and set standard calculations. The largest measured difference is 16.49% for patient 8, and the smallest difference is 0.01% for patient 2. The largest measured difference is 16.49% for patient 8, and the smallest difference is 0.01% for patient 2. CONCLUSION: Substantial variability in the depiction of lung cancer risk for hypothetical patients exists across the web-based LCRCs due to their respective inputs and risk prediction models. To foster informed decision-making in the SDM-LDCT context, the input variables, risk prediction models, risk depiction, and screening recommendations must be standardized to best practice.

What Exactly Is Shared Decision-Making? A Qualitative Study of Shared Decision-Making in Lung Cancer Screening.

BACKGROUND: Shared decision-making (SDM) is widely recommended and required by the Centers for Medicare and Medicaid for patients considering lung cancer screening (LCS). OBJECTIVE: We examined clinicians' communication practices and perceived barriers of SDM for LCS at three medical centers with established screening programs. DESIGN: Multicenter qualitative study of clinicians participating in LCS. APPROACH: We performed semi-structured interviews, which were transcribed and analyzed using directed content analysis, guided by a theoretical model of patient-clinician communication. PARTICIPANTS: We interviewed 24 clinicians including LCS coordinators (2), pulmonologists (3), and primary care providers (17), 4 of whom worked for the LCS program, a thoracic surgeon, and a radiologist. RESULTS: All clinicians agreed with the goal of SDM, to ensure the screening decision was congruent with the patient's values. The depth and type of information presented by each clinician role varied considerably. LCS coordinators presented detailed information including numeric estimates of benefit and harm. Most PCPs explained the process more generally, focusing on logistics and the high rate of nodule detection. No clinician explicitly elicited values or communication preferences. Many PCPs tailored the conversation based on their implicit understanding of patients' values and preferences, gained from past experiences. PCPs reported that time, lack of detailed personal knowledge of LCS, and patient preferences were barriers to SDM. Many clinicians perceived that a significant proportion of patients were not interested in specific percentages and preferred to receive a clinician recommendation. CONCLUSIONS: Our results suggest that clinicians support the goal of SDM for LCS decisions but PCPs may not perform some of its elements. The lack of completion of some elements, such as PCPs' lack of in-depth information exchange, may reflect perceived patient preferences for communication. As LCS is implemented, further research is needed to support a personalized, patient-centered approach to produce better outcomes.

A strategy to identify a ketoreductase that preferentially synthesizes pharmaceutically relevant (S)-alcohols using whole-cell biotransformation.

INTRODUCTION: Chemical industries are constantly in search of an expeditious and environmentally benign method for producing chiral synthons. Ketoreductases have been used as catalysts for enantioselective conversion of desired prochiral ketones to their corresponding alcohol. We chose reported promiscuous ketoreductases belonging to different protein families and expressed them in E. coli to evaluate their ability as whole-cell catalysts for obtaining chiral alcohol intermediates of pharmaceutical importance. Apart from establishing a method to produce high value (S)-specific alcohols that have not been evaluated before, we propose an in silico analysis procedure to predict product chirality. RESULTS: Six enzymes originating from Sulfolobus sulfotaricus, Zygosaccharomyces rouxii, Hansenula polymorpha, Corynebacterium sp. ST-10, Synechococcus sp. PCC 7942 and Bacillus sp. ECU0013 with reported efficient activity for dissimilar substrates are compared here to arrive at an optimal enzyme for the method. Whole-cell catalysis of ketone intermediates for drugs like Aprepitant, Sitagliptin and Dolastatin using E. coli over-expressing these enzymes yielded (S)-specific chiral alcohols. We explain this chiral specificity for the best-performing enzyme, i.e., Z. rouxii ketoreductase using in silico modelling and MD simulations. This rationale was applied to five additional ketones that are used in the synthesis of Crizotinib, MA-20565 (an antifungal agent), Sulopenem, Rivastigmine, Talampanel and Barnidipine and predicted the yield of (S) enantiomers. Experimental evaluation matched the in silico analysis wherein ~ 95% (S)-specific alcohol with a chemical yield of 23-79% was obtained through biotransformation. Further, the cofactor re-cycling was optimized by switching the carbon source from glucose to sorbitol that improved the chemical yield to 85-99%. CONCLUSIONS: Here, we present a strategy to synthesize pharmaceutically relevant chiral alcohols by ketoreductases using a cofactor balanced whole-cell catalysis scheme that is useful for the industry. Based on the results obtained in these trials, Zygosaccharomyces rouxii ketoreductase was identified as a proficient enzyme to obtain (S)-specific alcohols from their respective ketones. The whole-cell catalyst when combined with nutrient modulation of using sorbitol as a carbon source helped obtain high enantiomeric and chemical yield.

TEAM-UP for quality: a cluster randomized controlled trial protocol focused on preventing pressure ulcers through repositioning frequency and precipitating factors.

BACKGROUND: Pressure ulcers/injuries (PrUs), a critical concern for nursing homes (NH), are responsible for chronic wounds, amputations, septic infections, and premature deaths. PrUs occur most commonly in older adults and NH residence is a risk factor for their development, with at least one of every nine U.S. NH residents experiencing a PrU and many NHs having high incidence and prevalence rates, in some instances well over 20%. PrU direct treatment costs are greater than prevention costs, making prevention-focused protocols critical. Current PrU prevention protocols recommend repositioning residents at moderate, high, and severe risk every 2 h. The advent of visco-elastic (VE) high-density foam support-surfaces over the past decade may now make it possible to extend the repositioning interval to every 3 or 4 h without increasing PrU development. The TEAM-UP (Turn Everyone And Move for Ulcer Prevention) study aims to determine: 1) whether repositioning interval can be extended for NH residents without compromising PrU incidence and 2) how changes in medical severity interact with changes in risk level and repositioning schedule to predict PrU development. METHODS: In this proposed cluster randomized study, 9 NHs will be randomly assigned to one of three repositioning intervals (2, 3, or 4 h) for a 4-week period. Each enrolled site will use a single NH-wide repositioning interval as the standard of care for residents at low, moderate, and high risk of PrU development (N = 951) meeting the following criteria: minimum 3-day stay, without PrUs, no adhesive allergy, and using VE support surfaces (mattresses). An FDA-cleared patient monitoring system that records position/movement of these residents via individual wireless sensors will be used to visually cue staff when residents need repositioning and document compliance with repositioning protocols. DISCUSSION: This study will advance knowledge about repositioning frequency and clinically assessed PrU risk level in relation to PrU incidence and medical severity. Outcomes of this research will contribute to future guidelines for more precise preventive nursing practices and refinement of PrU prevention guidelines. TRIAL REGISTRATION: Clinical Trial Registration: NCT02996331 .

Comparison of Telephone and Televideo Modes for Delivery of Genetic Counseling: a Randomized Trial.

Telephone and televideo have yielded equivalent patient satisfaction and psychosocial outcomes when compared to in-person genetic counseling, yet little is known about how they compare to one another. In this randomized controlled trial, veterans received genetic counseling via telephone or traveled to a clinic to participate via encrypted televideo. Knowledge and visit satisfaction were assessed 2 weeks later. Travel time, mileage, and out-of-pocket costs were calculated for videoconferencing. Qualitative interviews were conducted with patients and counselors to assess acceptability. Of the 20 male patients randomized to telephone, 90% received counseling and provided outcomes; of the 18 randomized to televideo, 67% received counseling and 50% provided outcomes. Telephone patients answered a mean of 4.4 of eight questions correctly at baseline and 4.7 at follow-up; televideo means were 5.6 and 6.5, respectively. Satisfaction was 25.2 out of 30 for telephone and 26.9 for televideo. Televideo patients incurred a median of 2.8 h of travel time, 40 roundtrip miles, and $67.29 in costs. Patients and counselors found both modes acceptable for providing education and answering questions. Although patients liked the flexibility of telephone, counselors felt patients missed more appointments and were distracted when using telephone. A noted advantage of videoconferencing was reading body language. Further evaluation of alternative delivery modes is needed.

Patient, Provider, and Combined Interventions for Managing Osteoarthritis in Primary Care: A Cluster Randomized Trial.

BACKGROUND: A single-site study showed that a combined patient and provider intervention improved outcomes for patients with knee osteoarthritis, but it did not assess separate effects of the interventions. OBJECTIVE: To examine whether patient-based, provider-based, and patient-provider interventions improve osteoarthritis outcomes. DESIGN: Cluster randomized trial with assignment to patient, provider, and patient-provider interventions or usual care. (ClinicalTrials.gov: NCT01435109). SETTING: 10 Duke University Health System community-based primary care clinics. PARTICIPANTS: 537 outpatients with symptomatic hip or knee osteoarthritis. INTERVENTION: The telephone-based patient intervention focused on weight management, physical activity, and cognitive behavioral pain management. The provider intervention involved electronic delivery of patient-specific osteoarthritis treatment recommendations to providers. MEASUREMENTS: The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score at 12 months. Secondary outcomes were objective physical function (Short Physical Performance Battery) and depressive symptoms (Patient Health Questionnaire). Linear mixed models assessed the difference in improvement among groups. RESULTS: No difference was observed in WOMAC score changes from baseline to 12 months in the patient (-1.5 [95% CI, -5.1 to 2.0]; P = 0.40), provider (2.5 [CI, -0.9 to 5.9]; P = 0.152), or patient-provider (-0.7 [CI, -4.2 to 2.8]; P = 0.69) intervention groups compared with usual care. All groups had improvements in WOMAC scores at 12 months (range, -3.7 to -7.7). In addition, no differences were seen in objective physical function or depressive symptoms at 12 months in any of the intervention groups compared with usual care. LIMITATIONS: The study involved 1 health care network. Data on provider referrals were not collected. CONCLUSION: Contrary to a previous study of a combined patient and provider intervention for osteoarthritis in a Department of Veterans Affairs medical center, this study found no statistically significant improvements in the osteoarthritis intervention groups compared with usual care. PRIMARY FUNDING SOURCE: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

A Combined Patient and Provider Intervention for Management of Osteoarthritis in Veterans: A Randomized Clinical Trial.

BACKGROUND: Management of osteoarthritis requires both medical and behavioral strategies, but some recommended therapies are underused. OBJECTIVE: To examine the effectiveness of a combined patient and provider intervention for improving osteoarthritis outcomes. DESIGN: Cluster randomized clinical trial with assignment to osteoarthritis intervention and usual care groups. (ClinicalTrials.gov: NCT01130740). SETTING: Department of Veterans Affairs Medical Center in Durham, North Carolina. PARTICIPANTS: 30 providers (clusters) and 300 outpatients with symptomatic hip or knee osteoarthritis. INTERVENTION: The telephone-based patient intervention focused on weight management, physical activity, and cognitive behavioral pain management. The provider intervention involved delivery of patient-specific osteoarthritis treatment recommendations to primary care providers through the electronic medical record. MEASUREMENTS: The primary outcome was total score on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 12 months. Secondary outcomes were WOMAC function and pain subscale scores, physical performance (Short Physical Performance Battery), and depressive symptoms (Patient Health Questionnaire-8). Linear mixed models that were adjusted for clustering of providers assessed between-group differences in improvement in outcomes. RESULTS: At 12 months, WOMAC scores were 4.1 points lower (indicating improvement) in the osteoarthritis intervention group versus usual care (95% CI, -7.2 to -1.1 points; P = 0.009). WOMAC function subscale scores were 3.3 points lower in the intervention group (CI, -5.7 to -1.0 points; P = 0.005). WOMAC pain subscale scores (P = 0.126), physical performance, and depressive symptoms did not differ between groups. Although more patients in the osteoarthritis intervention group received provider referral for recommended osteoarthritis treatments, the numbers who received them did not differ. LIMITATION: The study was conducted in a single Veterans Affairs medical center. CONCLUSION: The combined patient and provider intervention resulted in modest improvement in self-reported physical function in patients with hip and knee osteoarthritis. PRIMARY FUNDING SOURCE: Department of Veterans Affairs, Health Services Research and Development Service.

In silico-based high-throughput screen for discovery of novel combinations for tuberculosis treatment.

There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an in silico kinetic platform in which the major metabolic pathways in Mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The in silico-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).

Randomized Trial of Telegenetics vs. In-Person Cancer Genetic Counseling: Cost, Patient Satisfaction and Attendance.

Telegenetics-genetic counseling via live videoconferencing-can improve access to cancer genetic counseling (CGC) in underserved areas, but studies on cancer telegenetics have not applied randomized methodology or assessed cost. We report cost, patient satisfaction and CGC attendance from a randomized trial comparing telegenetics with in-person CGC among individuals referred to CGC in four rural oncology clinics. Participants (n = 162) were randomized to receive CGC at their local oncology clinic in-person or via telegenetics. Cost analyses included telegenetics system; mileage; and personnel costs for genetic counselor, IT specialist, and clinic personnel. CGC attendance was tracked via study database. Patient satisfaction was assessed 1 week post-CGC via telephone survey using validated scales. Total costs were $106 per telegenetics patient and $244 per in-person patient. Patient satisfaction did not differ by group on either satisfaction scale. In-person patients were significantly more likely to attend CGC than telegenetics patients (89 vs. 79 %, p = 0.03), with bivariate analyses showing an association between lesser computer comfort and lower attendance rate (Chi-square = 5.49, p = 0.02). Our randomized trial of telegenetics vs. in-person counseling found that telegenetics cost less than in-person counseling, with high satisfaction among those who attended. This study provides support for future randomized trials comparing multiple service delivery models on longer-term psychosocial and behavioral outcomes.

Implementation of new clinical programs in the VHA healthcare system: the importance of early collaboration between clinical leadership and research.

Collaboration between policy, research, and clinical partners is crucial to achieving proven quality care. The Veterans Health Administration has expended great efforts towards fostering such collaborations. Through this, we have learned that an ideal collaboration involves partnership from the very beginning of a new clinical program, so that the program is designed in a way that ensures quality, validity, and puts into place the infrastructure necessary for a reliable evaluation. This paper will give an example of one such project, the Lung Cancer Screening Demonstration Project (LCSDP). We will outline the ways that clinical, policy, and research partners collaborated in design, planning, and implementation in order to create a sustainable model that could be rigorously evaluated for efficacy and fidelity. We will describe the use of the Donabedian quality matrix to determine the necessary characteristics of a quality program and the importance of the linkage with engineering, information technology, and clinical paradigms to connect the development of an on-the-ground clinical program with the evaluation goal of a learning healthcare organization. While the LCSDP is the example given here, these partnerships and suggestions are salient to any healthcare organization seeking to implement new scientifically proven care in a useful and reliable way.