The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Decolonization in Nursing Homes to Prevent Infection and Hospitalization.

BACKGROUND: Nursing home residents are at high risk for infection, hospitalization, and colonization with multidrug-resistant organisms. METHODS: We performed a cluster-randomized trial of universal decolonization as compared with routine-care bathing in nursing homes. The trial included an 18-month baseline period and an 18-month intervention period. Decolonization entailed the use of chlorhexidine for all routine bathing and showering and administration of nasal povidone-iodine twice daily for the first 5 days after admission and then twice daily for 5 days every other week. The primary outcome was transfer to a hospital due to infection. The secondary outcome was transfer to a hospital for any reason. An intention-to-treat (as-assigned) difference-in-differences analysis was performed for each outcome with the use of generalized linear mixed models to compare the intervention period with the baseline period across trial groups. RESULTS: Data were obtained from 28 nursing homes with a total of 28,956 residents. Among the transfers to a hospital in the routine-care group, 62.2% (the mean across facilities) were due to infection during the baseline period and 62.6% were due to infection during the intervention period (risk ratio, 1.00; 95% confidence interval [CI], 0.96 to 1.04). The corresponding values in the decolonization group were 62.9% and 52.2% (risk ratio, 0.83; 95% CI, 0.79 to 0.88), for a difference in risk ratio, as compared with routine care, of 16.6% (95% CI, 11.0 to 21.8; P<0.001). Among the discharges from the nursing home in the routine-care group, transfer to a hospital for any reason accounted for 36.6% during the baseline period and for 39.2% during the intervention period (risk ratio, 1.08; 95% CI, 1.04 to 1.12). The corresponding values in the decolonization group were 35.5% and 32.4% (risk ratio, 0.92; 95% CI, 0.88 to 0.96), for a difference in risk ratio, as compared with routine care, of 14.6% (95% CI, 9.7 to 19.2). The number needed to treat was 9.7 to prevent one infection-related hospitalization and 8.9 to prevent one hospitalization for any reason. CONCLUSIONS: In nursing homes, universal decolonization with chlorhexidine and nasal iodophor led to a significantly lower risk of transfer to a hospital due to infection than routine care. (Funded by the Agency for Healthcare Research and Quality; Protect ClinicalTrials.gov number, NCT03118232.).

Pilot study of a telehealth intervention for personalized self-management for eating symptoms after gastroesophageal cancer surgery.

BACKGROUND AND OBJECTIVES: Following gastric and esophageal cancer surgery, patients often experience significant, prolonged eating-related symptoms. One promising approach to help patients improve their eating-related quality of life (QOL) is through self-management coaching to aid in diet modification. We performed a randomized pilot study of a nutritionist-led telehealth intervention for the self-management of eating after gastroesophageal cancer surgery. METHODS: Patients who were within 30 days of resuming oral intake after undergoing surgery for gastric and/or esophageal cancer were consented and then randomized to the intervention or usual care. The intervention was performed by a nutritionist trained in self-management coaching and delivered in four telehealth sessions over 4 months. The following outcomes were measured at baseline and at 6 months after baseline: QOL (EORTC QLQC30), weight, body mass index, and sarcopenia. RESULTS: Fifty-three patients were enrolled. 22/27 usual care and 21/26 intervention patients completed the study for a retention rate of 81%. Differences between the intervention and control groups were not statistically significant, but the intervention group had indications of greater improvements in overall QOL as measured by EORTC QLQC30 Summary Score (8.7 vs. 2.3, p = 0.17) as well as greater improvements in 4/5 functional domains (p > 0.3). The intervention group also had slightly more weight gain (6 kg vs. 3 kg, p = 0.3) and less sarcopenia (3/16 vs. 9/18, p = 0.07). CONCLUSIONS: This pilot study demonstrated the feasibility and acceptability of a telehealth intervention for self-management of eating symptoms after gastroesophageal cancer surgery. There were trends toward improved overall QOL in the intervention group. A larger study is needed to validate the results.

Reducing Hospitalizations and Multidrug-Resistant Organisms via Regional Decolonization in Hospitals and Nursing Homes.

Importance: Infections due to multidrug-resistant organisms (MDROs) are associated with increased morbidity, mortality, length of hospitalization, and health care costs. Regional interventions may be advantageous in mitigating MDROs and associated infections. Objective: To evaluate whether implementation of a decolonization collaborative is associated with reduced regional MDRO prevalence, incident clinical cultures, infection-related hospitalizations, costs, and deaths. Design, Setting, and Participants: This quality improvement study was conducted from July 1, 2017, to July 31, 2019, across 35 health care facilities in Orange County, California. Exposures: Chlorhexidine bathing and nasal iodophor antisepsis for residents in long-term care and hospitalized patients in contact precautions (CP). Main Outcomes and Measures: Baseline and end of intervention MDRO point prevalence among participating facilities; incident MDRO (nonscreening) clinical cultures among participating and nonparticipating facilities; and infection-related hospitalizations and associated costs and deaths among residents in participating and nonparticipating nursing homes (NHs). Results: Thirty-five facilities (16 hospitals, 16 NHs, 3 long-term acute care hospitals [LTACHs]) adopted the intervention. Comparing decolonization with baseline periods among participating facilities, the mean (SD) MDRO prevalence decreased from 63.9% (12.2%) to 49.9% (11.3%) among NHs, from 80.0% (7.2%) to 53.3% (13.3%) among LTACHs (odds ratio [OR] for NHs and LTACHs, 0.48; 95% CI, 0.40-0.57), and from 64.1% (8.5%) to 55.4% (13.8%) (OR, 0.75; 95% CI, 0.60-0.93) among hospitalized patients in CP. When comparing decolonization with baseline among NHs, the mean (SD) monthly incident MDRO clinical cultures changed from 2.7 (1.9) to 1.7 (1.1) among participating NHs, from 1.7 (1.4) to 1.5 (1.1) among nonparticipating NHs (group × period interaction reduction, 30.4%; 95% CI, 16.4%-42.1%), from 25.5 (18.6) to 25.0 (15.9) among participating hospitals, from 12.5 (10.1) to 14.3 (10.2) among nonparticipating hospitals (group × period interaction reduction, 12.9%; 95% CI, 3.3%-21.5%), and from 14.8 (8.6) to 8.2 (6.1) among LTACHs (all facilities participating; 22.5% reduction; 95% CI, 4.4%-37.1%). For NHs, the rate of infection-related hospitalizations per 1000 resident-days changed from 2.31 during baseline to 1.94 during intervention among participating NHs, and from 1.90 to 2.03 among nonparticipating NHs (group × period interaction reduction, 26.7%; 95% CI, 19.0%-34.5%). Associated hospitalization costs per 1000 resident-days changed from $64 651 to $55 149 among participating NHs and from $55 151 to $59 327 among nonparticipating NHs (group × period interaction reduction, 26.8%; 95% CI, 26.7%-26.9%). Associated hospitalization deaths per 1000 resident-days changed from 0.29 to 0.25 among participating NHs and from 0.23 to 0.24 among nonparticipating NHs (group × period interaction reduction, 23.7%; 95% CI, 4.5%-43.0%). Conclusions and Relevance: A regional collaborative involving universal decolonization in long-term care facilities and targeted decolonization among hospital patients in CP was associated with lower MDRO carriage, infections, hospitalizations, costs, and deaths.

Chlorhexidine and Mupirocin for Clearance of Methicillin-Resistant Staphylococcus aureus Colonization After Hospital Discharge: A Secondary Analysis of the Changing Lives by Eradicating Antibiotic Resistance Trial.

BACKGROUND: The CLEAR Trial demonstrated that a multisite body decolonization regimen reduced post-discharge infection and hospitalization in methicillin-resistant Staphylococcus aureus (MRSA) carriers. Here, we describe decolonization efficacy. METHODS: We performed a large, multicenter, randomized clinical trial of MRSA decolonization among adult patients after hospital discharge with MRSA infection or colonization. Participants were randomized 1:1 to either MRSA prevention education or education plus decolonization with topical chlorhexidine, oral chlorhexidine, and nasal mupirocin. Participants were swabbed in the nares, throat, axilla/groin, and wound (if applicable) at baseline and 1, 3, 6, and 9 months after randomization. The primary outcomes of this study are follow-up colonization differences between groups. RESULTS: Among 2121 participants, 1058 were randomized to decolonization. By 1 month, MRSA colonization was lower in the decolonization group compared with the education-only group (odds ration [OR] = 0.44; 95% confidence interval [CI], .36-.54; P ≤ .001). A similar magnitude of reduction was seen in the nares (OR = 0.34; 95% CI, .27-.42; P < .001), throat (OR = 0.55; 95% CI, .42-.73; P < .001), and axilla/groin (OR = 0.57; 95% CI, .43-.75; P < .001). These differences persisted through month 9 except at the wound site, which had a relatively small sample size. Higher regimen adherence was associated with lower MRSA colonization (P ≤ .01). CONCLUSIONS: In a randomized, clinical trial, a repeated post-discharge decolonization regimen for MRSA carriers reduced MRSA colonization overall and at multiple body sites. Higher treatment adherence was associated with greater reductions in MRSA colonization.

Decolonization to Reduce Postdischarge Infection Risk among MRSA Carriers.

BACKGROUND: Hospitalized patients who are colonized with methicillin-resistant Staphylococcus aureus (MRSA) are at high risk for infection after discharge. METHODS: We conducted a multicenter, randomized, controlled trial of postdischarge hygiene education, as compared with education plus decolonization, in patients colonized with MRSA (carriers). Decolonization involved chlorhexidine mouthwash, baths or showers with chlorhexidine, and nasal mupirocin for 5 days twice per month for 6 months. Participants were followed for 1 year. The primary outcome was MRSA infection as defined according to Centers for Disease Control and Prevention (CDC) criteria. Secondary outcomes included MRSA infection determined on the basis of clinical judgment, infection from any cause, and infection-related hospitalization. All analyses were performed with the use of proportional-hazards models in the per-protocol population (all participants who underwent randomization, met the inclusion criteria, and survived beyond the recruitment hospitalization) and as-treated population (participants stratified according to adherence). RESULTS: In the per-protocol population, MRSA infection occurred in 98 of 1063 participants (9.2%) in the education group and in 67 of 1058 (6.3%) in the decolonization group; 84.8% of the MRSA infections led to hospitalization. Infection from any cause occurred in 23.7% of the participants in the education group and 19.6% of those in the decolonization group; 85.8% of the infections led to hospitalization. The hazard of MRSA infection was significantly lower in the decolonization group than in the education group (hazard ratio, 0.70; 95% confidence interval [CI], 0.52 to 0.96; P=0.03; number needed to treat to prevent one infection, 30; 95% CI, 18 to 230); this lower hazard led to a lower risk of hospitalization due to MRSA infection (hazard ratio, 0.71; 95% CI, 0.51 to 0.99). The decolonization group had lower likelihoods of clinically judged infection from any cause (hazard ratio, 0.83; 95% CI, 0.70 to 0.99) and infection-related hospitalization (hazard ratio, 0.76; 95% CI, 0.62 to 0.93); treatment effects for secondary outcomes should be interpreted with caution owing to a lack of prespecified adjustment for multiple comparisons. In as-treated analyses, participants in the decolonization group who adhered fully to the regimen had 44% fewer MRSA infections than the education group (hazard ratio, 0.56; 95% CI, 0.36 to 0.86) and had 40% fewer infections from any cause (hazard ratio, 0.60; 95% CI, 0.46 to 0.78). Side effects (all mild) occurred in 4.2% of the participants. CONCLUSIONS: Postdischarge MRSA decolonization with chlorhexidine and mupirocin led to a 30% lower risk of MRSA infection than education alone. (Funded by the AHRQ Healthcare-Associated Infections Program and others; ClinicalTrials.gov number, NCT01209234 .).

A Prospective Randomized Controlled Trial Comparing Medial-Pivot versus Posterior-Stabilized Total Knee Arthroplasty.

BACKGROUND: The medial-pivot (MP) design for total knee arthroplasty (TKA) aims to restore more natural "ball-and-socket" knee kinematics compared to the traditional posterior-stabilized (PS) implants for TKA. The objective of this study is to determine if there was any difference in functional outcomes between patients undergoing MP-TKA vs PS-TKA. METHODS: This prospective randomized controlled trial consisted of 43 patients undergoing MP-TKA vs 45 patients receiving a single-radius PS-TKA design. The primary outcome was postoperative range of motion (ROM). Secondary outcomes included the Western Ontario and McMaster Universities Arthritis Index, Oxford Knee Score, Knee Society Score (KSS), and radiological outcomes. All study patients were followed-up for 2 years after surgery. RESULTS: Patients undergoing MP-TKA had comparable ROM at 1 year (114.6° ± 16.3° vs 111.3° ± 17.8° respectively, P = .88) and 2 years after surgery (114.9° ± 15.5° vs 114.9° ± 16.4° respectively, P = .92) compared to PS-TKA. There were also no differences in Western Ontario and McMaster Universities Arthritis Index (26.8 ± 19.84 vs 22.0 ± 12.03 respectively, P = .14), Oxford Knee Score (42.7 ± 8.1 vs 42.3 ± 6.7 respectively, P = .18), KSS clinical scores (82.9 ± 16.96 vs 81.42 ± 10.45 respectively, P = .12) and KSS functional scores (76.2 ± 18.81 vs 73.93 ± 8.53 respectively, P = .62) at 2-year follow-up. There was no difference in postoperative limb alignment or complications. CONCLUSION: This study demonstrated excellent results in both the single-radius PS-TKA design and MP-TKA design. No differences were identified at 2-year follow-up with respect to postoperative ROM and patient-reported outcome measures.

Conventional Follow-up Versus Mobile Application Home Monitoring for Postoperative Anterior Cruciate Ligament Reconstruction Patients: A Randomized Controlled Trial.

PURPOSE: To determine whether a mobile app can reduce the need for in-person visits and examine the resulting societal cost differences between mobile and conventional follow-up for postoperative anterior cruciate ligament (ACL) reconstruction patients. METHODS: Study design was a single-center, 2-arm parallel group randomized controlled trial. All patients undergoing ACL reconstruction aged 16 to 70 years were screened for inclusion in the study. Competent use of a mobile device and ability to communicate in English was required. Patients were randomly assigned to receive follow-up via a mobile app or conventional appointments. Analysis was intention-to-treat. The primary outcome was the number of in-person visits to any health care professional during the first 6 postoperative weeks. Secondary outcomes included analysis of costs incurred by the health care system and personal patient costs related to both methods of follow-up. Patient-reported satisfaction and convenience scores, rates of complications, and clinical outcomes were also analyzed. RESULTS: Sixty patients were analyzed. Participants in the app group attended a mean of 0.36 in-person visits versus 2.44 in-person visits in the conventional group (95% confidence interval 0.08-0.28; P < .0001). On average, patients in the app group spent $211 (Canadian dollars) less than the conventional group over 6 weeks (P < .0001) on personal costs related to follow-up. Health care system costs were also significantly less in the app group ($157.5 vs CAD $202.2; P < .0001). There was no difference between groups in patient satisfaction, convenience, complication rates, or clinical outcome measures. CONCLUSIONS: Mobile follow-up can eliminate a significant number of in-person visits during the first 6 postoperative weeks in patients undergoing ACL reconstruction with cost savings to both the patient and health care system. This method should be considered for dissemination among similar orthopaedic procedures during early postoperative care. LEVEL OF EVIDENCE: I: Prospective randomized controlled trial.

Long-Term Results of Revision Total Hip Arthroplasty Using a Modern Extensively Porous-Coated Femoral Stem.

BACKGROUND: The use of an extensively porous-coated uncemented cobalt-chrome monoblock femoral stem for revision total hip arthroplasty (THA) is well established with excellent mid-term results. The aim of this study is to report the long-term survivorship of these implants in femoral stem revisions. METHODS: This is a long-term retrospective review of prospectively collected data of 55 femoral stem revisions in 55 patients using a contemporary, cementless extensively porous-coated cobalt-chrome monoblock stem. All patients between 2001 and 2006 who underwent first time femoral stem revision with a contemporary, cementless extensively porous-coated cobalt-chrome monoblock stem were included. Harris Hip Score, Western Ontario and McMaster Universities Index, and University of California Los Angeles activity scores were recorded preoperatively and at latest follow-up. Radiographs were analyzed for evidence of loosening, subsidence, osteolysis, and bony union. This study included 55 patients, comprising of 36 females (66%) and 19 males (34%) with a mean age of 66.4 ± 9.3 years at the time of surgery. The mean time interval from index procedure was 9.8 ± 2.9 years. Mean time from revision THA to final follow-up was 13.2 ± 2.17 years with a minimum of 10 years of follow-up. RESULTS: Indications for revision included aseptic loosening (33), prosthetic joint infection (13), and periprosthetic fracture (10). Significant improvement in Harris Hip Score (85.1 ± 1.77 vs 51.8 ± 2.3, P < .001), Western Ontario and McMaster Universities Index (17.6 ± 0.77 vs 33.3 ± 0.8, P < .001), and University of California Los Angeles (5.25 ± 0.2 vs 2.7 ± 0.36, P < .001) scores were found at latest follow-up compared to preoperative. Fifty-four patients (98%) achieved stable bony ingrowth on radiographic analysis. All 10 patients treated for periprosthetic fractures achieved bony union of their fractures. Two patients suffered intraoperative periprosthetic fractures and were treated with a cable-plating system. There were no mechanical failures and no femoral stem re-revisions. One patient was diagnosed with a deep infection and was treated with chronic suppressive antibiotic therapy due to significant medical comorbidities. CONCLUSION: Revision of the femoral component with a contemporary extensively porous-coated cobalt-chrome femoral stem has excellent functional outcomes, radiographic outcomes, and long-term survivorship with minimal complications.

The SHIELD Orange County Project: Multidrug-resistant Organism Prevalence in 21 Nursing Homes and Long-term Acute Care Facilities in Southern California.

BACKGROUND: Multidrug-resistant organisms (MDROs) spread between hospitals, nursing homes (NHs), and long-term acute care facilities (LTACs) via patient transfers. The Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County is a regional public health collaborative involving decolonization at 38 healthcare facilities selected based on their high degree of patient sharing. We report baseline MDRO prevalence in 21 NHs/LTACs. METHODS: A random sample of 50 adults for 21 NHs/LTACs (18 NHs, 3 LTACs) were screened for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), extended-spectrum ß-lactamase-producing organisms (ESBL), and carbapenem-resistant Enterobacteriaceae (CRE) using nares, skin (axilla/groin), and peri-rectal swabs. Facility and resident characteristics associated with MDRO carriage were assessed using multivariable models clustering by person and facility. RESULTS: Prevalence of MDROs was 65% in NHs and 80% in LTACs. The most common MDROs in NHs were MRSA (42%) and ESBL (34%); in LTACs they were VRE (55%) and ESBL (38%). CRE prevalence was higher in facilities that manage ventilated LTAC patients and NH residents (8% vs <1%, P < .001). MDRO status was known for 18% of NH residents and 49% of LTAC patients. MDRO-colonized adults commonly harbored additional MDROs (54% MDRO+ NH residents and 62% MDRO+ LTACs patients). History of MRSA (odds ratio [OR] = 1.7; confidence interval [CI]: 1.2, 2.4; P = .004), VRE (OR = 2.1; CI: 1.2, 3.8; P = .01), ESBL (OR = 1.6; CI: 1.1, 2.3; P = .03), and diabetes (OR = 1.3; CI: 1.0, 1.7; P = .03) were associated with any MDRO carriage. CONCLUSIONS: The majority of NH residents and LTAC patients harbor MDROs. MDRO status is frequently unknown to the facility. The high MDRO prevalence highlights the need for prevention efforts in NHs/LTACs as part of regional efforts to control MDRO spread.

Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin.

Objectives: We evaluated the antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from participants in a Phase 2 study of ridinilazole, a novel targeted-spectrum agent for treatment of C. difficile infection. Methods: Participants received ridinilazole (200 mg twice daily) or vancomycin (125 mg four times daily) for 10 days (ClinicalTrials.gov: NCT02092935). The MICs of ridinilazole and comparators for C. difficile isolates from stool samples were determined by agar dilution. Toxin gene profiling was performed by multiplex PCR and ribotype identification by capillary electrophoresis. Results: Eighty-nine isolates were recovered from 88/100 participants (one participant had two strains at baseline). The median colony count (cfu/g stool) was 1.9 × 104 (range: 2.5 × 102-7.0 × 106). Twelve participants (three received ridinilazole and nine received vancomycin) experienced recurrence, confirmed by immunoassays for free toxin in stool samples. The ribotype of eight out of nine isolates obtained at recurrence matched those of the initial isolates. All isolates, including those obtained at recurrence, were susceptible to ridinilazole within the expected range [median (range) MIC: 0.12 (0.06-0.5) mg/L]. The median (range) vancomycin MIC was 1 (0.5-4.0) mg/L. At baseline, 13.6% and 13.3% of samples in the ridinilazole and vancomycin groups were positive for VRE, increasing to 23.7% and 29.7% by day 40, respectively. Common ribotypes included 014-20 (14 isolates), 027 (13), 106 (7), 002 (7), 078-126 (4), 001 (4), 087 (3) and 198 (3). Toxin gene profiling of nearly all baseline isolates (98.9%) revealed a binary toxin gene (cdtA/cdtB) prevalence of 35%. Conclusions: Ridinilazole potently inhibited recovered C. difficile isolates. Recurrence was not associated with altered susceptibility.

Probing the ligand preferences of the three types of bacterial pantothenate kinase.

Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4'-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK.

Phosphoproteomics Identified an NS5A Phosphorylation Site Involved in Hepatitis C Virus Replication.

The non-structural protein 5A (NS5A) is a hepatitis C virus (HCV) protein indispensable for the viral life cycle. Many prior papers have pinpointed several serine residues in the low complexity sequence I region of NS5A responsible for NS5A phosphorylation; however, the functions of specific phosphorylation sites remained obscure. Using phosphoproteomics, we identified three phosphorylation sites (serines 222, 235, and 238) in the NS5A low complexity sequence I region. Reporter virus and replicon assays using phosphorylation-ablated alanine mutants of these sites showed that Ser-235 dominated over Ser-222 and Ser-238 in HCV replication. Immunoblotting using an Ser-235 phosphorylation-specific antibody showed a time-dependent increase in Ser-235 phosphorylation that correlated with the viral replication activity. Ser-235 phosphorylated NS5A co-localized with double-stranded RNA, consistent with its role in HCV replication. Mechanistically, Ser-235 phosphorylation probably promotes the replication complex formation via increasing NS5A interaction with the human homologue of the 33-kDa vesicle-associated membrane protein-associated protein. Casein kinase Iα (CKIα) directly phosphorylated Ser-235 in vitro. Inhibition of CKIα reduced Ser-235 phosphorylation and the HCV RNA levels in the infected cells. We concluded that NS5A Ser-235 phosphorylated by CKIα probably promotes HCV replication via increasing NS5A interaction with the 33-kDa vesicle-associated membrane protein-associated protein.

Small Molecule Restores Itaconate Sensitivity in Salmonella enterica: A Potential New Approach to Treating Bacterial Infections.

In the context of increasing global antibiotic resistance, the need for alternative therapeutic targets is great. Although new antibiotics and resistance inhibitors provide temporary solutions, they are bound to become obsolete. In this work, we propose a new approach, coined "bacterio-modulation" that aims to restore macrophage potency towards bacterial strains that are able to survive in phagolysosomes. One key defense in the macrophage's arsenal is itaconate, an endogenous molecule with antimicrobial activity. Some intracellular pathogens have evolved to produce itaconate-degrading enzymes, which are required for intracellular proliferation and to promote pathogenicity. We herein present the first molecule able to resensitize Salmonella enterica to itaconate.

Current Orthopaedic Surgeon Practices for Nonarthroplasty Treatment of Osteoarthritis of Adult Hip and Knee.

Evidence-based guidelines have recently been published for the nonarthroplasty treatment of osteoarthritis of the hip and knee and are becoming an expected part of comprehensive patient care. To understand how current treatment practices correlate with these guidelines, a survey was administered to 50 consecutive hip replacement and 50 consecutive knee replacement patients immediately before arthroplasty for osteoarthritis in one group practice. This article is a compilation of patients' usage of the modalities suggested in two such exemplary guidelines and demonstrates that patient and surgeon preferences, as well as factors such as preoperative Oxford score, body mass index, age, and joint involved, affect usage of one or more of the commonly employed preoperative modalities. This information provides orthopaedic surgeons and administrators with a compilation of responses that reflects surgeon and patient preferences for treatment before surgery.

The New WHO Category of "Molecularly Defined Renal Carcinomas": Clinical and Diagnostic Features and Management Implications.

The evolution of classification of renal tumors has been impacted since the turn of the millennium by rapid progress in histopathology, immunohistochemistry, and molecular genetics. Together, these features have enabled firm recognition of specific, classic types of renal cell carcinomas, such as clear cell renal cell carcinoma, that in current practice trigger histologic-type specific management and treatment protocols. Now, the fifth Edition World Health Classification's new category of "Molecularly defined renal carcinomas" changes the paradigm, defining a total of seven entities based specifically on their fundamental molecular underpinnings. These tumors, which include TFE3-rearranged, TFEB-altered, ELOC-mutated, fumarate hydratase-deficient, succinate dehydrogenase-deficient, ALK-rearranged, and SMARCB1-deficient renal medullary carcinoma, encompass a wide clinical and histopathologic phenotypic spectrum of tumors. Already, important management aspects are apparent for several of these entities, while emerging therapeutic angles are coming into view. A brief, clinically-oriented introduction of the entities in this new category, focusing on relevant diagnostic, molecular, and management aspects, is the subject of this review.

Fluoroscopy Versus Imageless Optical Navigation in Direct Anterior Approach Total Hip Arthroplasty.

BACKGROUND: Utilization of the direct anterior approach (DAA) for total hip arthroplasty (THA) has risen in popularity. Accurate implant placement is a critical factor that influences patient outcomes. The goal of this study was to compare the accuracy and precision of fluoroscopy with imageless optical navigation in DAA THA. METHODS: This was a cohort study of 640 consecutive primary DAA THAs performed with intraoperative fluoroscopy (n = 300 patients) or imageless optical navigation (n = 304 patients). Accuracy was compared by measuring acetabular cup inclination, anteversion, and leg-length discrepancy (LLD). The proportion of implants placed within the Lewinnek safe zone and those placed within a more precise target of 40 ± 5° inclination and 20 ± 5° anteversion was evaluated. RESULTS: According to the Lewinnek criteria, there was no difference in the percentage of implants placed within both inclination and anteversion targets (fluoroscopy: 90.3%; navigation: 88.8%, P = 0.519). Using the more precise targets, navigation increased the implants positioned correctly for both inclination and anteversion (fluoroscopy: 50.3%; navigation: 65.6%, P < 0.001). Navigation increased the proportion of implants positioned within the target anteversion zone (fluoroscopy: 71.3%; navigation: 83.8%, P < 0.001) but not inclination (fluoroscopy: 71.9%; navigation: 76.9%, P = 0.147). The mean LLD was higher with the use of fluoroscopy compared with navigation (5.5 mm, standard deviation: 4.1; 4.6 mm, SD: 3.4, P < 0.005). No difference in dislocation rate was observed ( P = 0.643). CONCLUSION: Both fluoroscopy and imageless optical navigation demonstrated accurate acetabular implant positioning during DAA THA. Navigation was more precise and associated with improved acetabular anteversion placement and restoration of LLD. Navigation is an accurate alternative to fluoroscopy with decreased radiation exposure.

Impact of traditional versus nontraditional initiation dosing schedule of paliperidone palmitate on 30-day readmission and safety.

Introduction: Paliperidone palmitate (PP), a second-generation long-acting injectable antipsychotic, requires 2 injections upon initiation. Due to the fast-paced nature of the inpatient setting, the second dose may be administered earlier than recommended by labeled use despite the lack of evidence that evaluates this practice. Methods: This was a retrospective chart review that investigated the outcomes associated with the timing of the second PP initiation dose with the aim of comparing patients who received the second PP dose fewer than 3 days after the first injection with those who received it between 3 and 11 days after the first injection. The primary outcomes included 30-day psychiatric readmission, index hospitalization length of stay, and time until the next psychiatric hospitalization. Secondary outcomes included 6-month readmission and the percentage of patients who experienced an adverse event after the second injection. Results: No statistically significant differences were observed between groups for 30-day readmission. There was a statistically significant shortened index length of hospitalization (median, 2 vs 4 days; P < 0.001) and a non-statistically significant trend for time until the next psychiatric hospitalization (median, 25 vs 47 days) when comparing those who received the nontraditional loading regimen to those who received the traditional labeled loading regimen. No differences were observed in the secondary outcomes or safety/tolerability. Discussion: The results of the study indicate that there are no significant differences in readmission rates and adverse drug reactions in those who received the second PP dose earlier than recommended per labeled use. Larger, controlled studies are needed to further investigate clinical and safety outcomes.

Short term outcomes following robotic arm-assisted lateral unicompartmental knee arthroplasty.

Introduction: Robotic-arm assisted medial unicompartmental knee arthroplasty (RA-UKA) is associated with improved accuracy of implant positioning and excellent early functional outcomes. However, there is paucity of evidence regarding outcomes following RA-UKA for isolated lateral compartment osteoarthritis. The purpose of this study was to assess the short-term clinical and patient reported outcomes of lateral compartment UKA, utilising robotic-arm assistance. Methods: This was a retrospective study of prospectively collected data of 21 consecutive patients who underwent lateral RA-UKA. The study included 9 (42.9%) males and 12 (57.1%) females with a mean age of 63.4 ± 9.2 years. The Oxford Knee Score (OKS) was measured pre-operatively and at 1-year post-operatively, while range of motion (ROM) and complications were also recorded. Results: There was significant improvement of OKS at 1 year's follow up compared with the baseline score (21.8 ± 5.6 vs. 45.2 ± 2.8 respectively; p < 0.001). There was also an improvement in pre-operative ROM when compared to ROM at 1 year's follow up (123.5° ± 8° vs. 131.5° ± 6.3° respectively; p < 0.001). None of the study patients underwent revision surgery within 1 year's follow-up. Conclusion: In our study, lateral RA-UKA resulted in significant improvements in clinical and patient reported outcomes with low complications rates. Further long-term comparative studies are needed to assess the utility of lateral RA-UKA vs. conventional UKA.

Use of an Artificial Intelligence Conversational Agent (Chatbot) for Hip Arthroscopy Patients Following Surgery.

Purpose: The purpose of this study was to evaluate the use of an AI conversational agent during the postoperative recovery of patients undergoing elective hip arthroscopy. Methods: Patients undergoing hip arthroscopy were enrolled in a prospective cohort for their first 6 weeks following surgery. Patients used standard SMS text messaging to interact with an artificial intelligence (AI) chatbot ("Felix") used to initiate automated conversations regarding elements of postoperative recovery. Patient satisfaction was measured at 6 weeks after surgery using a Likert scale survey. Accuracy was determined by measuring the appropriateness of chatbot responses, topic recognition, and examples of confusion. Safety was measured by evaluating the chatbot's responses to any questions with potential medical urgency. Results: Twenty-six patients were enrolled with a mean age of 36 years, and 58% (n = 15) were male. Overall, 80% of patients (n = 20) rated the helpfulness of Felix as good or excellent. In the postoperative period, 12/25 (48%) patients reported being worried about a complication but were reassured by Felix and, thus, did not seek medical attention. Of a total of 128 independent patient questions, Felix handled 101/128 questions appropriately (79%), either by addressing them independently, or facilitating contact with the care team. Felix was able to adequately answer the patient question independently 31% of the time (n = 40/128). Of 10 patient questions that were thought to potentially represent patient complications, in 3 cases Felix did not adequately address or recognize the health concern-none of these situations resulted in patient harm. Conclusion: The results of this study demonstrate that the use of a chatbot or conversational agent can enhance the postoperative experience for hip arthroscopy patients, as demonstrated by high levels of patient satisfaction. Levels of Evidence: Level IV, therapeutic case series.