Repurposing ibudilast to mitigate Alzheimer's disease by targeting inflammation.

Alzheimer's disease is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. Hence, a multi-target drug would improve treatment efficacy. We applied a new multi-scale predictive modelling framework that integrates machine learning with biophysics and systems pharmacology to screen drugs for Alzheimer's disease using patients' tissue samples. Our predictive modelling framework identified ibudilast as a drug with repurposing potential to treat Alzheimer's disease. Ibudilast is a multi-target drug, as it is a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist. In addition, we predict that ibudilast inhibits off-target kinases (e.g. IRAK1 and GSG2). In Japan and other Asian countries, ibudilast is approved for treating asthma and stroke due to its anti-inflammatory potential. Based on these previous studies and on our predictions, we tested for the first time the efficacy of ibudilast in Fisher transgenic 344-AD rats. This transgenic rat model is unique as it exhibits hippocampal-dependent spatial learning and memory deficits and Alzheimer's disease pathology, including hippocampal amyloid plaques, tau paired-helical filaments, neuronal loss and microgliosis, in a progressive age-dependent manner that mimics the pathology observed in Alzheimer's disease patients. Following long-term treatment with ibudilast, transgenic rats were evaluated at 11 months of age for spatial memory performance and Alzheimer's disease pathology. We demonstrate that ibudilast-treatment of transgenic rats mitigated hippocampal-dependent spatial memory deficits, as well as hippocampal (hilar subregion) amyloid plaque and tau paired-helical filament load, and microgliosis compared to untreated transgenic rat. Neuronal density analysed across all hippocampal regions was similar in ibudilast-treated transgenic compared to untreated transgenic rats. Interestingly, RNA sequencing analysis of hippocampal tissue showed that ibudilast-treatment affects gene expression levels of the TLR and ubiquitin-proteasome pathways differentially in male and female transgenic rats. Based on the TLR4 signalling pathway, our RNA sequencing data suggest that ibudilast-treatment inhibits IRAK1 activity by increasing expression of its negative regulator IRAK3, and/or by altering TRAF6 and other TLR-related ubiquitin ligase and conjugase levels. Our results support that ibudilast can serve as a repurposed drug that targets multiple pathways including TLR signalling and the ubiquitin/proteasome pathway to reduce cognitive deficits and pathology relevant to Alzheimer's disease.

Enhancing return to work or school after a first episode of schizophrenia: the UCLA RCT of Individual Placement and Support and Workplace Fundamentals Module training.

BACKGROUND: This study evaluated in a rigorous 18-month randomized controlled trial the efficacy of an enhanced vocational intervention for helping individuals with a recent first schizophrenia episode to return to and remain in competitive work or regular schooling. METHODS: Individual Placement and Support (IPS) was adapted to meet the goals of individuals whose goals might involve either employment or schooling. IPS was combined with a Workplace Fundamentals Module (WFM) for an enhanced, outpatient, vocational intervention. Random assignment to the enhanced integrated rehabilitation program (N = 46) was contrasted with equally intensive clinical treatment at UCLA, including social skills training groups, and conventional vocational rehabilitation by state agencies (N = 23). All patients were provided case management and psychiatric services by the same clinical team and received oral atypical antipsychotic medication. RESULTS: The IPS-WFM combination led to 83% of patients participating in competitive employment or school in the first 6 months of intensive treatment, compared with 41% in the comparison group (p < 0.005). During the subsequent year, IPS-WFM continued to yield higher rates of schooling/employment (92% v. 60%, p < 0.03). Cumulative number of weeks of schooling and/or employment was also substantially greater with the IPS-WFM intervention (45 v. 26 weeks, p < 0.004). CONCLUSIONS: The results clearly support the efficacy of an enhanced intervention focused on recovery of participation in normative work and school settings in the initial phase of schizophrenia, suggesting potential for prevention of disability.

Maternal periconceptional and first trimester protein restriction in beef heifers: effects on maternal performance and early fetal growth.

This study evaluated the effect of protein restriction during the periconception (PERI) and first trimester (POST) periods on maternal performance, physiology and early fetal growth. Yearling nulliparous heifers (n=360) were individually fed a diet high or low in protein (HPeri and LPeri respectively) beginning 60 days before conception. From 24 to 98 days post-conception (dpc), half of each treatment group changed to the alternative post-conception high- or low-protein diet (HPost and LPost respectively), yielding four groups in a 2×2 factorial design with a common diet until parturition. Protein restriction was associated with lower bodyweight subsequent to reduced (but positive) average daily weight gain (ADG) during the PERI and POST periods. During the POST period, ADG was greater in LPeri than HPeri heifers and tended to be greater in LPost than HPost heifers during the second and third trimester. Bodyweight was similar at term. The pregnancy rate did not differ, but embryo loss between 23 and 36 dpc tended to be greater in LPeri than HPeri heifers. Overall, a greater proportion of male fetuses was detected (at 60 dpc 63.3% male vs 36.7% female). Protein restriction altered maternal plasma urea, non-esterified fatty acids, progesterone, leptin and insulin-like growth factor 1 at critical stages of fetal development. However, profiles varied depending on the sex of the conceptus.

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.

Acute Pediatric Monteggia Fractures: A Conservative Approach to Stabilization.

BACKGROUND: In 2015, a multicenter study group proposed a treatment algorithm for pediatric Monteggia fractures based upon the ulnar fracture pattern. This strategy recommends surgical stabilization for all complete ulna fractures. The purpose of this study was to evaluate whether an initial nonoperative approach to pediatric Monteggia fractures resulted in poorer outcomes and a higher rate of complications. METHODS: This institutional review board approved retrospective study evaluated all Monteggia fractures presenting to a level 1 pediatric trauma center between 2008 and 2014. Chart and radiographic reviews were performed on 94 patients who met inclusion criteria. The mean age was 5.5 years (range, 1 to 13 y). The mean clinical follow-up was 18 weeks. Major complications were defined as those requiring an unplanned second procedure (other than implant removal) or that may result in long-term disability (residual radial head subluxation/dislocation). Univariate (P<0.05) and Multivariate Classification and Regression Tree (CART) (P<0.05) analyses were used to identify variables associated with the need for surgical stabilization. RESULTS: At final follow-up, there were no cases of residual radiocapitellar joint subluxation or dislocation and all fractures had healed. The majority (83%) of patients were successfully managed with a cast. Univariate analysis found Bado type and maximum ulna angulation as significant predictors (P<0.05), whereas the CART analysis found ulna angulation >36.5 degrees as the only primary predictor of requiring surgical stabilization. Overall, good outcomes were achieved in all patients with few major complications. CONCLUSIONS: Although treatment algorithms are intended to minimize complications and maximize good outcomes, we believe that an unintentional consequence of the recently proposed pediatric Monteggia fracture treatment guideline may be the overtreatment of these injuries. In our cohort, the majority of patients were able to avoid the operating room and surgical implants without compromising outcomes or complications. This more conservative approach, however, requires close monitoring of patients in the first 3 weeks during which most reductions were lost. LEVEL OF EVIDENCE: Level IV-therapeutic studies, case series.

Shoulder linked arthroplasty in patients with obstetric brachial plexus palsy can improve quality of life and function at short-term follow-up.

BACKGROUND: Patients with obstetric brachial plexus palsy (OBPP) are prone to develop degenerative shoulder disease at a younger age than the general population. To date, no reports have been published on the complexities or outcome of shoulder arthroplasty (SA) in this unique patient group. METHODS: We reviewed of 9 SAs in 9 patients (3 men and 6 women) with OBPP with mean follow-up 5.1 years (range, 2.6-7.6 years). Patients were a mean age of 29 years (range, 16-56 years). Patients had undergone a mean of 3 previous operations (range, 2-6). All patients underwent linked constrained SA. RESULTS: The mean Oxford Shoulder Score increased from 8 (range, 3-10) preoperatively to 21 (range, 12-32) at the final follow-up (P < .001) predominantly due to pain relief. Mean range of active forward elevation and abduction improved from 35° and 39° to 46° and 45°, respectively. Patients improved significantly in 2 of 8 Short-Form 36-Item health-related quality of life domains, bodily pain (P = .013) and mental health (P = .035), and the overall physical component summary score (P = .006). Range of motion had mild improvements. Three required reoperation (33%), comprising 1 excision of heterotopic ossification, 1 trimming of a prominent screw, and 1 deltoid rupture repair. CONCLUSIONS: SA is effective at relieving pain and health-related quality of life for young patients with OBPP; however, compared with the general population, the complication rate is high and functional gains are small.

Eliminating tuberculosis one neighborhood at a time.

OBJECTIVES: We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. METHODS: In 1996, we mapped reported TB cases (1985-1995) and positive tuberculin skin test (TST) reactors (1993-1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. RESULTS: Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. CONCLUSIONS: Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States.

Assessment of a novel method for teaching veterinary parasitology.

A student-centered innovative method of teaching veterinary parasitology was launched and evaluated at the Ross University School of Veterinary Medicine (RUSVM) in St. Kitts, where Parasitology is a required course for second-semester veterinary students. A novel method, named Iron Parasitology, compared lecturer-centered teaching with student-centered teaching and assessed the retention of parasitology knowledge of students in their second semester and again when they reached their seventh semester. Members of five consecutive classes chose to participate in Iron Parasitology with the opportunity to earn an additional 10 points toward their final grade by demonstrating their knowledge, communication skills, clarity of message, and creativity in the Iron Parasitology exercise. The participants and nonparticipants were assessed using seven parameters. The initial short-term study parameters used to evaluate lecturer- versus student-centered teaching were age, gender, final Parasitology course grade without Iron Parasitology, RUSVM overall grade point average (GPA), RUSVM second-semester GPA, overall GPA before RUSVM, and prerequisite GPA before RUSVM. The long-term reassessment study assessed retention of parasitology knowledge in members of the seventh-semester class who had Iron Parasitology as a tool in their second semester. These students were invited to complete a parasitology final examination during their seventh semester. There were no statistically significant differences for the parameters measured in the initial study. In addition, Iron Parasitology did not have an effect on the retention scores in the reassessment study.

Potential Alzheimer's early biomarkers in a transgenic rat model and benefits of diazoxide/dibenzoylmethane co-treatment on spatial memory and AD-pathology.

Alzheimer's disease (AD) is the major form of dementia prevalent in older adults and with a high incidence in females. Identification of early biomarkers is essential for preventive intervention to delay its progression. Furthermore, due to its multifactorial nature, a multi-target approach could be therapeutically beneficial. Our studies included 4- (pre-pathology) and 11-month (mild-pathology) TgF344-AD rats, a transgenic Alzheimer's model that exhibits age-dependent AD progression. We identified two potential early biomarker genes for AD, early growth response 2 (EGR2) and histone 1H2AA (HIST1H2AA), in the hippocampus of 4-month females. Out of 17,168 genes analyzed by RNA sequencing, expression of these two genes was significantly altered in 4-month TgF344-AD rats compared to wild-type littermates. We also evaluated co-treatment with diazoxide (DZ), a potassium channel activator, and dibenzoylmethane (DIB), which inhibits eIF2α-P activity, on TgF344-AD and wild-type rats. DZ/DIB-treatment mitigated spatial memory deficits and buildup of hippocampal Aß plaques and tau PHF in 11-month TgF344-AD rats but had no effect on wild-type littermates. To our knowledge, this preclinical study is the first to report EGR2 and HIST1H2AA as potential AD biomarkers in females, and the benefits of DZ/DIB-treatment in AD. Evaluations across multiple AD-related models is warranted to corroborate our findings.

Dosimetric evaluation of adaptive planning for five-fraction gynecologic template-based interstitial brachytherapy.

PURPOSE: The purpose of this work was to evaluate whether inter-fraction imaging and replanning enhance treatment delivery adherence to clinical planning objectives in the context of a 5-fraction template-based interstitial brachytherapy (TISB) approach for gynecologic cancer treatment. METHODS AND MATERIALS: This retrospective study analyzed nineteen patients who underwent 5 fractions of interstitial brachytherapy over 3 days using the Syed-Neblett template. A verification CT scan was acquired for applicator assessment and reviewed by a radiation oncologist and medical physicist before each fraction. Eleven patients required replanning at least once during the treatment course. Replanning on the verification CT scan consisted of generating new target and organ-at-risk contours, digitizing catheter positions, and optimizing source dwell times to meet planning objectives. Dwell times and positions from the initial treatment plan were evaluated on the new contours to assess the dose that would have been delivered without replanning (nonadapted). Significance of nonadapted versus adapted dose differences were evaluated using a 2-sided Wilcoxon sum rank test. RESULTS: The average (min, max) change in dose (Gy) between the clinically delivered plans and the nonadapted plans were HR-CTV D90%: -6.5 (-0.6, -15.1), HR-CTV D98%: -6.5 (-0.4, -12.6), Bladder D2cc: -0.5 (0.0, -2.8), Bowel D2cc: -0.8 (0.0, -3.2), Rectum D2cc: -1.1 (0.0, -11.5), Sigmoid D2cc: -1.4 (-0.1, -5.4). Dosimetric changes in HR-CTV coverage were significantly improved with replanning while organ-at-risk differences were nonsignificant (p > 0.05). Fraction 3 was the most common fraction indicated for replanning. CONCLUSIONS: Replanning template-based interstitial brachytherapy can improve target coverage and adherence to planning goals.

Eliminating tuberculosis one neighborhood at a time.

OBJECTIVES: We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. METHODS: In 1996, we mapped reported TB cases (1985-1995) and positive tuberculin skin test (TST) reactors (1993-1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. RESULTS: Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. CONCLUSIONS: Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States.

[Eliminating tuberculosis one neighborhood at a time]. / Eliminación de la tuberculosis, un vecindario por vez.

OBJECTIVES: We evaluated a strategy for preventing tuberculosis (TB) in communities most affected by it. METHODS: In 1996, we mapped reported TB cases (1985-1995) and positive tuberculin skin test (TST) reactors (1993-1995) in Smith County, Texas. We delineated the 2 largest, densest clusters, identifying 2 highest-incidence neighborhoods (180 square blocks, 3153 residents). After extensive community preparation, trained health care workers went door-to-door offering TST to all residents unless contraindicated. TST-positive individuals were escorted to a mobile clinic for radiography, clinical evaluation, and isoniazid preventive treatment (IPT) as indicated. To assess long-term impact, we mapped all TB cases in Smith County during the equivalent time period after the project. RESULTS: Of 2258 eligible individuals, 1291 (57.1%) were tested, 229 (17.7%) were TST positive, and 147 were treated. From 1996 to 2006, there were no TB cases in either project neighborhood, in contrast with the preintervention decade and the continued occurrence of TB in the rest of Smith County. CONCLUSIONS: Targeting high-incidence neighborhoods for active, community-based screening and IPT may hasten TB elimination in the United States.

Interstitial Brachytherapy for Lip Cancer: Technical Aspects to Individualize Treatment Approach and Optimize Outcomes.

Primary radiation therapy using interstitial brachytherapy (IBT) provides excellent local tumor control for early-stage squamous cell carcinoma of the lip. Technical aspects of treatment are important to optimize outcomes. In this report, we discuss patient selection criteria, procedural details, and dosimetric considerations for performing IBT for cancers of the lip. Catheters are inserted across the length of tumor entering and exiting approximately 5 mm beyond the palpable tumor extent. A custom mouthpiece is fabricated to facilitate normal tissue sparing. Patients undergo computed tomography imaging, the gross tumor volume is contoured based on physical examination and computed tomography findings, and an individualized brachytherapy plan is generated with the goals of achieving gross tumor volume D90% ≥ 90% and minimizing V150%. Ten patients with primary (n = 8) or recurrent (n = 2) cancers of the lip who received high-dose-rate lip IBT using 2.0- to 2.5-week treatment regimens are described (median prescription: 47.6 Gy in 14 fractions of 3.4 Gy). Local tumor control was 100%. There were no cases of acute grade ≥4 or late grade ≥2 toxicity, and cosmesis scores were graded as good to excellent in all patients. IBT represents an excellent treatment option for patients with lip squamous cell carcinoma. With careful attention to technical considerations furthered described in the present report, high rates of tumor control, low rates of toxicity, and favorable esthetic and functional outcomes can be achieved with IBT for lip cancer.

Timapiprant, a prostaglandin D2 receptor antagonist, ameliorates pathology in a rat Alzheimer's model.

We investigated the relevance of the prostaglandin D2 pathway in Alzheimer's disease, because prostaglandin D2 is a major prostaglandin in the brain. Thus, its contribution to Alzheimer's disease merits attention, given the known impact of the prostaglandin E2 pathway in Alzheimer's disease. We used the TgF344-AD transgenic rat model because it exhibits age-dependent and progressive Alzheimer's disease pathology. Prostaglandin D2 levels in hippocampi of TgF344-AD and wild-type littermates were significantly higher than prostaglandin E2. Prostaglandin D2 signals through DP1 and DP2 receptors. Microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in TgF344-AD than in wild-type rats. Expression of the major brain prostaglandin D2 synthase (lipocalin-type PGDS) was the highest among 33 genes involved in the prostaglandin D2 and prostaglandin E2 pathways. We treated a subset of rats (wild-type and TgF344-AD males) with timapiprant, a potent highly selective DP2 antagonist in development for allergic inflammation treatment. Timapiprant significantly mitigated Alzheimer's disease pathology and cognitive deficits in TgF344-AD males. Thus, selective DP2 antagonists have potential as therapeutics to treat Alzheimer's disease.

Targeting the GTV in medically inoperable endometrial cancer using brachytherapy.

PURPOSE: We aimed to determine the relationship between gross tumor volume (GTV) dose and tumor control in women with medically inoperable endometrial cancer, and to demonstrate the feasibility of targeting a GTV-focused volume using imaged-guided brachytherapy. METHODS AND MATERIALS: An endometrial cancer database was used to identify patients. Treatment plans were reviewed to determine doses to GTV, clinical target volume (CTV), and OARs. Uterine recurrence-free survival was evaluated as a function of CTV and GTV doses. Brachytherapy was replanned with a goal of GTV D98 EQD2 ≥ 80 Gy, without regard for coverage of the uninvolved uterus and while respecting OAR dose constraints. RESULTS: Fifty-four patients were identified. In the delivered plans, GTV D90 EQD2 ≥ 80 Gy was achieved in 36 (81.8%) patients. Uterine recurrence-free survival was 100% in patients with GTV D90 EQD2 ≥ 80 Gy and 66.7% in patients with EQD2 < 80 Gy (p = 0.001). On GTV-only replans, GTV D98 EQD2 ≥ 80 Gy was achieved in 39 (88.6%) patients. Mean D2cc was lower for bladder (47.1 Gy vs. 73.0 Gy, p < 0.001), and sigmoid (47.0 Gy vs. 58.0 Gy, p = 0.007) on GTV-only replans compared to delivered plans. Bladder D2cc was ≥ 80 Gy in 11 (25.0%) delivered plans and four (9.1%) GTV-only replans (p = 0.043). Sigmoid D2cc was ≥ 65 Gy in 20 (45.4%) delivered plans and 10 (22.7%) GTV-only replans (p = 0.021). CONCLUSIONS: OAR dose constraints should be prioritized over CTV coverage if GTV coverage is sufficient. Prospective evaluation of image-guided brachytherapy to a reduced, GTV-focused volume is warranted.

Imaging of the wrist at 1.5 Tesla using isotropic three-dimensional fast spin echo cube.

PURPOSE: To compare three-dimensional fast spin echo Cube (3D-FSE-Cube) with conventional 2D-FSE in MR imaging of the wrist. MATERIALS AND METHODS: The wrists of 10 volunteers were imaged in a 1.5 Tesla MRI scanner using an eight-channel wrist coil. The 3D-FSE-Cube images were acquired in the coronal plane with 0.5-mm isotropic resolution. The 2D-FSE images were acquired in both coronal and axial planes for comparison. An ROI was placed in fluid, cartilage, and muscle for SNR analysis. Comparable coronal and axial images were selected for each sequence, and paired images were randomized and graded for blurring, artifact, anatomic details, and overall image quality by three blinded musculoskeletal radiologists. RESULTS: SNR of fluid, cartilage and muscle at prescribed locations were higher using 3D-FSE-Cube, without reaching statistical significance. Fluid-cartilage CNR was also higher with 3D-FSE-Cube, but not statistically significant. Blurring, artifact, anatomic details, and overall image quality were significantly better on coronal 3D-FSE-Cube images (P < 0.001), but significantly better on axial 2D-FSE images compared with axial 3D-FSE-Cube reformats (P < 0.01). CONCLUSION: Isotropic data from 3D-FSE-Cube allows reformations in arbitrary scan planes, which may make multiple 2D acquisitions unnecessary, and improve depiction of complex wrist anatomy. However, axial reformations suffer from blurring, likely due to T2 decay during the long echo train, limiting overall image quality in this plane.

Does directly observed therapy (DOT) reduce drug resistant tuberculosis?

BACKGROUND: Directly observed therapy (DOT) is a widely recommended and promoted strategy to manage tuberculosis (TB), however, there is still disagreement about the role of DOT in TB control and the impact it has on reducing the acquisition and transmission of drug resistant TB. This study compares the portion of drug resistant genotype clusters, representing recent transmission, within and between communities implementing programs differing only in their directly observed therapy (DOT) practices. METHODS: Genotype clusters were defined as 2 or more patient members with matching IS6110 restriction fragment length polymorphism (RFLP) and spoligotype patterns from all culture-positive tuberculosis cases diagnosed between January 1, 1995 and December 31, 2001. Logistic regression was used to compute maximum-likelihood estimates of odds ratios (ORs) and 95% confidence intervals (CIs) comparing cluster members with and without drug resistant isolates. In the universal DOT county, all patients received doses under direct observation of health department staff; whereas in selective DOT county, the majority of received patients doses under direct observation of health department staff, while some were able to self-administer doses. RESULTS: Isolates from 1,706 persons collected during 1,721 episodes of tuberculosis were genotyped. Cluster members from the selective DOT county were more than twice as likely than cluster members from the universal DOT county to have at least one isolate resistant to isoniazid, rifampin, and/or ethambutol (OR = 2.3, 95% CI: 1.7, 3.1). Selective DOT county isolates were nearly 5 times more likely than universal DOT county isolates to belong to clusters with at least 2 resistant isolates having identical resistance patterns (OR = 4.7, 95% CI: 2.9, 7.6). CONCLUSIONS: Universal DOT for tuberculosis is associated with a decrease in the acquisition and transmission of resistant tuberculosis.

Functional alignment achieves soft-tissue balance in total knee arthroplasty as measured with quantitative sensor-guided technology.

AIMS: Total knee arthroplasty (TKA) using functional alignment aims to implant the components with minimal compromise of the soft-tissue envelope by restoring the plane and obliquity of the non-arthritic joint. The objective of this study was to determine the effect of TKA with functional alignment on mediolateral soft-tissue balance as assessed using intraoperative sensor-guided technology. METHODS: This prospective study included 30 consecutive patients undergoing robotic-assisted TKA using the Stryker PS Triathlon implant with functional alignment. Intraoperative soft-tissue balance was assessed using sensor-guided technology after definitive component implantation; soft-tissue balance was defined as intercompartmental pressure difference (ICPD) of < 15 psi. Medial and lateral compartment pressures were recorded at 10°, 45°, and 90° of knee flexion. This study included 18 females (60%) and 12 males (40%) with a mean age of 65.2 years (SD 9.3). Mean preoperative hip-knee-ankle deformity was 6.3° varus (SD 2.7°). RESULTS: TKA with functional alignment achieved balanced medial and lateral compartment pressures at 10° (25.0 psi (SD 6.1) vs 23.1 psi (SD 6.7), respectively; p = 0.140), 45° (21.4 psi (SD 5.9) vs 20.6 psi (SD 5.9), respectively; p = 0.510), and 90° (21.2 psi (SD 7.1) vs 21.6 psi (SD 9.0), respectively; p = 0.800) of knee flexion. Mean ICPD was 6.1 psi (SD 4.5; 0 to 14) at 10°, 5.4 psi (SD 3.9; 0 to 12) at 45°, and 4.9 psi (SD 4.45; 0 to 15) at 90° of knee flexion. Mean postoperative limb alignment was 2.2° varus (SD 1.0°). CONCLUSION: TKA using the functional alignment achieves balanced mediolateral soft-tissue tension through the arc of knee flexion as assessed using intraoperative pressure-sensor technology. Further clinical trials are required to determine if TKA with functional alignment translates to improvements in patient satisfaction and outcomes compared to conventional alignment techniques. Cite this article: Bone Joint J 2021;103-B(3):507-514.

Gentamicin pre-soaking of hamstring autografts decreases infection rates in anterior cruciate ligament reconstruction.

AIMS: Graft infection following anterior cruciate ligament reconstruction (ACLR) may lead to septic arthritis requiring multiple irrigation and debridement procedures, staged revision operations, and prolonged courses of antibiotics. To our knowledge, there are no previous studies reporting on how gentamicin pre-soaking of hamstring grafts influences infection rates following ACLR. We set out to examine this in our study accordingly. METHODS: This retrospective study included 2,000 patients (1,156 males and 844 females) who underwent primary ACLR with hamstring autografts between 2007 to 2017. This included 1,063 patients who received pre-soaked saline hamstring grafts for ACLR followed by 937 patients who received pre-soaked gentamicin hamstring grafts for ACLR. All operative procedures were completed by a single surgeon using a standardized surgical technique. Medical notes were reviewed and data relating to the following outcomes recorded: postoperative infection, clinical progress, causative organisms, management received, and outcomes. RESULTS: Superficial wound infection developed in 14 patients (1.31 %) receiving pre-saline soaked hamstring grafts compared to 13 patients (1.38 %) receiving pre-gentamicin soaked hamstring grafts, and this finding was not statistically significant (p = 0.692). All superficial wound infections were treated with oral antibiotics with no further complications. There were no recorded cases of septic arthritis in patients receiving pre-gentamicin soaked grafts compared to nine patients (0.85%) receiving pre-saline soaked grafts, which was statistically significant (p = 0.004). CONCLUSION: Pre-soaking hamstring autographs in gentamicin does not affect superficial infection rates but does reduce deep intra-articular infection rates compared to pre-soaking hamstring grafts in saline alone. These findings suggest that pre-soaking hamstring autografts in gentamicin provides an effective surgical technique for reducing intra-articular infection rates following ACLR.Cite this article: Bone Jt Open 2021;2(1):66-71.

Direct-contact co-culture between smooth muscle and endothelial cells inhibits TNF-alpha-mediated endothelial cell activation.

We used a direct-contact endothelial cell-smooth muscle cell (EC-SMC) co-culture to examine whether quiescent SMCs regulate the EC inflammatory response to tumor necrosis factor (TNF)-alpha. ECs were cultured under static and physiological flow conditions. Compared with TNF-alpha-treated ECs in monoculture, TNF-alpha-treated ECs in co-culture had less NF-kappaB nuclear translocation; less intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin surface protein expression; no change in TNF receptor expression, but greater Kruppel-like factor 2 (KLF2) gene expression. After flow preconditioning for 24 h at 15 dyne/cm(2), and exposure of ECs to flow and TNF-alpha for 4.5 h, ECs in co-culture had less ICAM-1, VCAM-1, and E-selectin surface protein expression. Exposure to flow greatly increased KLF2 gene expression levels in both EC cultures; as a result, ECs in co-culture and monoculture had similar levels of post-flow KLF2 gene expression. The reduced levels of TNF-alpha-induced adhesion molecule expression in co-culture required the presence of quiescent SMCs; adhesion to decellularized extracellular matrix (ECM) or co-culture with fibroblasts produced only a modest reduction in EC adhesion molecule expression. Furthermore, co-culture of quiescent SMCs and ECs on the opposite side of a 10-microm-thick porous membrane did not alter the TNF-alpha-mediated ICAM-1 surface protein expression. Although the ECM produced by SMCs plays some role in reducing TNF-alpha-mediated inflammation, these results suggest that the direct contact between ECs and quiescent SMCs is required to inhibit TNF-alpha-mediated activation.