Wolbachia depletion blocks transmission of lymphatic filariasis by preventing chitinase-dependent parasite exsheathment.

Lymphatic filariasis is a vector-borne neglected tropical disease prioritized for global elimination. The filarial nematodes that cause the disease host a symbiotic bacterium, Wolbachia, which has been targeted using antibiotics, leading to cessation of parasite embryogenesis, waning of circulating larvae (microfilariae [mf]), and gradual cure of adult infection. One of the benefits of the anti-Wolbachia mode of action is that it avoids the rapid killing of mf, which can drive inflammatory adverse events. However, mf depleted of Wolbachia persist for several months in circulation, and thus patients treated with antibiotics are assumed to remain at risk for transmitting infections. Here, we show that Wolbachia-depleted mf rapidly lose the capacity to develop in the mosquito vector through a defect in exsheathment and inability to migrate through the gut wall. Transcriptomic and Western blotting analyses demonstrate that chitinase, an enzyme essential for mf exsheathment, is down-regulated in Wolbachia-depleted mf and correlates with their inability to exsheath and escape the mosquito midgut. Supplementation of in vitro cultures of Wolbachia-depleted mf with chitinase enzymes restores their ability to exsheath to a similar level to that observed in untreated mf. Our findings elucidate a mechanism of rapid transmission-blocking activity of filariasis after depletion of Wolbachia and adds to the broad range of biological processes of filarial nematodes that are dependent on Wolbachia symbiosis.

AWZ1066S, a highly specific anti-Wolbachia drug candidate for a short-course treatment of filariasis.

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases that together affect ∼157 million people and inflict severe disability. Both diseases are caused by parasitic filarial nematodes with elimination efforts constrained by the lack of a safe drug that can kill the adult filaria (macrofilaricide). Previous proof-of-concept human trials have demonstrated that depleting >90% of the essential nematode endosymbiont bacterium, Wolbachia, using antibiotics, can lead to permanent sterilization of adult female parasites and a safe macrofilaricidal outcome. AWZ1066S is a highly specific anti-Wolbachia candidate selected through a lead optimization program focused on balancing efficacy, safety and drug metabolism/pharmacokinetic (DMPK) features of a thienopyrimidine/quinazoline scaffold derived from phenotypic screening. AWZ1066S shows superior efficacy to existing anti-Wolbachia therapies in validated preclinical models of infection and has DMPK characteristics that are compatible with a short therapeutic regimen of 7 days or less. This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.

Comparing 1-year and 10-year whole blood metal ion results following Birmingham hip resurfacing for osteoarthritis.

BACKGROUND: Patients with metal-on-metal hip arthroplasty may develop adverse reactions to metal debris that can lead to clinically concerning symptoms, often needing revision surgery. As such, many regulatory authorities advocate for routine blood metal ion measurement. This study compares whole blood metal ion levels obtained 1 year following Birmingham Hip Resurfacing (BHR) to levels obtained at a minimum 10-year follow-up. METHODS: A retrospective chart review was conducted to identify all patients who underwent a BHR for osteoarthritis with a minimum 10-year follow-up. Whole blood metal ion levels were obtained at final follow-up in June 2019. These results were compared with patients' metal ion levels at 1 year. RESULTS: Of the 211 patients who received a BHR, 71 patients (54 males and 17 females) had long-term metal ion levels assessed (mean follow-up 12.7 ± 1.4 yr). The mean cobalt and chromium levels for patients with unilateral BHRs (43 males and 13 females) were 3.12 ± 6.31 µg/L and 2.62 ± 2.69 µg/L, respectively; for patients with bilateral BHRs (11 males and 4 females) cobalt and chromium levels were 2.78 ± 1.02 µg/L and 1.83 ± 0.65 µg/L, respectively. Thirty-five patients (27 male and 8 female) had metal ion levels tested at 1 year postoperatively. The mean changes in cobalt and chromium levels were 2.29 µg/L (p = 0.0919) and 0.57 µg/L (p = 0.1612), respectively. CONCLUSION: Our results suggest that regular metal ion testing as per current regulatory agency guidelines may be impractical for asymptomatic patients. Metal ion levels may in fact have little utility in determining the risk of failure and should be paired with radiographic and clinical findings to determine the need for revision.

Birmingham Hip Resurfacing for osteoarthritis - a Canadian retrospective cohort study with a minimum 10-year follow-up.

BACKGROUND: Young men with osteoarthritis of the hip are a growing segment of the population requiring arthroplasty, and there is compelling evidence that the Birmingham Hip Resurfacing (BHR) system provides good functional outcomes and durability in young, active men. We reviewed the survivorship and clinical outcomes of patients who underwent BHR with a minimum follow-up of 10 years. METHODS: We analyzed survivorship using the Kaplan-Meier method. Functional scoring was performed using the Harris Hip Score (HHS), the University of California, Los Angeles (UCLA) Activity Score, and a visual analogue scale (VAS). RESULTS: In total, 211 patients (243 hips) were included in the study. Of these, 107 patients (127 hips) were available for long-term clinical follow-up, with a mean duration of 12.4 ± 1.4 years. The proportion of male participants with BHRs surviving past 13 years was 93.8% (95% confidence interval [CI] 87.9%-100%) compared with 87% (95% CI 77.8%-97.3%) of female patients. Eleven patients (11 hips) underwent BHR revision. Upon final follow-up, the median HHS was 93.9 in males and 93.6 in females (p = 0.27); median UCLA Activity Score was 8.2 in males and 7.2 in females (p < 0.001), and the median VAS score was 81.9 in males and 81.3 in females (p = 0.35). The median acetabular component inclination was 45.5° ± 6.0° (range 34.6°-57.2°) in males and 44.6° ± 5.9° (range 29°-58.9°) in females. The most common femoral head size was 50 mm with a 56 mm or 58 mm cup (36.3%). CONCLUSION: This study confirms that BHR provides good to excellent functional outcomes, lasting functional improvements, and acceptable durability beyond 10 years in men. Survivorship following BHR is inferior in women; however, HHS and VAS scores were similar in women and men.

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis.

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.

One-stage versus 2-stage bilateral total joint arthroplasty: a matched cohort study.

Background: Patients with bilateral end-stage hip or knee arthritis want to know if it is safe to have bilateral surgery under a single anesthetic, to restore their quality of life as quickly as possible. The purpose of this study was to assess if there is an increase in the rate of postoperative medical adverse events, length of stay (LOS), blood transfusion rate and 30-day readmission rate among patients who undergo 1-stage bilateral total hip arthroplasty (BTHA) and 1-stage bilateral total knee arthroplasty (BTKA) compared with patients who undergo 2-stage BTHA and BTKA. Methods: Our study cohorts included patients who underwent BTHA and BTKA between Apr. 1, 2009, and Jan. 31, 2016, in Alberta, Canada. To minimize selection bias associated with our retrospective study design, we matched patients who underwent 1-stage BTHA and BTKA with patients with patients who underwent 2-stage BTHA and BTKA, respectively, for age, sex and number of presurgical risk factors using propensity score in a matching ratio of 1:1. Results: Our study included 1645 patients who underwent BTHA and 4125 patients who underwent BTKA. We matched 195 patients who underwent 1-stage BTHA and 302 patients who underwent 1-stage BTKA with patients who underwent 2-stage BTHA and BTKA, respectively. There was no significant difference in postoperative medical adverse events between the 1-stage and 2-stage matched cohort groups for both BTHA (adjusted odds ratio [OR] 1.3, 95% confidence interval [CI] 0.3-4.9) and BTKA (adjusted OR 0.9, 95% CI 0.3-2.6). There was no difference in inpatient, 30- or 90-day mortality between the 2 groups for BTHA or BTKA. Patients who underwent 1-stage BTHA and BTKA had a shorter acute length of stay but increased total length of stay (acute care and rehabilitation unit) and were less likely to be discharged home postoperatively. One-stage BTHA and BTKA were associated with higher odds of blood transfusion than 2-stage BTHA and BTKA. The 30-day readmission rate was significantly lower for 1-stage BTHA than for the 2-stage BTHA matched cohort (adjusted OR 0.3, 95% CI 0.1-0.8), whereas there was no difference in the 30-day readmission rate (adjusted OR 0.6, 95% CI 0.2-1.7) between the 1-stage and 2-stage BTKA matched cohorts. Finally, operating room time was significantly lower for 1-stage BTHA (49.6 min less) and 1-stage BTKA (66.7 min less) than for the 2-stage arthroplasty procedures. Conclusion: Healthy patients who undergo 1-stage BTHA and BTKA have postoperative medical complication rates comparable to those of patients who undergo 2-stage procedures with the additional benefits of a shorter acute length of stay, but they do have a higher risk of blood transfusion and are less likely to be discharged directly home from the acute care hospital. A multicentre randomized controlled trial on this topic is currently being condcuted by the Canadian Arthroplasty Society.

Contexte: Les patients atteints d'arthrite bilatérale de la hanche ou du genou au stade terminal veulent savoir s'il est sécuritaire de subir une chirurgie bilatérale avec une seule anesthésie pour retrouver leur qualité de vie le plus rapidement possible. Le but de cette étude était de comparer le taux de complications postopératoires de nature médicale, la durée du séjour hospitalier, le taux de transfusions sanguines et le taux de réadmissions à 30 jours chez les patients selon que les arthroplasties totales de la hanche bilatérales (ATHB) et les arthroplasties totales du genou bilatérales (ATGB) se font en 1 étape ou en 2 étapes. Méthodes: Les cohortes de notre étude incluaient des patients qui ont subi des ATHB et des ATGB entre le 1er avril 2009 et le 31 janvier 2016 en Alberta, au Canada. Pour réduire le biais de sélection associé à notre protocole d'étude rétrospective, nous avons assorti les patients soumis aux ATHB et aux ATGB en 1 étape à ceux qui les ont subies en 2 étapes, respectivement, selon l'âge, le sexe et le nombre de facteurs de risque préopératoires, avec score de propension et rapport 1:1. Résultats: Notre étude a regroupé 1645 patients soumis à des ATHB et 4125 patients soumis à des ATGB. Nous avons assortis 195 patients soumis aux ATHB en 1 étape et 302 patients soumis aux ATGB en 1 étape avec des patients soumis à des ATHB et des ATGB en 2 étapes, respectivement. On n'a noté aucune différence significative quant aux complications postopératoires de nature médicale entre les groupes des cohortes assorties pour les interventions en 1 et en 2 étapes, tant avec les ATHB (rapport des cotes [RC] ajusté 1,3, intervalle de confiance [IC] de 95% 0,3­4,9), qu'avec les ATGB (RC ajusté 0,9, IC de 95% 0,3­2,6). Il n'y a pas eu de différences au plan de la mortalité à 30 jours ou à 90 jours chez les patients hospitalisés des 2 groupes avec les ATHB ou les ATGB. Les patients soumis aux ATHB et aux ATGB en 1 étape ont séjourné moins longtemps en soins actifs, mais la durée totale de leur séjour a été plus longue (soins actifs et réadaptation) et ils étaient moins susceptibles de retourner à la maison au moment de leur congé hospitalier après l'intervention. Les ATHB et les ATGB en 1 étape ont été associées à un risque plus grand de transfusions sanguines que les ATHB et les ATGB en 2 étapes. Le taux de réadmission à 30 jours a été significativement plus faible avec les ATHB en 1 étape que dans la cohorte assortie soumise aux ATHB en 2 étapes (RC ajusté 0,3, IC de 95% 0,1­0,8), tandis qu'il n'y a eu aucune différence au plan des taux de réadmission à 30 jours (RC ajusté 0,6, IC de 95% 0,2­1,7) entre les cohortes assorties soumises aux ATGB en 1 et 2 étapes. En terminant, le temps opératoire a été significativement plus bref avec les ATHB et les ATGB en 1 étape (respectivement 49,6 minutes et 66,7 minutes de moins) comparativement aux arthroplasties en 2 étapes. Conclusion: Les patients en bonne santé qui subissent des ATHB et des ATGB en 1 étape ont des taux de complications postopératoires de nature médicale comparables à ceux qui les subissent en 2 étapes, avec l'avantage additionnel d'un séjour hospitalier plus bref en soins actifs; mais ils sont exposés à un risque plus grand de transfusions sanguines et sont moins susceptibles de retourner directement à la maison en quittant l'hôpital de soins actifs. La Société canadienne d'arthroplastie procède actuellement à un essai randomisé et contrôlé multicentrique à ce sujet.

Does body mass index affect the rate of adverse outcomes in total hip and knee arthroplasty? A retrospective review of a total joint replacement database

Background: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are reliable surgical options to treat pain and disability resulting from degenerative conditions around the hip and knee. Obesity is a modifiable risk factor that contributes to significant morbidity. The purpose of this study was to retrospectively compare outcomes in primary hip and knee arthroplasty for patients with increased body mass index (BMI) and those with normal BMI, using data from the registry of the Alberta Bone and Joint Health Institute (ABJHI). Methods: We retrospectively reviewed the data compiled in the ABJHI registry between March 2010 and July 2016. We reviewed outcomes with respect to length of stay, discharge destination, 30-day readmission, postoperative infection, postoperative transfusion requirements, postoperative adverse events and in-hospital postoperative mechanical complications. Results: A total of 10 902 patients (6076 women, 4826 men) who underwent THA and 16 485 patients (10 057 women, 6428 men) who underwent TKA were included in the study. For both THA and TKA, patients with increased BMI had an increased number of in-hospital medical events, had an increased rate of deep infection, were less likely to be discharged home (p < 0.001) and had decreased transfusion requirements (p < 0.001) than patients whose weight was in the normal range. Increased BMI increased the rate of 30-day readmission and length of stay in the THA cohort but not in the TKA cohort. Increased BMI had no effect on acute postoperative dislocation or periprosthetic fractures. Patients with a BMI of 30 kg/m2 or greater required a THA 1.7 years earlier than patients of normal weight, patients whose BMI was 35 kg/m2 or greater required a THA 3.4 years earlier, and patients whose BMI was 40 kg/m2 or greater required a THA 5.8 years earlier. In the TKA cohort, patients with a BMI of 30 kg/m2 or greater required a TKA 2.7 years earlier than patients whose weight was in the normal range, patients with a BMI of 35 kg/m2 or greater required a TKA 4.6 years earlier, and patients whose BMI was 40 kg/m2 or greater required a TKA 7.6 years earlier. Conclusion: Our study quantifies the effects of obesity in primary hip and knee arthroplasty. It provides a greater understanding of the risks in the obese population when contemplating joint arthroplasty.

Contexte: La prothèse totale de la hanche (PTH) et la prothèse totale du genou (PTG) sont des options chirurgicales fiables pour traiter la douleur et l'invalidité résultant de maladies dégénératives de la hanche et du genou. L'obésité est un facteur de risque modifiable qui contribue significativement à la morbidité. Le but de cette étude était de comparer de manière rétrospective le résultat des interventions primaires pour prothèses de la hanche et du genou selon que les patients avaient un indice de masse corporelle (IMC) normal ou élevé à partir des données du registre de l'Alberta Bone and Joint Health Institute (ABJHI). Méthodes: Nous avons analysé de manière rétrospective les données compilées par le registre de l'ABJHI entre mars 2010 et juillet 2016. Nous avons passé en revue les paramètres suivants : durée du séjour hospitalier, destination post-congé, réadmissions dans les 30 jours, infections postopératoires, besoins transfusionnels postopératoires, complications postopératoires et complications mécaniques postopératoires perhospitalières. Résultats: En tout, 10 902 patients (6076 femmes, 4826 hommes) ayant subi une PTH et 16 485 patients (10 057 femmes, 6428 hommes) ayant subi une PTG ont été inclus dans l'étude. Tant pour la PTH que pour la PTG, les patients ayant un IMC élevé ont présenté un plus grand nombre de complications médicales en cours d'hospitalisation; ils ont aussi présenté un nombre plus élevé d'infections profondes, étaient moins susceptibles de pouvoir retourner chez eux au moment de leur congé (p < 0,001) et ont eu moins besoin de transfusions (p < 0,001) comparativement aux patients dont le poids se situait dans l'éventail des valeurs normales. L'IMC élevé a été en corrélation avec une augmentation du taux de réadmission à 30 jours et de la durée du séjour dans la cohorte soumise à une PTH, mais non dans la cohorte soumise à une PTG. L'IMC élevé n'a exercé aucun effet sur la dislocation postopératoire aiguë ou les fractures périprothétiques. Les patients ayant un IMC de 30 kg/m2 ou plus ont eu besoin d'une PTH 1,7 an plus tôt que les patients de poids normal, les patients ayant un IMC de 35 kg/m2 ou plus ont eu besoin d'une PTH 3,4 ans plus tôt, et les patients ayant un IMC de 40 kg/m2 ou plus ont eu besoin d'une PTH 5,8 ans plus tôt. Dans la cohorte soumise à la PTG, les patients ayant un IMC de 30 kg/m2 ou plus ont eu besoin d'une PTG 2,7 ans plus tôt que les patients de poids normal, les patients ayant un IMC de 35 kg/m2 ou plus ont eu besoin d'une PTG 4,6 ans plus tôt, et les patients ayant un IMC de 40 kg/m2 ou plus ont eu besoin d'une PTG 7,6 ans plus tôt. Conclusion: Notre étude quantifie les effets de l'obésité sur le recours aux interventions primaires pour prothèse de la hanche et du genou. Elle permet de mieux comprendre les risques auxquels est exposée la population obèse lorsqu'une intervention pour prothèse articulaire est envisagée.

Understanding the role of total knee arthroplasty for primary treatment of tibial plateau fracture: a systematic review of the literature.

BACKGROUND: Surgical fixation of tibial plateau fracture in elderly patients with open reduction and internal fixation (ORIF) provides inferior outcomes compared with younger patients. Primary total knee arthroplasty (TKA) may be of benefit in elderly patients with a combination of osteoporotic bone and metaphyseal comminution. However, there continues to be conflicting evidence on the use of TKA for primary treatment of tibial plateau fracture. This systematic review was performed to quantify the outcomes and perioperative complication rates of TKA for primary treatment of tibial plateau fracture. MATERIALS AND METHODS: A comprehensive search of MEDLINE, Embase, and PubMed databases from inception through March 2018 was performed in accordance with PRISMA guidelines. Two reviewers independently screened papers for inclusion and identified studies featuring perioperative complications and outcomes of primary TKA for tibial plateau fracture. Weighted means and standard deviations are presented for each outcome. RESULTS: Seven articles (105 patients) were eligible for inclusion. All-cause mortality was 4.75 ± 4.85%. The total complication rate was 15.2 ± 17.3%. Regarding outcomes, Knee Society scores were most commonly reported. The average Knee Society Knee Score was 85.6 ± 5.5, while the average Knee Society Function Score was 64.6 ± 13.7. Average range of motion at final follow-up was 107.5 ± 10.0°. CONCLUSIONS: Primary TKA for select tibial plateau fractures has acceptable clinical outcomes but does not appear to be superior to ORIF. It may be appropriate to treat certain geriatric patients with TKA to allow for early mobilization and reduce the need for reoperation. Other factors may need to be considered in deciding the optimal treatment. LEVEL OF EVIDENCE: Level III.

Intermittent v. continuous energy restriction: differential effects on postprandial glucose and lipid metabolism following matched weight loss in overweight/obese participants.

The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (>70 %) energy restriction (ER) interspersed with normal eating. Studies to date comparing IER to continuous energy restriction (CER) have predominantly measured fasting indices of cardiometabolic risk. This study aimed to compare the effects of IER and CER on postprandial glucose and lipid metabolism following matched weight loss. In all, twenty-seven (thirteen male) overweight/obese participants (46 (sem 3) years, 30·1 (sem 1·0) kg/m2) who were randomised to either an IER intervention (2638 kJ for 2 d/week with an overall ER of 22 (sem 0·3) %, n 15) or a CER intervention (2510 kJ below requirements with overall ER of 23 (sem 0·8) %) completed the study. Postprandial responses to a test meal (over 360 min) and changes in anthropometry (fat mass, fat-free mass, circumferences) were assessed at baseline and upon attainment of 5 % weight loss, following a 7-d period of weight stabilisation. The study found no statistically significant difference in the time to attain a 5 % weight loss between groups (median 59 d (interquartile range (IQR) 41-80) and 73 d (IQR 48-128), respectively, P=0·246), or in body composition (P≥0·437). For postprandial measures, neither diet significantly altered glycaemia (P=0·266), whereas insulinaemia was reduced comparatively (P=0·903). The reduction in C-peptide tended (P=0·057) to be greater following IER (309 128 (sem23 268) to 247781 (sem20 709) pmol×360 min/l) v. CER (297 204 (sem25 112) to 301 655 (sem32 714) pmol×360 min/l). The relative reduction in TAG responses was greater (P=0·045) following IER (106 (sem30) to 68 (sem 15) mmol×360 min/l) compared with CER (117 (sem 43) to 130 (sem 31) mmol×360 min/l). In conclusion, these preliminary findings highlight underlying differences between IER and CER, including a superiority of IER in reducing postprandial lipaemia, which now warrant targeted mechanistic evaluation within larger study cohorts.

An Item Bank for Abuse of Prescription Pain Medication from the Patient-Reported Outcomes Measurement Information System (PROMIS®).

OBJECTIVE: There is a need to monitor patients receiving prescription opioids to detect possible signs of abuse. To address this need, we developed and calibrated an item bank for severity of abuse of prescription pain medication as part of the Patient-Reported Outcomes Measurement Information System (PROMIS ® ). METHODS: Comprehensive literature searches yielded an initial bank of 5,310 items relevant to substance use and abuse, including abuse of prescription pain medication, from over 80 unique instruments. After qualitative item analysis (i.e., focus groups, cognitive interviewing, expert review, and item revision), 25 items for abuse of prescribed pain medication were included in field testing. Items were written in a first-person, past-tense format, with a three-month time frame and five response options reflecting frequency or severity. The calibration sample included 448 respondents, 367 from the general population (ascertained through an internet panel) and 81 from community treatment programs participating in the National Drug Abuse Treatment Clinical Trials Network. RESULTS: A final bank of 22 items was calibrated using the two-parameter graded response model from item response theory. A seven-item static short form was also developed. The test information curve showed that the PROMIS ® item bank for abuse of prescription pain medication provided substantial information in a broad range of severity. CONCLUSION: The initial psychometric characteristics of the item bank support its use as a computerized adaptive test or short form, with either version providing a brief, precise, and efficient measure relevant to both clinical and community samples.

Investigation into the acute effects of total and partial energy restriction on postprandial metabolism among overweight/obese participants.

The intermittent energy restriction (IER) approach to weight loss involves short periods of substantial (75-100 %) energy restriction (ER) interspersed with normal eating. This study aimed to characterise the early metabolic response to these varying degrees of ER, which occurs acutely and prior to weight loss. Ten (three female) healthy, overweight/obese participants (36 (SEM 5) years; 29·0 (sem 1·1) kg/m2) took part in this acute three-way cross-over study. Participants completed three 1-d dietary interventions in a randomised order with a 1-week washout period: isoenergetic intake, partial 75 % ER and total 100 % ER. Fasting and postprandial (6-h) metabolic responses to a liquid test meal were assessed the following morning via serial blood sampling and indirect calorimetry. Food intake was also recorded for two subsequent days of ad libitum intake. Relative to the isoenergetic control, postprandial glucose responses were increased following total ER (+142 %; P=0·015) and to a lesser extent after partial ER (+76 %; P=0·051). There was also a delay in the glucose time to peak after total ER only (P=0·024). Both total and partial ER interventions produced comparable reductions in postprandial TAG responses (-75 and -59 %, respectively; both P<0·05) and 3-d energy intake deficits of approximately 30 % (both P=0·015). Resting and meal-induced thermogenesis were not significantly affected by either ER intervention. In conclusion, our data demonstrate the ability of substantial ER to acutely alter postprandial glucose-lipid metabolism (with partial ER producing the more favourable overall response), as well as incomplete energy-intake compensation amongst overweight/obese participants. Further investigations are required to establish how metabolism adapts over time to the repeated perturbations experienced during IER, as well as the implications for long-term health.

Evaluating PROMIS® instruments and methods for patient-centered outcomes research: Patient and provider voices in a substance use treatment setting.

PURPOSE: Our work as a primary research site of the Patient-Reported Outcomes Measurement Information System (PROMIS®), combined with support from the Patient-Centered Outcomes Research Institute, allowed us to evaluate the real-world applicability and acceptability of PROMIS measures in an addiction medicine setting. METHODS: As part of a 3-month prospective observational study, 225 outpatients at a substance abuse treatment clinic completed PROMIS item banks for alcohol use (as well as 15 additional item banks from 8 other PROMIS domains, including emotional distress, sleep, and pain), with assessments at intake, 1-month follow-up, and 3-month follow-up. A subsample of therapists and their patients completed health domain importance ratings and qualitative interviews to elicit feedback regarding the content and format of the patients' assessment results. RESULTS: The importance ratings revealed that depression, anxiety, and lack of emotional support were rated highest of the non-alcohol-related domains among both patients and clinicians. General alcohol use was considered most important by both patients and clinicians. Based on their suggestions, changes were made to item response feedback to facilitate comprehension and communication. CONCLUSIONS: Both therapists and patients agreed that their review of the graphical display of scores, as well as individual item responses, helped them to identify areas of greatest concern and was useful for treatment planning. The results of our pilot work demonstrated the value and practicality of incorporating a comprehensive health assessment within a substance abuse treatment setting.

Measuring nonspecific factors in treatment: item banks that assess the healthcare experience and attitudes from the patient's perspective.

PURPOSE: Nonspecific factors that accompany healthcare treatments, such as patients' attitudes and expectations, are important parts of the experience of care and can influence outcomes. However, no precise, concise, and generalizable instruments to measure these factors exist. We report on the development and calibration of new item banks, titled the Healing Encounters and Attitudes Lists (HEAL), that assess nonspecific factors across a broad range of treatments and conditions. METHODS: The instrument development methodology of the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) was used. Patient focus groups and clinician interviews informed our HEAL conceptual model. Literature searches of eight databases yielded over 500 instruments and resulted in an initial item pool of several thousand items. After qualitative item analysis, including cognitive interviewing, 296 items were included in field testing. The calibration sample included 1657 respondents, 1400 obtained through an Internet panel and 257 from conventional and integrative medicine clinics. Following exploratory and confirmatory factor analyses, the HEAL item banks were calibrated using item response theory. RESULTS: The final HEAL item banks were Patient-Provider Connection (57 items), Healthcare Environment (25 items), Treatment Expectancy (27 items), Positive Outlook (27 items), and Spirituality (26 items). Short forms were also developed from each item bank. A six-item short form, Attitudes toward Complementary and Alternative Medicine (CAM), was also created. CONCLUSIONS: HEAL item banks provided substantial information across a broad range of each construct. HEAL item banks showed initial evidence of predictive and concurrent validity, suggesting that they are suitable for measuring nonspecific factors in treatment.

Anesthesia for hip arthroscopy: a narrative review.

PURPOSE: Hip arthroscopy is a minimally invasive surgical procedure indicated for the treatment of specific hip disorders. In this narrative review, we aim to examine the key components in providing anesthesia for this procedure. SOURCE: MEDLINE(®), PubMed, and EMBASE™ databases were searched for peer-reviewed articles discussing the anesthetic management of patients undergoing hip arthroscopy. PRINCIPAL FINDINGS: The primary anesthetic regimen used for hip arthroscopy should balance patient factors, preferences of the surgeon, and the demands of the procedure itself. Both general and neuraxial anesthetic techniques are well suited for this mostly ambulatory surgical procedure. There is a lack of current literature specifically comparing the benefits and risks of the two techniques in this setting. Postoperative pain management consists mainly of intravenous and oral opioids; however, a variety of regional anesthesia techniques, such as lumbar plexus block and fascia iliaca block, can be performed pre- or postoperatively. Overall, hip arthroscopy is safe, although positioning-related difficulties, extravasation of irrigation fluid, hypothermia, infections, and thromboembolic events are potential perioperative complications that warrant specific monitoring and prompt treatment. CONCLUSIONS: Until now, the anesthetic technique for hip arthroscopy has not been well studied. Thus, increasing emphasis should be directed towards examining relevant clinical outcomes that can better inform evidence-based decision-making in the anesthetic management of hip arthroscopy patients. In the meantime, awareness of potential complications and vigilant monitoring are paramount in providing safe anesthetic care for patients undergoing hip arthroscopy.

Wolbachia filarial interactions.

Wolbachia pipientis is a widespread intracellular bacterial symbiont of arthropods and is common in insects. One of their more exotic and unexpected hosts is the filarial nematodes, notable for the parasites responsible for onchocerciasis (river blindness), lymphatic filariasis (elephantiasis) and dirofilariasis (heartworm). Wolbachia are only present in a subgroup of the filarial nematodes and do not extend to other groups of nematodes either parasitic or free-living. In the medically and veterinary important species that host Wolbachia, the symbiont has become an essential partner to key biological processes in the life of the nematode to the point where antibiotic elimination of the bacteria leads to a potent and effective anti-filarial drug treatment. We review the cellular and molecular basis of Wolbachia filarial interactions and highlight the key processes provided by the endosymbiont upon which the nematodes have become entirely dependent. This dependency is primarily restricted to periods of the lifecycle with heavy metabolic demands including growth and development of larval stages and embryogenesis in the adult female. Also, the longevity of filarial parasites is compromised following depletion of the symbiont, which for the first time has delivered a safe and effective treatment to kill adult parasites with antibiotics.

Targeting a microbiota Wolbachian aminoacyl-tRNA synthetase to block its pathogenic host.

The interplay between humans and their microbiome is crucial for various physiological processes, including nutrient absorption, immune defense, and maintaining homeostasis. Microbiome alterations can directly contribute to diseases or heighten their likelihood. This relationship extends beyond humans; microbiota play vital roles in other organisms, including eukaryotic pathogens causing severe diseases. Notably, Wolbachia, a bacterial microbiota, is essential for parasitic worms responsible for lymphatic filariasis and onchocerciasis, devastating human illnesses. Given the lack of rapid cures for these infections and the limitations of current treatments, new drugs are imperative. Here, we disrupt Wolbachia's symbiosis with pathogens using boron-based compounds targeting an unprecedented Wolbachia enzyme, leucyl-tRNA synthetase (LeuRS), effectively inhibiting its growth. Through a compound demonstrating anti-Wolbachia efficacy in infected cells, we use biophysical experiments and x-ray crystallography to elucidate the mechanism behind Wolbachia LeuRS inhibition. We reveal that these compounds form adenosine-based adducts inhibiting protein synthesis. Overall, our study underscores the potential of disrupting key microbiota to control infections.

Extensively duplicated and transcriptionally active recent lateral gene transfer from a bacterial Wolbachia endosymbiont to its host filarial nematode Brugia malayi.

BACKGROUND: Lymphatic filariasis is a neglected tropical disease afflicting more than 120 million people, while another 1.3 billion people are at risk of infection. The nematode worm Brugia malayi is one of the causative agents of the disease and exists in a mutualistic symbiosis with Wolbachia bacteria. Since extensive lateral gene transfer occurs frequently between Wolbachia and its hosts, we sought to measure the extent of such LGT in B. malayi by whole genome sequencing of Wolbachia-depleted worms. RESULTS: A considerable fraction (at least 115.4-kbp, or 10.6%) of the 1.08-Mbp Wolbachia wBm genome has been transferred to its nematode host and retains high levels of similarity, including 227 wBm genes and gene fragments. Complete open reading frames were transferred for 32 of these genes, meaning they have the potential to produce functional proteins. Moreover, four transfers have evidence of life stage-specific regulation of transcription at levels similar to other nematode transcripts, strengthening the possibility that they are functional. CONCLUSIONS: There is extensive and ongoing transfer of Wolbachia DNA to the worm genome and some transfers are transcribed in a stage-specific manner at biologically relevant levels.

Requirement of lipid II biosynthesis for cell division in cell wall-less Wolbachia, endobacteria of arthropods and filarial nematodes.

Obligate Wolbachia endobacteria have a reduced genome and retained genes are hypothesized to be crucial for survival. Although intracellular bacteria do not need a stress-bearing peptidoglycan cell wall, Wolbachia encode proteins necessary to synthesize the peptidoglycan precursor lipid II. The activity of the enzymes catalyzing the last two steps of this pathway was previously shown, and Wolbachia are sensitive to inhibition of lipid II synthesis. A puzzling characteristic of Wolbachia is the lack of genes for l-amino acid racemases essential for lipid II synthesis. Transcription analysis showed the expression of a possible alternative racemase metC, and recombinant Wolbachia MetC indeed had racemase activity that may substitute for the absent l-Ala racemase. However, enzymes needed to form mature peptidoglycan are absent and the function of Wolbachia lipid II is unknown. Inhibition of lipid II biosynthesis resulted in enlargement of Wolbachia cells and redistribution of Wolbachia peptidoglycan-associated lipoprotein, demonstrating that lipid II is required for coordinated cell division and may interact with the lipoprotein. We conclude that lipid II is essential for Wolbachia cell division and that this function is potentially conserved in the Gram-negative bacteria.

Corallopyronin A specifically targets and depletes essential obligate Wolbachia endobacteria from filarial nematodes in vivo.

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases. Corallococcus coralloides synthesizes corallopyronin A, a noncompetitive inhibitor of RNA polymerase ineffective against Mycobacterium spp. Corallopyronin A depleted Wolbachia from infected insect cells (1.89 Thus the antibiotic is effective against intracellular bacteria despite the many intervening surfaces (blood vessels, pleura, worm cuticle) and membranes (worm cell, vesicle, Wolbachia inner and outer membranes). Corallopyronin A is an antibiotic to develop further for filariasis elimination without concern for cross-resistance development in tuberculosis.