Asia-Pacific consensus on long-term and sequential therapy for osteoporosis.

Objectives: This study aimed to present the Asia-Pacific consensus on long-term and sequential therapy for osteoporosis, offering evidence-based recommendations for the effective management of this chronic condition. The primary focus is on achieving optimal fracture prevention through a comprehensive, individualized approach. Methods: A panel of experts convened to develop consensus statements by synthesizing the current literature and leveraging clinical expertise. The review encompassed long-term anti-osteoporosis medication goals, first-line treatments for individuals at very high fracture risk, and the strategic integration of anabolic and antiresorptive agents in sequential therapy approaches. Results: The panelists reached a consensus on 12 statements. Key recommendations included advocating for anabolic agents as the first-line treatment for individuals at very high fracture risk and transitioning to antiresorptive agents following the completion of anabolic therapy. Anabolic therapy remains an option for individuals experiencing new fractures or persistent high fracture risk despite antiresorptive treatment. In cases of inadequate response, the consensus recommended considering a switch to more potent medications. The consensus also addressed the management of medication-related complications, proposing alternatives instead of discontinuation of treatment. Conclusions: This consensus provides a comprehensive, cost-effective strategy for fracture prevention with an emphasis on shared decision-making and the incorporation of country-specific case management systems, such as fracture liaison services. It serves as a valuable guide for healthcare professionals in the Asia-Pacific region, contributing to the ongoing evolution of osteoporosis management.

Experimental and computational understanding of pulsatile release mechanism from biodegradable core-shell microparticles.

Next-generation therapeutics require advanced drug delivery platforms with precise control over morphology and release kinetics. A recently developed microfabrication technique enables fabrication of a new class of injectable microparticles with a hollow core-shell structure that displays pulsatile release kinetics, providing such capabilities. Here, we study this technology and the resulting core-shell microstructures. We demonstrated that pulsatile release is governed by a sudden increase in porosity of the polymeric matrix, leading to the formation of a porous path connecting the core to the environment. Moreover, the release kinetics within the range studied remained primarily independent of the particle geometry but highly dependent on its composition. A qualitative technique was developed to study the pattern of pH evolution in the particles. A computational model successfully modeled deformations, indicating sudden expansion of the particle before onset of release. Results of this study contribute to the understanding and design of advanced drug delivery systems.

Lipase-catalyzed esterification in water enabled by nanomicelles. Applications to 1-pot multi-step sequences.

Esterification in an aqueous micellar medium is catalyzed by a commercially available lipase in the absence of any co-factors. The presence of only 2 wt% designer surfactant, TPGS-750-M, assists in a 100% selective enzymatic process in which only primary alcohols participate (in a 1 : 1 ratio with carboxylic acid). An unexpected finding is also disclosed where the simple additive, PhCF3 (1 equiv. vs. substrate), appears to significantly extend the scope of usable acid/alcohol combinations. Taken together, several chemo- and bio-catalyzed 1-pot, multi-step reactions can now be performed in water.

2021 Asia-Pacific League of Associations for Rheumatology clinical practice guideline for treatment of gout.

BACKGROUND: Gout is the most prevalent inflammatory arthritis in the Asia-Pacific region and worldwide. This clinical practice guideline (CPG) aims to provide recommendations based on systematically obtained evidence and values and preferences tailored to the unique needs of patients with gout and hyperuricemia in Asia, Australasia, and the Middle East. The target users of these guidelines are general practitioners and specialists, including rheumatologists, in these regions. METHODS: Relevant clinical questions were formulated by the Steering Committee. Systematic reviews of evidence were done, and certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation methodology. A multi-sectoral consensus panel formulated the final recommendations. RESULTS: The Asia-Pacific League of Associations for Rheumatology Task Force developed this CPG for treatment of gout with 3 overarching principles and 22 recommendation statements that covered the treatment of asymptomatic hyperuricemia (2 statements), treatment of acute gout (4 statements), prophylaxis against gout flare when initiating urate-lowering therapy (3 statements), urate-lowering therapy (3 statements), treatment of chronic tophaceous gout (2 statements), treatment of complicated gout and non-responders (2 statements), treatment of gout with moderate to severe renal impairment (1 statement), and non-pharmacologic interventions (5 statements). CONCLUSION: Recommendations for clinically relevant scenarios in the management of gout were formulated to guide physicians in administering individualized care.

Intervention thresholds to identify postmenopausal women with high fracture risk: A single center study based on the Philippines FRAX model.

OBJECTIVES: This study is designed to estimate appropriate intervention thresholds for the Philippines Fracture Risk Assessment Tool (FRAX) model to identify postmenopausal women with high fracture risk. METHODS: Age dependent intervention thresholds were calculated for a woman of body mass index 25 kg/m2 aged 50-80 years with a previous fragility fracture without other clinical risk factors. Fixed thresholds were developed using a database of 1546 postmenopausal women who underwent dual-energy X-ray absorptiometry for clinical reasons. Major and hip fracture risks were estimated using clinical risk factors with and without bone mineral density (BMD) input. Women were categorized to high risk and low risk groups according to the age dependent thresholds. The best cut-points were determined considering the optimum sensitivity and specificity using receiver operating characteristic analysis. RESULTS: The age dependent intervention thresholds of major fracture risk ranged from 2.8 to 6.9% while hip fracture risk ranged from 0.4 to 3.0% between 50 and 80 years of age. Major fracture threshold of 3.75% and hip fracture threshold of 1.25% were the best fixed thresholds observed and non-inclusion BMD in the fracture risk estimations did not change the values. As a hybrid method, 3% major fracture and 1% hip fracture risks for those < 70 years old and age-dependent thresholds for those aged 70 years and above can be recommended. CONCLUSIONS: The intervention thresholds estimated in the current study can be applied to identify Filipino postmenopausal women with a high fracture risk. Clinicians should decide on the type of thresholds most appropriate.

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend.

A review presenting water as the logical reaction medium for the future of organic chemistry. A discussion is offered that covers both the "on water" and "in water" phenomena, and how water is playing unique roles in each, specifically with regard to its use in organic synthesis.

Immersive Video Modeling Versus Traditional Video Modeling for Teaching Central Venous Catheter Insertion to Medical Residents.

Background  Central Venous Catheter (CVC) placement is a common critical care procedure. Simulated practice has been shown to reduce its iatrogenic complications. Video modeling (VM) is an instructional adjunct that improves the quality and success of CVC insertion. Immersive VM can improve recall and skill translation, but its role in teaching medical procedures is not established. Research question/hypothesis We hypothesized that, relative to traditional VM, immersive VM would decrease cognitive load and enhance ultrasound-guided CVC insertion skill acquisition. Methods Thirty-two resident physicians from four specialties were randomized into traditional (control) or immersive VM (intervention) groups for three CVC training sessions. Cognitive load was quantified via NASA Task Load Index (TLX). Mean (± standard deviations) values were compared using two-tailed t-tests. Skill acquisition was quantified by procedural time and the average 5-point [EM1] [TB2] entrustment score of three expert raters. Results Overall entrustment scores improved from the first (3.44±0.98) to the third (4.06±1.23; p<0.002) session but were not significantly different between the control and intervention groups. There were no significant differences between NASA TLX scores or procedural time. Conclusion We found no significant difference in entrustment, cognitive load, or procedural time. Immersive VM was not found to be superior to traditional VM for teaching CVC insertion.

Water-Sculpting of a Heterogeneous Nanoparticle Precatalyst for Mizoroki-Heck Couplings under Aqueous Micellar Catalysis Conditions.

Powdery, spherical nanoparticles (NPs) containing ppm levels of palladium ligated by t-Bu3P, derived from FeCl3, upon simple exposure to water undergo a remarkable alteration in their morphology leading to nanorods that catalyze Mizoroki-Heck (MH) couplings. Such NP alteration is general, shown to occur with three unrelated phosphine ligand-containing NPs. Each catalyst has been studied using X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), and cryogenic transmission electron microscopy (cryo-TEM) analyses. Couplings that rely specifically on NPs containing t-Bu3P-ligated Pd occur under aqueous micellar catalysis conditions between room temperature and 45 °C, and show broad substrate scope. Other key features associated with this new technology include low residual Pd in the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a member of the Hancock family of alkaloids, is suggestive of potential industrial applications.

Renal microvascular oxygen tension during hyperoxia and acute hemodilution assessed by phosphorescence quenching and excitation with blue and red light.

PURPOSE: The kidney plays a central physiologic role as an oxygen sensor. Nevertheless, the direct mechanism by which this occurs is incompletely understood. We measured renal microvascular partial pressure of oxygen (PkO2) to determine the impact of clinically relevant conditions that acutely change PkO2 including hyperoxia and hemodilution. METHODS: We utilized two-wavelength excitation (red and blue spectrum) of the intravascular phosphorescent oxygen sensitive probe Oxyphor PdG4 to measure renal tissue PO2 in anesthetized rats (2% isoflurane, n = 6) under two conditions of altered arterial blood oxygen content (CaO2): 1) hyperoxia (fractional inspired oxygen 21%, 30%, and 50%) and 2) acute hemodilutional anemia (baseline, 25% and 50% acute hemodilution). The mean arterial blood pressure (MAP), rectal temperature, arterial blood gases (ABGs), and chemistry (radiometer) were measured under each condition. Blue and red light enabled measurement of PkO2 in the superficial renal cortex and deeper cortical and medullary tissue, respectively. RESULTS: PkO2 was higher in the superficial renal cortex (~ 60 mmHg, blue light) relative to the deeper renal cortex and outer medulla (~ 45 mmHg, red light). Hyperoxia resulted in a proportional increase in PkO2 values while hemodilution decreased microvascular PkO2 in a linear manner in both superficial and deeper regions of the kidney. In both cases (blue and red light), PkO2 correlated with CaO2 but not with MAP. CONCLUSION: The observed linear relationship between CaO2 and PkO2 shows the biological function of the kidney as a quantitative sensor of anemic hypoxia and hyperoxia. A better understanding of the impact of changes in PkO2 may inform clinical practices to improve renal oxygen delivery and prevent acute kidney injury.

RéSUMé: OBJECTIF: Les reins jouent un rôle physiologique central en tant que détecteurs d'oxygène. Cependant, le mécanisme direct de ce rôle n'est pas complètement compris. Nous avons mesuré la pression partielle d'oxygène microvasculaire rénal (PkO2) afin de déterminer l'impact de conditions pertinentes d'un point de vue clinique qui modifient de façon aiguë la PkO2, y compris l'hyperoxie et l'hémodilution. MéTHODE: Nous avons utilisé l'excitation à deux longueurs d'onde (spectres rouge et bleu) de la sonde phosphorescente, sensible à l'oxygène, intravasculaire Oxyphor PdG4 afin de mesurer la PO2 dans le tissu rénal de rats sous anesthésie (isoflurane 2 %, n = 6) dans deux conditions de contenu en oxygène du sang artériel (CaO2) altéré : 1) hyperoxie (fraction d'oxygène inspiré 21 %, 30 % et 50 %) et 2) anémie par hémodilution aiguë (valeurs de base, hémodilution aiguë 25 % et 50 %). La tension artérielle moyenne (TAM), la température rectale, les gaz sanguins artériels et la chimie (radiomètre) ont été mesurés dans chacune des conditions. Les lumières bleue et rouge ont permis de mesurer la PkO2 dans le cortex rénal superficiel et les tissus cortical et médullaire plus profonds, respectivement. RéSULTATS: La PkO2 était plus élevée dans le cortex rénal superficiel (~ 60 mmHg, lumière bleue) comparativement au cortex rénal plus profond et à la zone médullaire extérieure (~ 45 mmHg, lumière rouge). L'hyperoxie a entraîné une augmentation proportionnelle des valeurs de PkO2, alors que l'hémodilution a diminué la PkO2 microvasculaire de façon linéaire tant dans les régions rénales superficielles que plus profondes. Dans les deux cas (lumières bleue et rouge), la PkO2 était corrélée au CaO2 mais pas à la TAM. CONCLUSION: La relation linéaire observée entre le CaO2 et la PkO2 montre la fonction biologique du rein en tant que détecteur quantitatif de l'hypoxie anémique et de l'hyperoxie. Une meilleure compréhension de l'impact des changements de la PkO2 pourrait guider les pratiques cliniques afin d'améliorer la distribution d'oxygène aux reins et prévenir l'insuffisance rénale aiguë.

Anesthesia in the modern world of apps and technology: Implications and impact on wellness.

Recent decades have seen an unprecedented leap in digital innovation, with far-reaching implications in healthcare. Anesthesiologists have historically championed the adoption of new technologies. However, the rapid evolution of these technologies has outpaced attempts at studying their potential impact on healthcare providers' well-being. This document introduces several categories of workplace technologies commonly encountered by the anesthesiologist. We examine examples of novel technology and the impact of these digital interventions on the anesthesiologist's well-being. We also review popular personalized technology aimed at improving wellness and the impact on well-being examined. Finally, technology acceptance models are introduced to improve technology adoption, which, when appropriately applied, may minimize the negative impacts of technology on anesthesiologists' well-being. Incorporating quantitative, serial assessments of well-being as part of technology implementation are proposed as a future direction for examining the wellness impact of technology on anesthesiologists.

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study.

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001-012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16-74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi.

Superselective Removal of Lead from Water by Two-Dimensional MoS2 Nanosheets and Layer-Stacked Membranes.

Point-of-use (POU) devices with satisfactory lead (Pb2+) removal performance are urgently needed in response to recent outbreaks of lead contamination in drinking water. This study experimentally demonstrated the excellent lead removal capability of two-dimensional (2D) MoS2 nanosheets in aqueous form and as part of a layer-stacked membrane. Among all materials ever reported in the literature, MoS2 nanosheets exhibit the highest adsorption capacity (740 mg/g), and the strongest selectivity/affinity toward Pb2+ with a distribution coefficient Kd that is orders of magnitude higher than that of other lead adsorption materials (5.2 × 107 mL/g). Density functional theory (DFT) simulation was performed to complement experimental measurements and to help understand the adsorption mechanisms. The results confirmed that the cation selectivity of MoS2 follows the order Pb2+ > Cu2+ ≫ Cd2+ > Zn2+, Ni2+ > Mg2+, K+, Ca2+. The membrane formed with layer-stacked MoS2 nanosheets exhibited a high water flux (145 L/m2/h/bar), while effectively decreasing Pb2+ concentration in drinking water from a few mg/L to less than 10 µg/L. The removal capacity of the MoS2 membrane is a few orders of magnitude higher than that of other literature-reported membrane filters. Therefore, the layer-stacked MoS2 membrane has great potential for POU removal of lead from drinking water.

Pediatric Airway Management in COVID-19 Patients: Consensus Guidelines From the Society for Pediatric Anesthesia's Pediatric Difficult Intubation Collaborative and the Canadian Pediatric Anesthesia Society.

The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) pandemic has challenged medical systems and clinicians globally to unforeseen levels. Rapid spread of COVID-19 has forced clinicians to care for patients with a highly contagious disease without evidence-based guidelines. Using a virtual modified nominal group technique, the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from 6 countries, generated consensus guidelines on airway management in pediatric anesthesia based on expert opinion and early data about the disease. PeDI-C identified overarching goals during care, including minimizing aerosolized respiratory secretions, minimizing the number of clinicians in contact with a patient, and recognizing that undiagnosed asymptomatic patients may shed the virus and infect health care workers. Recommendations include administering anxiolytic medications, intravenous anesthetic inductions, tracheal intubation using video laryngoscopes and cuffed tracheal tubes, use of in-line suction catheters, and modifying workflow to recover patients from anesthesia in the operating room. Importantly, PeDI-C recommends that anesthesiologists consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19. Airway procedures should be done in negative pressure rooms when available. Adequate time should be allowed for operating room cleaning and air filtration between surgical cases. Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic. Until further information is available, PeDI-C advises that clinicians consider these guidelines to enhance the safety of health care workers during airway management when performing aerosol-generating medical procedures. These guidelines have been endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society.

Video Modeling and Video Feedback to Reduce Time to Perform Intravenous Cannulation in Medical Students: A Randomized-Controlled Mixed-Methods Study.

PURPOSE: Combined video modeling (VM) and video feedback (VF) may be more beneficial than traditional feedback when teaching procedural skills. This study examined whether repeated VM and VF compared with VM alone reduced the time required for medical students to perform peripheral intravenous (IV) cannulation. METHODS: Twenty-five novice medical students were randomly assigned to groups in a one-way blinded embedded mixed-methods study to perform IV cannulation. Participants received standardized instruction and performed IV cannulation on each other while being audio-video recorded. They were assigned to review a video of an expert performing IV cannulation (VM alone), or both the expert video and a video of their own most recent IV cannulation (VM+VF), before returning to perform another IV cannulation. This was repeated for a total of four IV cannulation encounters and three video reviews. A post-test interview was also conducted and analyzed qualitatively using thematic content analysis. RESULTS: The median [interquartile range] time required to perform IV cannulation in the final encounter was significantly different between the VM+VF group vs VM alone group (126 [93-226] sec vs 345 [131-537] sec, respectively; median difference, 111 sec; 95% confidence interval, 8 to 391; P = 0.02). There was no significant difference in IV cannulation success between VM alone and VM+VF in the final encounter (75% vs 85% respectively; P = 0.65). For the VM+VF group, the time to perform IV cannulation was reduced after the final encounter compared with the baseline encounter (P = 0.002), which was not true of the VM alone group (P = 0.35). CONCLUSION: Video modeling and feedback shortened time to IV skill completion, reduced complications, and improved satisfaction in novice medical students.

RéSUMé: OBJECTIF: La combinaison d'une vidéo de démonstration (VD) et d'une vidéo de rétroaction (VR) pourrait être plus efficace que la rétroaction traditionnelle pour l'enseignement des habiletés nécessaires pour des procédures. Cette étude a cherché à savoir si la répétition d'une VD et d'une VR réduisait davantage le temps nécessaire à des étudiants en médecine pour effectuer une canulation intraveineuse périphérique (IV) par rapport à la seule VD. MéTHODES: Vingt-cinq étudiants en médecine novices ont été assignés par randomisation à des groupes d'une étude utilisant différentes méthodes intégrées d'apprentissage avec insu unilatéral pour la réalisation d'une canulation IV. Les participants ont reçu un enseignement standardisé et ont réalisé une canulation IV sur un autre participant tout en étant filmés (audio-vidéo). Selon leur groupe, ils devaient visionner la vidéo d'un expert effectuant une canulation IV (groupe VD uniquement) ou voir la vidéo de l'expert et une vidéo de leur plus récente canulation IV (groupe VD + VR) avant d'effectuer une autre canulation IV. La procédure a été répétée (total de 4 tentatives de canulations et 3 séances de vidéos). Un entretien post test a été également mené et analysé du point de vue qualitatif au moyen d'une analyse thématique du contenu. RéSULTATS: Le temps médian [plage interquartile] nécessaire pour effectuer la canulation IV au cours de la dernière tentative a été significativement différent entre le groupe VD+VR et le groupe VD seule (respectivement, 126 secondes [93 à 226 s] contre 345 s [131 à 537 s]; différence des médianes, 111 s; intervalle de confiance à 95 % : 8 à 391; P = 0,02). Il n'y a pas eu de différence significative entre le taux de réussite des canulations entre le groupe VD seule et le groupe VD+VR (respectivement, 75 % contre 85 %; P = 0,65). Pour le groupe VD+VR, le temps nécessaire à la canulation IV au moment de la dernière tentative a été plus court par rapport au temps mis au cours de la première tentative (P = 0,002), ce qui n'a pas été le cas pour le groupe VD seule (P = 0,35). CONCLUSION: La vidéo de démonstration et la vidéo de rétroaction ont permis de raccourcir le temps de réalisation des habiletés d'une canulation IV, ont réduit les complications et amélioré la satisfaction des étudiants en médecine novices.

Postpartum Breastfeeding and Cardiovascular Risk Assessment in Women Following Pregnancy Complications.

Background: Breastfeeding is associated with lower cardiovascular (CV) risk over the long-term, however, less is known about its immediate effects among women with a recent complicated pregnancy. The objective of this study is to investigate the short-term effects of breastfeeding on markers of cardiovascular disease risk among women ∼6 months after a pregnancy complicated by a hypertensive disorder, gestational diabetes, intrauterine growth restriction, abruption, or preterm birth. Materials and Methods: Our cross-sectional analysis includes 622 women seen at 6 months postpartum (interquartile range: 5.7-6.7) between November 2011 and December 2017 at a tertiary care center. Self-reported breastfeeding status and measured CV risk factors were assessed at the same visit. CV risk factors were compared between women who did not breastfeed (n = 100, 16%), those who breastfed for less than 6 months (n = 315, 51%), and those who breastfed for 6 months or more (n = 207, 33%) using multivariate logistic and linear regression. Results: Increased breastfeeding duration significantly decreased the likelihood of metabolic syndrome (adjusted odds ratio [95% confidence interval; CI]: 0.89 [0.79-0.99]), abnormal fasting glucose (0.79 [0.64-0.96]), and ratio of total cholesterol to high-density lipoprotein-cholesterol (HDL-C) (0.86 [0.78-0.95]). Furthermore, body mass index (estimated beta coefficients [95% CI] -0.10 [-0.18 to -0.02]), fasting glucose (-0.05 [-0.08 to -0.02]), triglycerides (-0.07 [-0.10 to -0.04]), and ratio of total cholesterol to HDL-C (-0.06 [-0.10 to -0.03]) also decreased with increased breastfeeding duration, while HDL-C increased (0.02 [-0.01 to -0.04]). Conclusions: Our findings suggest that breastfeeding is associated with decreased indicators of CV risk in a cohort of women with recent pregnancy complication.

Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.

BACKGROUND: Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS: We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS: Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4+CD25+FoxP3+ regulatory T cells and CD8+ memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4-CD8- double-negative T cells after 12 months. CD8+ memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). INTERPRETATION: These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. FUNDING: Pfizer, the National Institutes of Health, and the Central New York Community Foundation.