Corticosteroids or platelet-rich plasma injections for rotator cuff tendinopathy: a randomized clinical trial study

Background: Studies evaluating the role of both corticosteroids and platelet-rich plasma (PRP) in the treatment of rotator cuff (RC) tendinopathies have been contradicting. We compared structural and clinical changes in RC muscles after corticosteroids and PRP injections. Methods: This is a randomized double-blind clinical trial. All individuals with diagnosis of RC tendinitis during 2014�2017 were considered. Individuals were randomly allocated to either receive PRP or corticosteroids. Overall, 3cc of PRP was injected within the subacromial joint and another 3cc was injected at the site of the tendon tear, under the guide of sonography. For the corticosteroid group, 1cc of Depo-medrol 40mg and 1cc of lidocaine (2) was injected within the subacromial joint. Results: Overall, 58 patients entered the study. Comparison of pain, range of motion (ROM), Western Ontario RC (WORC), Disability of Arm-Hand-Shoulder (DASH) scores, and supraspinatus thickness showed significant improvement during follow-ups in both groups (p<0.05). During 3 months of follow-up, pain improvement was significantly better within the PRP group during (from 6.66±2.26 to 3.08±2.14 and 5.53±1.80 to 3.88±1.99, respectively; p=0.023). Regarding ROM, the PRP group had significant improvement in adduction (20.50°±8.23° to 28°±3.61° and 23.21°±7.09° to 28.46°±4.18° for the PRP and corticosteroid groups, respectively; p=0.011) and external rotation (59.66°±23.81° to 76.66°±18.30° and 57.14°±24.69° to 65.57°±26.39°, for the PRP and corticosteroid groups, respectively; p=0.036) compared to the corticosteroid group. Conclusion: We found that PRP renders similar results to that of corticosteroids in most clinical aspects among patients with RC tendinopathies; however, pain and ROM may show more significant improvement with the use of PRP. Considering that the use of corticosteroids may be contraindicated in some patients and may be associated with the risk of tendon rupture, we suggest the use of PRP in place of corticosteroid-based injections among patients with RC tendinopathy. Trial registration: Clinical trial registration code: IRCT201302174251N9 © 2021, The Author(s)

Allograft or autograft in skeletally immature anterior cruciate ligament reconstruction: A prospective evaluation using both partial and complete transphyseal techniques

Objective: We compared autografts and allograft using partial and complete transphyseal anterior cruciate ligament (ACL) reconstruction techniques among skeletally immature individuals. Methods: Male and females younger than 18 and 16 years old, respectively, diagnosed with ACL tear from April 2006 to March 2012 entered the study. One group had four-strand hamstring autograft, and the other had tibialis posterior allograft reconstruction. Those who had allografts either had hyper-laxity or recurvatum. Results: Achieved mean (± SD) 2000 International Knee Documentation Committee subjective score was not statistically different (P = 0.385) between allograft (n = 13) (84.3 ± 3.2) and autograft groups (n = 18) (85.6 ± 4.4). Mean Knee injury and Osteoarthritis Outcome Score (KOOS) subscale Knee-Related Quality of Life at 2 years was 78.0 ± 7.2 and 75 ± 7.4 for allograft and autograft groups, respectively (p = 0.261). Mean 2-year KOOS subscale Sports and Recreation was 82.1 ± 5.8 and 84.8 ± 6.6 for allograft and autograft groups, respectively (p = 0.244). No patient reported instability, giving way, or locking of the knee. Pivot shift test was negative in all patients; however, a minor positive Lachman test was found in six cases (46) within the allograft group and seven cases (39) in the autograft group. One postoperative septic arthritis was documented in the autograft group. Conclusion: Considering existing concern that joint laxity and recurvatum are among the precursors of non-contact ACL injury in adolescents, bone-patellar-bone autografts are not applicable in this age group because of the open physis; furthermore, considering that hamstring autografts are insufficient (size thickness and stretchability), we recommend soft tissue allografts for ACL reconstruction in skeletally immature patients. © 2019 The Author(s)

COVID-19 among patients with orthopedic surgery: our experience from the Middle East

Background: We report our experiences with COVID-19 in one of the largest referral orthopedic centers in the Middle East and aimed to describe the epidemiology and clinical characteristics of these patients. Methods: During February 20 and April 20, 2020, patients who underwent orthopedic surgery and healthcare staff who were in contact with these patients were screened for COVID-19. To identify patients who were in the incubation period of COVID-19 during their hospital stay, all patients were tested again for COVID-19 4 weeks after discharge. Results: Overall, 1244 patients underwent orthopedic surgery (1123 emergency and 121 elective) during the study period. Overall, 17 patients were diagnosed with COVID-19 during hospital admission and seven after discharge. Among the total 24 patients with COVID-19, 15 were (62.5) males with a mean (SD) age of 47.0±1.6 years old. Emergency surgeries were performed in 20 (83.3) patients, and elective surgery was done in the remaining 4 patients which included one case of posterior spinal fusion, spondylolisthesis, acromioclavicular joint dislocation, and one case of leg necrosis. A considerable number of infections occurred in patients with intertrochanteric fractures (n=7, 29.2), followed by pelvic fractures (n=2, 8.3), humerus fractures (n=2, 8.3), and tibial plateau fractures (n=2, 8.3). Fever (n=11, 45.8) and cough (n=10, 37.5) were the most common symptoms among patients. Laboratory examinations showed leukopenia in 2 patients (8.3) and lymphopenia in 4 (16.7) patients. One patient with a history of cancer died 2 weeks after discharge due to myocardial infarction. Among hospital staff, 26 individuals contracted COVID-19 during the study period, which included 13 (50) males. Physicians were the most commonly infected group (n = 11), followed by operation room technicians (n = 5), nurses (n = 4), and paramedics (n = 4). Conclusions: Patients who undergo surgical treatment for orthopedic problems, particularly lower limb fractures with limited ambulation, are at a higher risk of acquiring COVID-19 infections, although they may not be at higher risks for death compared to the general population. Orthopedic surgeons in particular and other hospital staff who are in close contact with these patients must be adequately trained and given appropriate personal protective equipment during the COVID-19 outbreak. © 2021, The Author(s)

The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3 associated phagocytosis

Macroautophagy/autophagy delivers damaged proteins and organelles to lysosomes for degradation, and plays important roles in maintaining tissue homeostasis by reducing tissue damage. The translocation of LC3 to the limiting membrane of the phagophore, the precursor to the autophagosome, during autophagy provides a binding site for autophagy cargoes, and facilitates fusion with lysosomes. An autophagy-related pathway called LC3-associated phagocytosis (LAP) targets LC3 to phagosome and endosome membranes during uptake of bacterial and fungal pathogens, and targets LC3 to swollen endosomes containing particulate material or apoptotic cells. We have investigated the roles played by autophagy and LAP in vivo by exploiting the observation that the WD domain of ATG16L1 is required for LAP, but not autophagy. Mice lacking the linker and WD domains, activate autophagy, but are deficient in LAP. The LAP −/- mice survive postnatal starvation, grow at the same rate as littermate controls, and are fertile. The liver, kidney, brain and muscle of these mice maintain levels of autophagy cargoes such as LC3 and SQSTM1/p62 similar to littermate controls, and prevent accumulation of SQSTM1 inclusions and tissue damage associated with loss of autophagy. The results suggest that autophagy maintains tissue homeostasis in mice independently of LC3-associated phagocytosis. Further deletion of glutamate E230 in the coiled-coil domain required for WIPI2 binding produced mice with defective autophagy that survived neonatal starvation. Analysis of brain lysates suggested that interactions between WIPI2 and ATG16L1 were less critical for autophagy in the brain, which may allow a low level of autophagy to overcome neonatal lethality. Abbreviations: CCD: coiled-coil domain; CYBB/NOX2: cytochrome b-245: beta polypeptide; GPT/ALT: glutamic pyruvic transaminase: soluble; LAP: LC3-associated phagocytosis; LC3: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; NOD: nucleotide-binding oligomerization domain; NADPH: nicotinamide adenine dinucleotide phosphate; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing Beclin 1-interacting protein; SLE: systemic lupus erythematosus; SQSTM1/p62: sequestosome 1; TLR: toll-like receptor; TMEM: transmembrane protein; TRIM: tripartite motif-containing protein; UVRAG: UV radiation resistance associated gene; WD: tryptophan-aspartic acid; WIPI: WD 40 repeat domain: phosphoinositide interacting

Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

BACKGROUND: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.)

Encrypted federated learning for secure decentralized collaboration in cancer image analysis.

Artificial intelligence (AI) has a multitude of applications in cancer research and oncology. However, the training of AI systems is impeded by the limited availability of large datasets due to data protection requirements and other regulatory obstacles. Federated and swarm learning represent possible solutions to this problem by collaboratively training AI models while avoiding data transfer. However, in these decentralized methods, weight updates are still transferred to the aggregation server for merging the models. This leaves the possibility for a breach of data privacy, for example by model inversion or membership inference attacks by untrusted servers. Somewhat-homomorphically-encrypted federated learning (SHEFL) is a solution to this problem because only encrypted weights are transferred, and model updates are performed in the encrypted space. Here, we demonstrate the first successful implementation of SHEFL in a range of clinically relevant tasks in cancer image analysis on multicentric datasets in radiology and histopathology. We show that SHEFL enables the training of AI models which outperform locally trained models and perform on par with models which are centrally trained. In the future, SHEFL can enable multiple institutions to co-train AI models without forsaking data governance and without ever transmitting any decryptable data to untrusted servers

Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel NNRTI, with TDF/FTC in ART-naive HIV-positive patients

INTRODUCTION: Doravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients (1). At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2. METHODS: Patients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre-specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined). RESULTS: Part 1 week 48 efficacy and safety results are shown below. CONCLUSIONS: In ART-naïve, HIV-1-positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment-emergent CNS AEs by week 8 than those who received EFV

HHV-6B Induces IFN-Lambda1 Responses in Cord Plasmacytoid Dendritic Cells through TLR9

Human herpesvirus type 6B (HHV-6B) is a strong inducer of IFN-alpha and has the capacity to promote Th1 responses and block Th2 responses in vitro. In this study we addressed whether inactivated HHV-6B can also induce IFN lambda responses and to what extent interferons alpha and lambda affect Th1/Th2 polarization. We show that inactivated HHV-6B induced IFN-lambda1 (IL-29) but not IFN-lambda2 (IL-28A) responses in plasmacytoid DC and that this induction was mediated through TLR9. We have previously shown that HHV-6B promotes Th1 responses and blocks Th2 responses in both humans and mice. We now show that neutralization of IFN-alpha but not IFN-lambda1 blocked the HHV-6B-induced enhancement of Th1 responses in MLR, but did not affect the HHV-6-induced dampening of Th2 responses. Similarly, blockage of TLR9 counteracted HHV-6Bs effects on the Th1/Th2 balance. In addition, IFN-alpha but not IFN-lambda1 promoted IFN-gamma production and blocked IL-5 and IL-13 production in purified CD4+ T-cells. The lack of effect of IFN-lambda1 correlated with the absence of the IFN-lambda receptor IL-28Ralfa chain on the cell surface of both resting and activated CD4+ T-cells. We conclude that inactivated HHV-6B is a strong inducer of IFN-lambda1 in plasmacytoid DC and that this induction is TLR9-dependent. However, human CD4+ T-cells do not express the IFN-lambda receptor and are refractory to IFN-lambda1 treatment. The HHV-6B-induced alterations in the Th1/Th2 balance are instead mediated mainly through TLR9 and IFN-alpha