Prevalence of rapidly progressive osteoarthritis of the hip following intra-articular steroid injections.

INTRODUCTION: Numerous studies have indicated that intra-articular steroid injections to the hip are beneficial for short-term pain relief. However, recent studies have drawn concerns of rapidly progressive osteoarthritis of the hip (RPOH) following intra-articular steroid injections. The prevalence of RPOH following intra-articular steroid injections varies widely in the literature. OBJECTIVE: To identify the prevalence of RPOH following intra-articular steroid injections, and to compare baseline characteristics between patients with and without RPOH. DESIGN: Case series. SETTING: Tertiary academic hospital. PATIENTS: A total of 924 patients (median [interquartile range; IQR] age: 59 [45-70] years; 579 female) who received an intra-articular hip steroid/anesthetic injection from January 2016 to March 2018 and had available pre- and post-injection imaging (prior to surgical intervention) were included in the study. INTERVENTIONS: Baseline and injection-related data-including demographics, age, body mass index, medical history, laterality, and steroid type-were collected from electronic medical records. MAIN OUTCOME MEASURES: Post-injection RPOH was determined via imaging review by a physiatry fellow, followed by an attending physiatrist and a musculoskeletal radiologist to confirm findings. RESULTS: The majority of patients received unilateral injections into the hip, and the most common steroids used were triamcinolone and methylprednisolone. Review of pre- and post-injection imaging revealed 26 cases of RPOH, for an overall prevalence of 2.8% (95% confidence interval [CI] 1.9%-4.1%). Compared to those without RPOH, patients with RPOH were significantly older (median age [IQR]: 64 [60-73] vs. 59 [44-70] years, p = .003) and had a shorter duration of symptoms prior to their injections (median [IQR]: 3 vs. 12 [6-36] months, p < .001). Adjusted regression analyses showed that age was associated with greater odds of RPOH (odds ratio [OR], 95% CI: 1.04, 1.01 to 1.07; p = .003). CONCLUSIONS: The prevalence of RPOH following intra-articular steroid injections into the hip was lower than previously reported but still clinically relevant. This should be considered when counseling patients prior to intra-articular hip steroid injections.

Outcomes of a COVID-19 recovery program for patients hospitalized with SARS-CoV-2 infection in New York City: A prospective cohort study.

BACKGROUND: In the spring of 2020, New York City was an epicenter of coronavirus disease 2019 (COVID-19). The post-hospitalization needs of COVID-19 patients were not understood and no outpatient rehabilitation programs had been described. OBJECTIVE: To evaluate whether a virtual rehabilitation program would lead to improvements in strength and cardiopulmonary endurance when compared with no intervention in patients discharged home with persistent COVID-19 symptoms. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: Between April and July 2020, 106 patients discharged home with persistent COVID-19 symptoms were treated. Forty-four patients performed virtual physical therapy (VPT); 25 patients performed home physical therapy (HPT); 17 patients performed independent exercise program (IE); and 20 patients did not perform therapy. INTERVENTIONS: All patients were assessed by physiatry. VPT sessions were delivered via secure Health Insurance Portability and Accountability Act compliant telehealth platform 1-2 times/week. Patients were asked to follow up 2 weeks after initial evaluation. MAIN OUTCOME MEASURES: Primary study outcome measures were the change in lower body strength, measured by the 30-second sit-to-stand test; and the change in cardiopulmonary endurance, measured by the 2-minute step test. RESULTS: At the time of follow-up, 65% of patients in the VPT group and 88% of patients in the HPT group met the clinically meaningful difference for improvement in sit-to-stand scores, compared with 50% and 17% of those in the IE group and no-exercise group (P = .056). The clinically meaningful difference for improvement in the step test was met by 74% of patients in the VPT group and 50% of patients in the HPT, IE, and no-exercise groups (P = .12). CONCLUSIONS: Virtual outpatient rehabilitation for patients recovering from COVID-19 improved lower limb strength and cardiopulmonary endurance, and an HPT program improved lower limb strength. Virtual rehabilitation seems to be an efficacious method of treatment delivery for recovering COVID-19 patients.

Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study.

BACKGROUND: We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. METHODS: A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. FINDINGS: Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. INTERPRETATION: This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. FUNDING: Defense Threat Reduction Agency.

RNAi-mediated gene silencing in non-human primates.

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.

Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA.

Short interfering RNAs (siRNAs) that mediate specific gene silencing through RNA interference (RNAi) are widely used to study gene function and are also being developed for therapeutic applications. Many nucleic acids, including double- (dsRNA) and single-stranded RNA (ssRNA), can stimulate innate cytokine responses in mammals. Despite this, few studies have questioned whether siRNA may have a similar effect on the immune system. This could significantly influence the in vivo application of siRNA owing to off-target effects and toxicities associated with immune stimulation. Here we report that synthetic siRNAs formulated in nonviral delivery vehicles can be potent inducers of interferons and inflammatory cytokines both in vivo in mice and in vitro in human blood. The immunostimulatory activity of formulated siRNAs and the associated toxicities are dependent on the nucleotide sequence. We have identified putative immunostimulatory motifs that have allowed the design of siRNAs that can mediate RNAi but induce minimal immune activation.

Swarm-cell differentiation in Salmonella enterica serovar typhimurium results in elevated resistance to multiple antibiotics.

Although a wealth of knowledge exists about the molecular and biochemical mechanisms governing the swimming motility of Salmonella enterica serovar Typhimurium, its surface swarming behavior has not been extensively characterized. When inoculated onto a semisolid agar medium supplemented with appropriate nutrients, serovar Typhimurium undergoes a morphological differentiation whereby single cells hyperflagellate and elongate into nonseptate, multinucleate swarm cells. Swarm migration is a collective behavior of groups of cells. We have isolated a MudJ insertion mutant of serovar Typhimurium 14028 that failed to swarm under any conditions. The site of the MudJ insertion was determined to be in the pmrK locus within the pmrHFIJKLM operon, which was previously demonstrated to confer resistance to cationic antimicrobial peptides. beta-Galactosidase assays, using the pmrK::lacZ transcriptional fusion, showed increased expression of the pmr operon in swarm cells compared to that in vegetative cells. In concurrence with the expression data, swarm cells exhibited greater tolerance to polymyxin. To compare the profiles of vegetative and swarm-cell resistance to other antibiotics, E-test strips representing a wide range of antibiotic classes were used. Swarm cells exhibited elevated resistance to a variety of antibiotics, including those that target the cell envelope, protein translation, DNA replication, and transcription. These observations, in addition to the dramatic morphological changes associated with the swarming phenotype, provide an intriguing model for examining global differences between the physiological states of vegetative and swarm cells of serovar Typhimurium.