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Background: Osteochondritis dissecans (OCD) occurs most commonly in the knees of young individuals. This condition is known to cause pain and discomfort in the knee and can lead to disability and early knee osteoarthritis. The cause is not well understood, and treatment plans are not well delineated. The Research in Osteochondritis Dissecans of the Knee (ROCK) group established a multicenter, prospective cohort to better understand this disease. Purpose: To provide a baseline report of the ROCK multicenter prospective cohort and present a descriptive analysis of baseline data for patient characteristics, lesion characteristics, and clinical findings of the first 1000 cases enrolled into the prospective cohort. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients were recruited from centers throughout the United States. Baseline data were obtained for patient characteristics, sports participation, patient-reported measures of functional capabilities and limitations, physical examination, diagnostic imaging results, and initial treatment plan. Descriptive statistics were completed for all outcomes of interest. Results: As of November 2020, a total of 27 orthopaedic surgeons from 17 institutions had enrolled 1004 knees with OCD, representing 903 patients (68.9% males; median age, 13.1 years; range, 6.3-25.4 years), into the prospective cohort. Lesions were located on the medial femoral condyle (66.2%), lateral femoral condyle (18.1%), trochlea (9.5%), patella (6.0%), and tibial plateau (0.2%). Most cases involved multisport athletes (68.1%), with the most common primary sport being basketball for males (27.3% of cases) and soccer for females (27.6% of cases). The median Pediatric International Knee Documentation Committee (Pedi-IKCD) score was 59.9 (IQR, 45.6-73.9), and the median Pediatric Functional Activity Brief Scale (Pedi-FABS) score was 21.0 (IQR, 5.0-28.0). Initial treatments were surgical intervention (55.4%) and activity restriction (44.0%). When surgery was performed, surgeons deemed the lesion to be stable at intraoperative assessment in 48.1% of cases. Conclusion: The multicenter ROCK group has been able to enroll the largest knee OCD cohort to date. This information is being used to further understand the pathology of OCD, including its cause, associated comorbidities, and initial presentation and symptoms. The cohort having been established is now being followed longitudinally to better define and elucidate the best treatment algorithms based on these presenting signs and symptoms.

© 2020 The Hong Kong Geriatrics Society and Hong Kong Association of Gerontology. Introduction. Delirium is a common complication of hip fracture that can be avoided or ameliorated by careful anticipatory case management. We aimed to investigate the incidence and risk factors of delirium in older patients with hip fracture treated in our structured integrated care unit, and to evaluate the impact of delirium on healthcare utilisation. Methods. We retrospectively reviewed records of patients aged ≥60 years and admitted to our unit from December 2014 to September 2018 with low-impact hip fracture. Our unit has implemented a structured integrated care programme based on the NICE guidelines. Primary outcome measure was the incidence of delirium. The diagnosis of delirium was established using the Confusion Assessment Method. Secondary outcome measures included length of hospital stay, readmission within 30 days of discharge, and mortality within 30 days and 1 year. Results. A total of 1304 patients were included and classified as non-delirium (349 men and 815 women; mean age, 79.2 years) and delirium (49 men and 91 women; mean age, 82.3 years). The overall within-episode incidence of delirium was thus 10.7%. Independent risk factors for delirium in older patients with hip fractures were age (odds ratio [OR]=1.028, p=0.02), surgical treatment (OR=2.202, p=0.006), dementia (OR=2.066, p=0.001), elevated body temperature (OR=1.966, p=0.001), urinary tract infection (OR=2.431, p

This Phase I, open‐label, two‐group, fixed‐sequence study evaluated the pharmacokinetics and safety of AL‐335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL‐335 800 mg once daily (QD) (days 1‐3, 11‐13, and 21‐23), simeprevir 150 mg QD (days 4‐23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15‐23). Group 2 (n = 16) received the same AL‐335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5‐23) and simeprevir 150 mg QD (days 14‐23). Blood samples were collected to determine plasma concentrations of AL‐335 (prodrug) and its metabolites, ALS‐022399 (monophosphate precursor) and ALS‐022227 (parent nucleoside), odalasvir, and simeprevir. Thirty‐two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL‐335 area under plasma concentration‐time curve over 24 hours (AUC 0‐24 h) 3‐, 4‐, and 7‐ to 8‐fold, respectively; ALS‐022399 AUC 0‐24 h increased 2‐, 2‐, and 3‐fold, respectively. Simeprevir had no effect on ALS‐022227 AUC 0‐24 h, whereas odalasvir with/without simeprevir increased ALS‐022227 AUC 0‐24 h 1.5‐fold. AL‐335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0‐24 h increased 1.5‐ to 2‐fold for both drugs when coadministered irrespective of AL‐335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL‐335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

Emtricitabine is a potent nucleoside reverse transcriptase inhibitor approved as a once-daily drug in combination with other antiretroviral agents for the treatment of HIV infection. Several phase I studies were conducted in healthy volunteers over the course of clinical development to evaluate whether pharmacokinetic drug-drug interactions exist between emtricitabine and other nucleoside antivirals that are extensively eliminated by renal excretion. Potential interactions with stavudine and famciclovir were evaluated in single-dose studies, whereas interactions with zidovudine and its major metabolite, zidovudine glucuronide, were evaluated in a multiple-dose study. Plasma pharmacokinetic profiles and, in some studies, urinary excretion data were evaluated when each drug was administered alone and in combination with emtricitabine. Safety and plasma pharmacokinetic profiles of each drug administered alone or with emtricitabine were consistent with historical data. Statistical analyses indicated that there were no significant interactions between emtricitabine and these 3 nucleoside antivirals.

The present study investigated the effect of enfuvirtide cross-reactive glycoprotein 41 (gp41) antibody on the efficacy or safety of enfuvirtide in patients participating in I of 2 24-week phase 3 clinical trials T-20 vs. optimized regimen only [TORO] 1 and TORO 2). Serum samples from human immunodeficiency virus-infected patients receiving enfuvirtide plus optimized background (OB) and from patients receiving OB only were evaluated for enfuvirtide cross-reactive gp41 antibodies. Most patients had detectable levels of antibody at baseline; 78% of patients treated with enfuvirtide plus OB had a greater than or equal to30% decrease in level of antibody, compared with 43% of patients treated with OB only. Baseline antibody status did not influence virological responses to enfuvirtide-containing treatment. Favorable virological responses were more common among patients who experienced a greater than or equal to30% decrease from baseline than among those who experienced either an increase or a lesser decrease. A decrease in virus load correlated with a decrease in level of antibody. Safety was unaffected by the presence of positive antibody at any time point or change in level of antibody. There was no evidence that enfuvirtide cross-reactive gp41 antibody affects the efficacy or safety of enfuvirtide.

Background: This study evaluated the potential for a pharmacokinetic (PK) interaction when sovaprevir (formerly ACH-1625), a novel NS3 HCV protease inhibitor, and ACH-3102, a second generation NS5A inhibitor, were coadministered. Sovaprevir was administered as an oral tablet, while ACH-3102 was administered as an oral liquid-filled capsule (LFC). This study also investigated whether a PK interaction existed between sovaprevir and the excipients of the ACH-3102 LFC. Methods: Twenty-four (24) healthy volunteers were divided into 4 groups. Subjects in Groups 1 (n=6) and 2 (n=6) each received a single 300 mg dose of sovaprevir with a standard meal on Day 1, followed by a washout period (Days 2 to 4), and then a single 300 mg dose of sovaprevir, co-administered with either 300 mg ACH-3102 LFC (Group 1) or placebo (Group 2) while fed a standard meal (Day 5). Subjects in Groups 3 (n=6) and 4 (n=6) each received a single 300 mg dose of sovaprevir while fasted on Day 1, followed by a washout period (Days 2 to4), and then a single 300 mg dose of sovaprevir co-administered with either 300 mg ACH3102 LFC (Group 3) or placebo (Group 4) while fasted (Day 5). Results: For sovaprevir, the respective mean Day 5/Day 1 ratios (coadministered with ACH- 3102 versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.96, 1.05 and 1.05 when fed, and 0.89, 0.77 and 0.77 when fasted. Similarly, for sovaprevir, the respective mean Day 5/Day 1 ratios (co-administered with placebo for ACH-3102 LFC versus dosed alone) of Cmax, AUC(0-24) and AUC(O-∞) were 0.84, 0.91 and 0.90 when fed, and 1.17, 1.12 and 1.08 when fasted. Mean observed Cmax, AUC(0-24) and AUC(0-192) of ACH-3102 when coadministered with sovaprevir were all within approximately 25% of values from previous studies. Conclusions: No clinically significant change was observed in the PK of either sovaprevir or ACH-3102 when co-administered in either the fed or fasted state. No clinically significant change was observed in the PK of sovaprevir when coadministered with the excipients of the ACH-3102 LFC. Co-administration of the two agents was safe and well-tolerated.

Background: ACH-2684 is a second-generation HCV NS3 protease inhibitor in Phase Ib development for the treatment of chronic HCV infection. ACH-2684 demonstrates potent activity in vitro against genotype-1 (GT1) HCV and, as compared to other protease inhibitors, has improved activity against multiple viral variants. Presented here are phase I study results in cirrhotic and non-cirrhotic patients with chronic HCV GT1 infection. Methods: ACH-2684 or placebo was administered to non-cirrhotic (n = 30) and cirrhotic (n = 8) patients with chronic HCV GT1 infection. Pharmacokinetic, (PK) viral load and safety assessments were collected on Days 1 through 35. Serial blood samples were collected on Day 1 and Day 3, and plasma non-compartmental pharmacokinetic parameters were determined. Drug efficiency was estimated by applying a single population viral dynamics model (Neumann et al, Science 1998, 282,103). Results: ACH-2684 was safe and well tolerated in non-cirrhotic and cirrhotic patients. There were no serious adverse events, and no discontinuations for safety concerns. Mean maximum reductions in plasma HCV RNA were 3.36, 3.73 and 4.16 log10 (IU/ml) at doses of 100 mg daily, 400 mg daily and 400 mg twice daily, respectively. In cirrhotic patients administered 400 mg daily, mean maximum reduction was 3.67 log10 (IU/ml). The systemic exposures were generally greater than doseproportional for the dose range studied in non-cirrhotics, and approximately 2-fold higher in cirrhotic versus non-cirrhotic patients. The drug efficiency of the 400 mg daily dose in non-cirrhotic and cirrhotic subjects was similar at 0.9993 ± 0.0005 and 0.9991 ± 0.0007, respectively. Conclusions: ACH-2684 was safe and well-tolerated, and produced more than a 3 log10 (IU/ml) mean maximum reduction in plasma HCV RNA levels in all groups. A 400 mg dose of ACH-2684 yielded approximately a 2-fold higher exposure in cirrhotics than non-cirrhotics, but was still safe and well-tolerated, and was equally effective in reducing HCV RNA levels. Viral kinetics parameters were robust and demonstrated high drug efficiency. These data provide evidence that ACH-2684 is a safe and well-tolerated protease inhibitor with potent anti-viral activity in both cirrhotic and non-cirrhotic patients with chronic GT-1 HCV infection, making it a promising candidate for future treatment of chronic HCV infection.