Coagulopathy and adverse outcomes in hospitalized patients with COVID-19: results from the NOR-Solidarity trial.

Background: Several studies have examined parameters of increased thrombogenicity in COVID-19, but studies examining their association with long-term outcome and potential effects of antiviral agents in hospitalized patients with COVID-19 are scarce. Objectives: To evaluate plasma levels of hemostatic proteins during hospitalization in relation to disease severity, treatment modalities, and persistent pulmonary pathology after 3 months. Methods: In 165 patients with COVID-19 recruited into the NOR-Solidarity trial (NCT04321616) and randomized to treatment with hydroxychloroquine, remdesivir, or standard of care, we analyzed plasma levels of hemostatic proteins during the first 10 days of hospitalization (n = 160) and at 3 months of follow-up (n = 100) by enzyme immunoassay. Results: Our main findings were as follows: (i) tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) were increased in patients with severe disease (ie, the combined endpoint of respiratory failure [Po2-to-FiO2 ratio, <26.6 kPa] or need for treatment at an intensive care unit) during hospitalization. Compared to patients without severe disease, tPA levels were a median of 42% (P < .001), 29% (P = .002), and 36% (P = .015) higher at baseline, 3 to 5 days, and 7 to 10 days, respectively. For TFPI, median levels were 37% (P = .003), 25% (P < .001), and 10% (P = .13) higher in patients with severe disease at these time points, respectively. No changes in thrombin-antithrombin complex; alpha 2-antiplasmin; a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; or antithrombin were observed in relation to severe disease. (ii) Patients treated with remdesivir had lower levels of TFPI than those in patients treated with standard of care alone. (iii) TFPI levels during hospitalization, but not at 3 months of follow-up, were higher in those with persistent pathology on chest computed tomography imaging 3 months after hospital admission than in those without such pathology. No consistent changes in thrombin-antithrombin complex, alpha 2-antiplasmin, ADAMTS-13, tPA, or antithrombin were observed in relation to pulmonary pathology at 3 months of follow-up. Conclusion: TFPI and tPA are associated with severe disease in hospitalized patients with COVID-19. For TFPI, high levels measured during the first 10 days of hospitalization were also associated with persistent pulmonary pathology even 3 months after hospital admittance.

Opportunistic Treatment of Hepatitis C Infection Among Hospitalized People Who Inject Drugs (OPPORTUNI-C): A Stepped Wedge Cluster Randomized Trial.

BACKGROUND: We aimed to evaluate the efficacy of opportunistic treatment of hepatitis C virus (HCV) infection among hospitalized people who inject drugs (PWID). METHODS: We performed a pragmatic, stepped wedge cluster randomized trial recruiting HCV RNA positive individuals admitted for inpatient care in departments of internal medicine, addiction medicine, and psychiatry at three hospitals in Oslo, Norway. Seven departments were sequentially randomized to change from control conditions (standard of care referral to outpatient care) to intervention conditions (immediate treatment initiation). The primary outcome was treatment completion, defined as dispensing the final package of the prescribed treatment within six months after enrolment. RESULTS: A total of 200 HCV RNA positive individuals were enrolled between 1 October 2019 and 31 December 2021 (mean age 47.4 years, 72.5% male, 60.5% injected past 3 months, 20.4% cirrhosis). Treatment completion was accomplished by 67 of 98 (68.4% [95% confidence interval {CI}: 58.2-77.4]) during intervention conditions and by 36 of 102 (35.3% [95% CI: 26.1-45.4]) during control conditions (risk difference 33.1% [95% CI: 20.0-46.2]; risk ratio 1.9 [95% CI: 1.4-2.6]). The intervention was superior in terms of treatment completion (adjusted odds ratio [aOR] 4.8 [95% CI: 1.8-12.8]; P = .002) and time to treatment initiation (adjusted hazard ratio [aHR] 4.0 [95% CI: 2.5-6.3]; P < .001). Sustained virologic response was documented in 60 of 98 (61.2% [95% CI: 50.8-70.9]) during intervention and in 66 of 102 (64.7% [95% CI: 54.6-73.9]) during control conditions. CONCLUSIONS: An opportunistic test-and-treat approach to HCV infection was superior to standard of care among hospitalized PWID. The model of care should be considered for broader implementation. Clinical Trials Registration. NCT04220645.

Hepatitis C treatment uptake among people who inject drugs in Oslo, Norway: A registry-based study.

BACKGROUND: Improving HCV treatment uptake among people who inject drugs (PWID) is crucial to achieving the WHO elimination targets. The aims were to evaluate HCV treatment uptake and HCV RNA prevalence in a large cohort of PWID in Norway. METHODS: Registry-based observational study where all users of the City of Oslo's low-threshold social and health services for PWID between 2010-2016 (n = 5330) were linked to HCV notifications (1990-2019) and dispensions of HCV treatment, opioid agonist treatment (OAT) and benzodiazepines (2004-2019). Cases were weighted to account for spontaneous HCV clearance. Treatment rates were calculated using person-time of observation, and factors associated with treatment uptake were analysed using logistic regression. HCV RNA prevalence was estimated among individuals alive by the end of 2019. RESULTS: Among 2436 participants with chronic HCV infection (mean age 46.8 years, 30.7% female, 73.3% OAT), 1118 (45.9%) had received HCV treatment between 2010-2019 (88.7% DAA-based). Treatment rates increased from 1.4/100 PY (95% CI 1.1-1.8) in the pre-DAA period (2010-2013) to 3.5/100 PY (95% CI 3.0-4.0) in the early DAA period (2014-2016; fibrosis restrictions) and 18.4/100 PY (95% CI 17.2-19.7) in the late DAA period (2017-2019; no restrictions). Treatment rates for 2018 and 2019 exceeded a previously modelled elimination threshold of 50/1000 PWID. Treatment uptake was less likely among women (aOR 0.74; 95% CI 0.62-0.89) and those aged 40-49 years (aOR 0.74; 95% CI 0.56-0.97), and more likely among participants with current OAT (aOR 1.21; 95% CI 1.01-1.45). The estimated HCV RNA prevalence by the end of 2019 was 23.6% (95% CI 22.3-24.9). CONCLUSION: Although HCV treatment uptake among PWID increased, strategies to improve treatment among women and individuals not engaged in OAT should be addressed.

High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway.

BACKGROUND AND AIMS: The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD: This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS: We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION: We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Markers of cellular senescence is associated with persistent pulmonary pathology after COVID-19 infection.

BACKGROUND: The lungs are the organ most likely to sustain serious injury from coronavirus disease 2019 (COVID-19). However, the mechanisms for long-term complications are not clear. Patients with severe COVID-19 have shorter telomere lengths and higher levels of cellular senescence, and we hypothesized that circulating levels of the telomere-associated senescence markers chitotriosidase, ß-galactosidase, cathelicidin antimicrobial peptide and stathmin 1 (STMN1) were elevated in hospitalized COVID-19 patients compared to controls and could be associated with pulmonary sequelae following hospitalization. METHODS: Ninety-seven hospitalized patients with COVID-19 who underwent assessment for pulmonary sequelae at three-month follow-up were included in the study. ß-Galactosidase and chitotriosidase were analysed by fluorescence; stathmin 1 and cathelicidin antimicrobial peptide were analysed by enzyme immuno-assay in plasma samples from the acute phase and after three-months. In addition, the classical senescence markers cyclin-dependent kinase inhibitor 1A and 2A were analysed by enzyme immuno-assay in peripheral blood mononuclear cell lysate after three months. RESULTS: We found elevated plasma levels of the senescence markers chitotriosidase and stathmin 1 in patients three months after hospitalization with COVID-19, and these markers in addition to protein levels of cyclin-dependent kinase inhibitor 2A in cell lysate, were associated with pulmonary pathology. The elevated levels of these markers seem to reflect both age-dependent (chitotriosidase) and age-independent (stathmin 1, cyclin-dependent kinase inhibitor 2A) processes. CONCLUSIONS: We suggest that accelerated ageing or senescence could be important for long-term pulmonary complications of COVID-19, and our findings may be relevant for future research exploring the pathophysiology and management of these patients.

Calcific tendinitis of the longus colli muscle. / Kalsifiserende tendinitt i m. longus colli.

BACKGROUND: Calcific tendinitis of the longus colli muscle is an aseptic inflammatory reaction to calcium hydroxyapatite crystal deposition in the cervical prevertebral space. CASE PRESENTATION: A 40-year-old woman presented with neck pain and odonyphagia. She had reduced mobility in her neck, tenderness to palpation and elevated CRP with normal leukocyte count and sedimentation rate. CT revealed a fluid collection in the retropharyngeal space and a calcific deposition in the longus colli muscle consistent with calcific tendinitis. She improved with NSAID therapy. Blood cultures taken on arrival showed no growth. INTERPRETATION: Acute calcific tendinitis of the longus colli muscle is an aseptic inflammatory process in the cervical prevertebral space and an important mimicker of retropharyngeal abscess and spondylodiscitis.

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19.

BACKGROUND: Immune dysregulation is a major factor in the development of severe coronavirus disease 2019 (COVID-19). The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited. We thus investigated the levels of these chemokines in COVID-19 patients. METHODS: Serial blood samples were obtained from patients hospitalized with COVID-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and 3-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. RESULTS: A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the 3-month follow-up. CONCLUSIONS: Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in COVID-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in COVID-19. CLINICAL TRIALS REGISTRATION: NCT04321616 and NCT04381819.

Peer support in small towns: A decentralized mobile Hepatitis C virus clinic for people who inject drugs.

BACKGROUND & AIMS: New models of HCV care are needed to reach people who inject drugs (PWID). The primary aim was to evaluate HCV treatment uptake among HCV RNA positive individuals identified by point-of-care (POC) testing and liver disease assessment in a peer-driven decentralized mobile clinic. METHODS: This prospective study included consecutive patients assessed in a mobile clinic visiting 32 small towns in Southern Norway from November 2019 to November 2020. The clinic was staffed by a bus driver and a social educator offering POC HCV RNA testing (GeneXpert®), liver disease staging (FibroScan® 402) and peer support. Viremic individuals were offered prompt pan-genotypic treatment prescribed by local hospital-employed specialists following a brief telephone assessment. RESULTS: Among 296 tested individuals, 102 (34%) were HCV RNA positive (median age 51 years, 77% male, 24% advanced liver fibrosis/cirrhosis). All participants had a history of injecting drug use, 71% reported past 3 months injecting, and 37% received opioid agonist treatment. Treatment uptake within 6 months following enrolment was achieved in 88%. Treatment uptake was negatively associated with recent injecting (aHR 0.60; 95% CI 0.36-0.98), harmful alcohol consumption (aHR 0.44; 95% CI 0.20-0.99), and advanced liver fibrosis/cirrhosis (aHR 0.44; 95% CI 0.25-0.80). HCV RNA prevalence increased with age (OR 1.81 per 10-year increase; 95% 1.41-2.32), ranging from 3% among those <30 years to 55% among those ≥60 years. CONCLUSIONS: A peer-driven mobile HCV clinic is an effective and feasible model of care that should be considered for broader implementation to reach PWID outside the urban centres.

Rapid Treatment Initiation for Hepatitis C Virus Infection: Potential Benefits, Current Limitations, and Real-World Examples.

The science for rapid treatment initiation for hepatitis C virus infection is in place. Easy and quick diagnostic tools can provide results within an hour. Necessary assessment before treatment initiation is now minimal and manageable. Treatment has a low dose burden and high tolerability. Although the critical components for rapid treatment are accessible, certain barriers prevent wider utilization, including insurance restrictions and delays in the health care system. Rapid treatment initiation can improve linkage to care by addressing many barriers to care at once, which is essential for achieving a care plateau. Young people with low health care engagement, finitely engaged people (eg, those who are incarcerated), or people with high-risk injection drug behavior, and thereby high risk for transmission of hepatitis C virus, can benefit the most from rapid treatment. Several innovative care models have demonstrated the potential for rapid treatment initiation by overcoming barriers to care with rapid diagnostic testing, decentralization, and simplification. Expanding these models is likely to be an important component for the elimination of hepatitis C virus infection. This article reviews the current motivation for rapid treatment initiation for hepatitis C virus infection and published literature describing rapid treatment initiation models.

Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial.

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.

Hepatitis C treatment and reinfection surveillance among people who inject drugs in a low-threshold program in Oslo, Norway.

BACKGROUND: The aims were to evaluate HCV treatment effectiveness, estimate reinfection rates, and demonstrate the feasibility of reinfection surveillance and retreatment among marginalized people who inject drugs (PWID). METHODS: Prospective observational study including consecutive HCV RNA positive individuals attending a low-threshold clinic in Oslo, Norway, between 2013 and 2020. Participants were offered individually tailored HCV treatment and post-treatment HCV RNA surveillance at three months intervals. RESULTS: Of 488 HCV RNA positive individuals, 363 initiated treatment (median age 48.7 years, 72.5% male, 17.2% liver cirrhosis, 54.3% unstable housing). All participants had a history of injecting drug use, 71.1% received opioid agonist treatment, and 70.1% reported recent (past 3 months) injecting. In intention-to-treat analysis, excluding those with HCV RNA results pending, virologic response was achieved in 306 of 340 (90.0%) participants. In modified intention-to-treat analysis, also excluding those with loss to follow-up during treatment, virologic response was achieved in 306 of 323 (94.7%). Virologic response was not associated with recent injecting drug use or socio-demographic factors. Reinfection surveillance was accomplished in 297 individuals (308.2 PY of follow-up; median 0.50 years). Eight cases of reinfection were detected for an incidence of 2.60/100 PY (95% CI 1.12-5.11) overall, and 3.74/100 PY (95% CI 1.62-7.37) among those with injecting drug use during follow-up (n = 205). Reinfection was associated with younger age (IRR 0.37; 95% CI 0.18-0.74), and all cases occurred in participants aged below 49 years with ongoing injecting drug use who reported mixed heroin/amphetamine injecting. Successful retreatment was provided in all cases and no second reinfections were observed. CONCLUSION: The findings consolidate previous evidence supporting the effectiveness of HCV treatment among PWID, provide novel data on reinfection rates and associated factors, and demonstrate the feasibility of reinfection surveillance and retreatment in a real-world setting.

High-intensity interval training to improve fitness in children with cerebral palsy.

AIM: To evaluate effects of high-intensity interval training (HIT) on aerobic exercise capacity, quality of life, and body composition in children with cerebral palsy (CP). METHODS: This was a baseline control trial. Children with CP, Gross Motor Function Classification System (GMFCS) levels I-IV, and age 10-17 years were included. The primary outcome, peak, and submaximum oxygen uptake (VO2peak, VO2submax) were measured at enrolment to the study (T0), after a pretraining period (T1), and after HIT (T2). Secondary outcomes were quality of life assessed with the KINDL questionnaire, and body composition measured using whole body dual-energy X-ray absorptiometry scanning. The exercise was performed on treadmills and consisted of 24 sessions, each with a total of 16 min of exercise at >85% of maximal heart rate. RESULTS: 20 children were included and 6 children dropped out. VO2peak increased by 10%, from a median of 37.3 (31.0-40.1) to 41.0 (36.6-48.5) mL/kg/min from T1 to T2 (p<0.01). VO2submax did not change; thereby, the percentage oxygen utilisation was reduced. Body composition was unchanged. Parent-reported quality of life improved, whereas quality of life reported by the children did not improve. CONCLUSIONS: Aerobic exercise capacity improved and per cent utilisation of VO2max declined after HIT in children with CP. Therefore, HIT can be a time efficient way to improve maximal capacity, and increase energy reserve in this patient group. TRIAL REGISTRATION NUMBER: NCT00965133.

Growth during infancy and early childhood in children with cerebral palsy: a population-based study.

AIM: To describe growth in infancy and early childhood in children with cerebral palsy (CP). METHOD: One hundred and four children with CP born at minimum 36 weeks' gestation in 2002 to 2010 were included. Prospectively collected growth data were requested from public health clinics. We calculated standard deviation (SD) scores (z-scores) for weight and height for 12 set age points for each child from birth to 5 years, and for head circumference from birth to 12 months. RESULTS: Children with CP had normal growth in weight and height if they were born non-small for gestational age (non-SGA) or had mild motor impairments (i.e. Gross Motor Function Classification System [GMFCS] I-II), whereas children born SGA or with severe motor impairments (GMFCS III-V) had reduced growth (p<0.001). Children with feeding difficulties in infancy had reduced growth in weight and height throughout early childhood, while children without feeding difficulties had normal growth. Head circumference growth decreased most severely among children born SGA, who had mean z-scores of -3.0 (95% confidence interval [CI] -3.7 to -2.2) at 1 year. INTERPRETATION: Children with mild CP had normal growth in weight and height until 5 years, and in head circumference during infancy. Feeding difficulties in infancy and being born SGA were strongly associated with reduced growth.

Assessment of body composition in children with cerebral palsy: a cross-sectional study in Norway.

AIM: The assessment of growth and body composition is challenging in children with cerebral palsy (CP). The aim of this study was to compare clinical assessments of body composition with measurements obtained using dual-energy X-ray absorptiometry (DXA) in this population. METHOD: Knee height, weight, and triceps and subscapular skinfold thickness (SFT) were measured in 47 children with CP (age range 8-18y; 18 females, 29 males). Height was estimated from knee height, and used to calculate body mass index (BMI). Using SFT measurements, body fat percentage was calculated by standard ('Slaughter') and CP-modified ('Gurka') equations and compared with results obtained using DXA. RESULTS: Children with severe gross motor function impairments (Gross Motor Function Classification System [GMFCS] level III or IV) exhibited stunted growth and had higher fat percentages and lower lean body mass than children classified in GMFCS level I or II. In 10 children classified as 'thin' according to their BMI (five of whom were assigned thinness grade of 2 or lower), percentage of body fat, as determined by DXA, was normal or high. The Slaughter equations significantly underestimated body fat percentages, whereas the precision of the CP-modified Gurka equations was excellent. INTERPRETATION: In this study, children with CP and severe motor impairments displayed stunted growth, but were not undernourished. Relying solely upon BMIs may be misleading in children with CP. Therefore, clinicians should be encouraged to measure SFT and to calculate body fat percentages using the CP-modified version of the Slaughter equation.

Feeding problems, growth and nutritional status in children with cerebral palsy.

AIM: The aim was to estimate the prevalence of feeding and nutritional problems in children with cerebral palsy (CP) in Norway. METHODS: Data were abstracted from the Norwegian CP Register for 661 (368 boys) children born 1996-2003 (mean age 6 years 7 months; SD: 1.5). For children born from 1999 to 2003, weight and height were available. Body mass index (BMI) (kg/m(2)) was used to assess nutritional status. RESULTS: One hundred and thirty-two (21%) children with CP were completely dependent on assistance during feeding. The prevalence of gastrostomy tube feeding was 14%. Longer duration of gastrostomy tube feeding was associated with higher weight and BMI, but not with height. Only 63% of the children with CP had normal BMI, 7% had grade 3 thinness, while the prevalence of overweight and obesity in our study was 16%. In all, 20% of the children had mean z-scores for weight and/or height below - 2 SD. CONCLUSION: Feeding problems in children with CP were common and associated with poor linear growth. A high proportion of the children were undernourished. Moreover, our results suggest that gastrostomy tube feeding may have been introduced too late in some children.