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ABSTRACT Given low seroconversion rates following human papillomavirus (HPV) infection, fixed external cutoffs may lead to errors in estimating HPV seroprevalence. We evaluated finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) among unvaccinated, sexually active, HPV-exposed women to determine study-specific HPV16 and HPV18 seropositivity thresholds. We included 399 women (aged 18–24 years) enrolled in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study between 2005 and 2011 in Montreal, Canada. Participants’ blood samples from up to six visits spanning 2 years were tested by multiplex serology for antibodies [median fluorescence intensity (MFI)] specific to bacterially expressed HPV16 and HPV18 L1 glutathione S-transferase fusion proteins. We applied FMM and GBTM to baseline and longitudinal antibody titer measurements, respectively, to define HPV type-specific seronegative and seropositive distributions. Study-specific thresholds were generated as five standard deviations above the mean seronegative antibody titers, mimicking cutoffs (HPV16: 422 MFI; HPV18: 394 MFI) derived from an external population of sexually inactive, HPV DNA-negative Korean women (aged 15–29 years). Agreement (kappa) of study-specific thresholds was evaluated against external cutoffs. Seroprevalence estimates using FMM (HPV16: 27.5%–43.2%; HPV18: 21.7%–49.5%) and GBTM (HPV16: 11.8%–11.8%; HPV18: 9.9%–13.4%) thresholds exceeded those of external cutoffs (HPV: 10.2%; HPV18: 9.7%). FMM thresholds showed slight-to-moderate agreement with external cutoffs (HPV16: 0.26%–0.46%; HPV18: 0.20%–0.56%), while GBTM thresholds exhibited high agreement (HPV16: 0.92%–0.92%; HPV18: 0.82%–0.99%). Kappa values suggest that GBTM, used for longitudinal serological data, and otherwise FMM, for cross-sectional data, are robust methods for determining the HPV serostatus without prior classification rules.IMPORTANCEWhile human papillomavirus (HPV) seropositivity has been employed as an epidemiologic determinant of the natural history of genital HPV infections, only a fraction of women incidentally infected with HPV respond by developing significant antibody levels. HPV seropositivity is often determined by a dichotomous fixed cutoff based on the seroreactivity of an external population of women presumed as seronegative, given the lack of evidence of HPV exposure. However, considering the variable nature of seroreactivity upon HPV infection, which arguably varies across populations, such externally defined cutoffs may lack specificity to the population of interest, causing inappropriate assessment of HPV seroprevalence and related epidemiologic uses of that information. This study demonstrates that finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) can be used to independently estimate seroprevalence or serve as the basis for defining study-specific seropositivity thresholds without requiring prior subjective assumptions, consequently providing a more apt internally valid discrimination of seropositive from seronegative individuals.

ObjectiveTo determine reliability among four experienced and calibrated readers in cross-sectional and longitudinal semi-quantitative MRI assessments of knee osteoarthritis (OA) in the Multicenter Osteoarthritis (MOST) study.DesignFrom all MOST participants with at least one knee with readable 60-month and 84-month paired knee MRIs (1.0 ​T extremity systems), we selected 10 subjects having a spectrum of baseline disease severity of cartilage, bone marrow lesions, and meniscal damage and a spectrum of longitudinal changes in severity at 24 months follow-up. MRIs were independently assessed using the WORMS grading system by four musculoskeletal radiologists with the chronological sequence known to the readers. Kappa statistics were used to determine agreement between each pair of readers and Kendall's coefficient of concordance to determine average agreement across readers.ResultsFor most features, cross-sectional reliability was substantial to almost perfect. Regarding longitudinal reliability (detection of longitudinal change), inter-reader reliability as weighted kappa values ranged from 0.62 to 0.78 for cartilage damage, 0.75-0.88 for bone marrow lesions, 0.75-0.92 for meniscal tears, 0.67-0.95 for meniscal extrusion, 0.51-0.77 for bone attrition, 0.43-0.76 for osteophytes, 0.31-0.70 for Hoffa-synovitis, and 0.47-0.85 for effusion-synovitis. Kendall's coefficient ranged from 0.65 to 0.98.ConclusionHigh levels of cross-sectional reliability and moderate to high longitudinal reliability was achieved using four experienced readers in semiquantitative MRI-assessment of most knee OA features.

Abstract Background Studies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients. Methods This is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000–2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson’s comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone). Results Of 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55–0.82), DSS (HR 0.58, 95%CI 0.45–0.76), and RFS (HR 0.61, 95%CI 0.47–0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07–1.55), DSS (HR 1.38, 95%CI 1.10–1.72), and RFS (HR 1.41, 95%CI 1.13–1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95–1.27), 1.24 (95%CI 1.03–1.48), and 1.22 (95%CI 1.03–1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too. Conclusions In our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Background: The treatment paradigm for locally advanced cervical cancer (LACC) has shifted from two-dimensional-brachytherapy (2D-BT) to three-dimensional-image-guided adaptive BT (3D-IGABT). In this retrospective study, we report our experience with the change from 2D-BT to 3D-IGABT. Methods: We reviewed 146 LACC patients (98 3D-IGABT and 48 2D-BT) who received chemoradiation between 2004 and 2019. The multivariable odds ratio (OR) for treatment-related toxicities and hazard ratios (HR) for locoregional control (LRC), distant control (DC), failure-free survival (FFS), cancer-specific survival (CSS) and overall survival (OS) are reported. Results: The median follow-up was 50.3 months. There was a significant decrease in overall late toxicities in the 3D-IGABT group compared to the 2D-BT group (OR 0.22[0.10–0.52]), late gastrointestinal (OR 0.31[0.10–0.93]), genitourinary (OR 0.31[0.09–1.01]) and vaginal toxicities (0% vs. 29.6%). Grade ≥ 3 toxicity was low in both groups (2D-BT: 8.2% acute, 13.3% late vs. 3D-IGABT: 6.3% acute, 4.4% late, NS). The five-year LRC, DC, FFS, CSS and OS for 3D-IGABT were 92.0%, 63.4%, 61.7%, 75.4% and 73.6%, compared to 87.3%, 71.8%, 63.7%, 76.3% and 70.8% for 2D-BT (NS). Conclusions: 3D-IGABT for the treatment of LACC is associated with a decrease in overall late gastrointestinal, genitourinary and vaginal toxicities. The disease control or survival outcomes were comparable to contemporary 3D-IGABT studies.

Summary: Background: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. Methods: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. Findings: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8–6.3), two (5.1; 3.5–7.6) and five years (4.1; 3.0–5.5) compared to baseline (16.2; 14.4–18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68–0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70–0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year−1 [0.28–0.41]). We didn't find predictive factors for effectiveness. Interpretation: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. Funding: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Coronavirus disease 2019 (COVID-19) is a viral infection caused by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which spreads rapidly from person to person and manifests in most symptomatic patients as a respiratory illness, similar to prior SARS viruses. Neurologic manifestations of COVID-19 are uncommon; those so far reported include encephalopathy, stroke from large-vessel occlusion, and polyneuropathy. We report a unique neurologic complication of COVID-19 in a patient who had extensive cerebral small-vessel ischemic lesions resembling cerebral vasculitis in a characteristic combined imaging pattern of ischemia, hemorrhage, and punctuate postcontrast enhancement. Also, a characteristic lower extremity skin rash was present in our patient. Our observation lends support to the increasingly suspected mechanism of endotheliitis associated with this novel coronavirus.

Abstract The Himalayan ecosystem is fragile and needs robust management strategies for sustainability of natural resources such as water and vegetation. Therefore, reliable precipitation estimation becomes quite important from operational and regulation standpoints. It is crucial for numerous activities including policy/planning, agriculture, reservoir operations, disaster management, and others. In addition, reliable information on temporal variability of precipitation is also crucial for various applications such as agricultural and hydrological. The western Himalaya receives two distinct weather systems during summer and winter. Summer is responsible (largely) for rainfall and winter is for snowfall. Therefore, we hypothesize that there may not be a single set of parameterization schemes that can represent well both the weather systems. To investigate, we set up the WRF modeling system and performed six experiments with a combination of three microphysics (MP3, MP3, and WSM6) and two cumulus schemes (KF, and BMJ). It was found that the precipitation along the Himalayan foothills (near to basin terminal) is underestimated in four out of six experiments. Only experiments with BMJ cumulus scheme along with WSM6 and MP8 microphysics were able to show a considerable amount of precipitation along these foothills. It was noted that all six experiments showed high precipitation in the upstream region and over the mountain peaks and ridges in North-Western Himalaya. For DJF, each experiment was found to have large biases and none of them represented the observation with high confidence. However, the selection of observation reference data itself is a challenging task because of data paucity in this region. Therefore, the closest experiment to the most appropriate observation was selected as the reliable configuration (MP8_KF: MP8 microphysics and KF cumulus scheme) for DJF precipitation simulation. In this study we have, for the first time, reported the role of seasonal sensitivity for the climate scale simulations as we found that different schemes were suitable for different weather systems.

ObjectiveTo review and discuss the putative role of light, sleep, and the biological clock in cluster headache.DiscussionCluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage.ConclusionsWe hypothesize that light, sleep, and the biological clock can change the brain's state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.

Nerve growth factor (a-NGF) inhibitors have been developed for pain treatment including symptomatic osteoarthritis (OA) and have proven analgesic efficacy and improvement in functional outcomes in patients with OA. However, despite initial promising data, a-NGF clinical trials focusing on OA treatment had been suspended in 2010. Reasons were based on concerns regarding accelerated OA progression but were resumed in 2015 including detailed safety mitigation based on imaging. In 2021, an FDA advisory committee voted against approving tanezumab (one of the a-NGF compounds being evaluated) and declared that the risk evaluation and mitigation strategy was not sufficient to mitigate potential safety risks. Future clinical trials evaluating the efficacy of a-NGF or comparable molecules will need to define strict eligibility criteria and will have to include strategies to monitor safety closely. While disease-modifying effects are not the focus of a-NGF treatments, imaging plays an important role to evaluate eligibility of potential participants and to monitor safety during the course of these studies. Aim is to identify subjects with on-going safety findings at the time of inclusion, define those potential participants that are at increased risk for accelerated OA progression and to withdraw subjects from on-going studies in a timely fashion that exhibit imaging-confirmed structural safety events such as rapid progressive OA. OA efficacy- and a-NGF studies apply imaging for different purposes. In OA efficacy trials image acquisition and evaluation aims at maximizing sensitivity in order to capture structural effects between treated and non-treated participants in longitudinal fashion. In contrast, the aim of imaging in a-NGF trials is to enable detection of structural tissue alterations that either increase the risk of a negative outcome (eligibility) or may result in termination of treatment (safety).

Despite decades of research efforts and multiple clinical trials aimed at discovering efficacious disease-modifying osteoarthritis (OA) drugs (DMOAD), we still do not have a drug that shows convincing scientific evidence to be approved as an effective DMOAD. It has been suggested these DMOAD clinical trials were in part unsuccessful since eligibility criteria and imaging-based outcome evaluation were solely based on conventional radiography. The OA research community has been aware of the limitations of conventional radiography being used as a primary imaging modality for eligibility and efficacy assessment in DMOAD trials. An imaging modality for DMOAD trials should be able to depict soft tissue and osseous pathologies that are relevant to OA disease progression and clinical manifestations of OA. Magnetic resonance imaging (MRI) fulfills these criteria and advances in technology and increasing knowledge regarding imaging outcomes likely should play a more prominent role in DMOAD clinical trials. In this perspective article, we will describe MRI-based tools and analytic methods that can be applied to DMOAD clinical trials with a particular emphasis on knee OA. MRI should be the modality of choice for eligibility screening and outcome assessment. Optimal MRI pulse sequences must be chosen to visualize specific features of OA.

BackgroundTo determine whether population-adjusted rates of physical rehabilitation need (ie, disability-related epidemiological data) are associated with the workforce supply (ie, combined rates of practicing physical therapists (PTs) and occupational therapists (OTs) per 10 000 population) across high-income countries (HICs), adjusted for socio-demographic and economic covariates. MethodsThis is a cross-national ecological study. Hierarchical, multiple linear regressions analyzed current international data across 35 HICs using: current PTs and OTs supply data obtained from the international professional federations (outcome variable); needs data obtained from the Global Burden of Disease 2017 (GBD 2017); and finally relevant socio-demographic variables and supply-side covariates extracted from the World Bank, GBD 2017, the supply data sources, and the Global Health Expenditure Database. ResultsThe PTs and OTs per capita varied greatly across the 35 HICs, differing by as much as 40-fold. Denmark had the greatest supply per capita. Physical rehabilitation need was not a significant, independent predictor of workforce supply regardless of the multiple regression model used (P >.10). In the final model, after Bonferroni correction, 3 covariates were significant, independent predictors of the supply variable: gross national income (GNI) per capita and the current health expenditure in % of gross domestic product (GDP) were positive factors for workforce supply, while population size was a negative factor (all P