Empirical sample-specific approaches to define HPV16 and HPV18 seropositivity in unvaccinated, young, sexually active women.

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.

Identifying major histocompatibility complex class II-DR molecules in bovine and swine peripheral blood monocyte-derived macrophages using mAb-L243.

Major histocompatibility complex class II (MHC-II) molecules are involved in immune responses against pathogens and vaccine candidates' immunogenicity. Immunopeptidomics for identifying cancer and infection-related antigens and epitopes have benefited from advances in immunopurification methods and mass spectrometry analysis. The mouse anti-MHC-II-DR monoclonal antibody L243 (mAb-L243) has been effective in recognising MHC-II-DR in both human and non-human primates. It has also been shown to cross-react with other animal species, although it has not been tested in livestock. This study used mAb-L243 to identify Staphylococcus aureus and Salmonella enterica serovar Typhimurium peptides binding to cattle and swine macrophage MHC-II-DR molecules using flow cytometry, mass spectrometry and two immunopurification techniques. Antibody cross-reactivity led to identifying expressed MHC-II-DR molecules, together with 10 Staphylococcus aureus peptides in cattle and 13 S. enterica serovar Typhimurium peptides in swine. Such data demonstrates that MHC-II-DR expression and immunocapture approaches using L243 mAb represents a viable strategy for flow cytometry and immunopeptidomics analysis of bovine and swine antigen-presenting cells.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

Frequency and Clinical Features of Space Headache Experienced by Astronauts During Long-Haul Space Flights.

BACKGROUND AND OBJECTIVES: Few anecdotal cases and 1 small retrospective study during short-duration space missions suggest that headache may occur early in flight, as part of the space motion syndrome. Whether headaches may also occur at later stages of space flights is unknown. We aimed to prospectively characterize the incidence, timing, clinical features, and management of space headaches during long-duration flights. METHODS: We prospectively evaluated the occurrence, characteristics, and evolution of space headaches and the effects of treatment and countermeasures during long-haul flights with onboard questionnaires and correlated them with prevailing temperature, pressure, and ambient O2 and CO2 levels, measured within the International Space Station. In addition, we analyzed retrospective headache data from a different astronaut cohort. Headache data were reported using descriptive statistics and correlation data with intraindividual logistic regression models. Astronauts were included through (inter)national aerospace organizations. RESULTS: In the prospective study, 22/24 (91.7%) astronauts (mean ± SD age: 46.6 ± 6.5 years, 95.8% male) experienced ≥1 episode of headache during a total of 3,596 space days. A total of 378 episodes were reported (median 9; range 1-128) with detailed information on 189. Phenotypically, 170/189 (89.9%) episodes were tension-type headache (TTH) and 19/189 (10.1%) were migraine. Episodes in the first week differed from those in later periods in terms of phenotype (migraine 12/51 [23.5%] vs 7/138 [5.1%]; TTH 39/51 [86.5%] vs 131/138 [94.9%]; overall p = 0.0002) and accompanying symptoms: nausea: 17.6% vs 6.9%, p = 0.05; vomiting: 9.8% vs 0.7%, p = 0.005; nasal congestion: 52.9% vs 29.7%, p = 0.004; facial edema: 41.2% vs 1.4%, p < 0.001; and duration (p = 0.001). Severity and treatments were similar: acute antiheadache medication: 55.6%; other medication: 22.4%; and alternative treatments: 41.1%. Headache occurrence was not associated with temperature or ambient pressure/levels of O2 and CO2 (all p > 0.05). In the retrospective study, 23/42 (54.8%) astronauts (43.5 ± 7.2 years, 90.5% male) reported experiencing ≥1 headache episode during mission. Nasal congestion was the most common (8/33; 24.2%) accompanying symptom. Seventeen of 42 astronauts have been previously described. DISCUSSION: Astronauts during space flights frequently experience headaches. These most often have characteristics of TTHs but sometimes have migrainous features, particularly during the first week of flight in astronauts without a history of recurrent headaches before or after the space flight.

Intra-Articular Mineralization on Computerized Tomography of the Knee and Risk of Cartilage Damage: The Multicenter Osteoarthritis Study.

OBJECTIVE: Intra-articular (IA) mineralization may contribute to osteoarthritis (OA) structural progression. We studied the association of IA mineralization on knee computed tomography (CT) with cartilage damage worsening on knee magnetic resonance imaging (MRI), with a focus on location- and tissue-specific effects. METHODS: Participants from the Multicenter Osteoarthritis Study with knee CT and MRI scans were included. Presence of IA mineralization on CT was defined as a Boston University Calcium Knee Score >0 anywhere in the knee. Cartilage worsening on MRI was defined as any increase in the MRI OA Knee Score, including incident damage. We evaluated the association of whole-knee, compartment-specific (ie, medial or lateral), and subregion-specific (ie, location-matched) IA mineralization at baseline with cartilage worsening at two years' follow-up in the corresponding locations using binomial regression with generalized estimating equations, adjusting for age, sex, and body mass index (BMI). RESULTS: We included 1,673 participants (mean age 60 years, 56% female, mean BMI 29). Nine percent had any IA mineralization in the knee, and 47.4% had any cartilage worsening on follow-up. Mineralization of any tissue in the knee, regardless of location, was not associated with MRI cartilage worsening. However, cartilage mineralization was associated with 1.39 (95% confidence interval 1.04-1.88) times higher risk of cartilage worsening in the same compartment, with similar results in subregion-specific analysis. CONCLUSION: CT-detected IA mineralization in the cartilage was associated with higher risk of MRI cartilage worsening in the same compartment and subregion over two years. These findings suggest potential localized, tissue-specific effects of IA mineralization on cartilage pathology in knee OA.

A perspective on the evolution of semi-quantitative MRI assessment of osteoarthritis: Past, present and future.

OBJECTIVE: This perspective describes the evolution of semi-quantitative (SQ) magnetic resonance imaging (MRI) in characterizing structural tissue pathologies in osteoarthritis (OA) imaging research over the last 30 years. METHODS: Authors selected representative articles from a PubMed search to illustrate key steps in SQ MRI development, validation, and application. Topics include main scoring systems, reading techniques, responsiveness, reliability, technical considerations, and potential impact of artificial intelligence (AI). RESULTS: Based on original research published between 1993 and 2023, this article introduces available scoring systems, including but not limited to Whole-Organ Magnetic Resonance Imaging Score (WORMS) as the first system for whole-organ assessment of the knee and the now commonly used MRI Osteoarthritis Knee Score (MOAKS) instrument. Specific systems for distinct OA subtypes or applications have been developed as well as MRI scoring instruments for other joints such as the hip, the fingers or thumb base. SQ assessment has proven to be valid, reliable, and responsive, aiding OA investigators in understanding the natural history of the disease and helping to detect response to treatment. AI may aid phenotypic characterization in the future. SQ MRI assessment's role is increasing in eligibility and safety evaluation in knee OA clinical trials. CONCLUSIONS: Evidence supports the validity, reliability, and responsiveness of SQ MRI assessment in understanding structural aspects of disease onset and progression. SQ scoring has helped explain associations between structural tissue damage and clinical manifestations, as well as disease progression. While AI may support human readers to more efficiently perform SQ assessment in the future, its current application in clinical trials still requires validation and regulatory approval.

Serologic response to human papillomavirus genotypes following vaccination: findings from the HITCH cohort study.

BACKGROUND: Human papillomavirus (HPV) infection contributes to approximately 5% of the worldwide cancer burden. The three-dose HPV vaccine has demonstrated immunogenicity and efficacy. Humoral responses may be critical for preventing, controlling, and/or eliminating HPV infection. Using data from the HITCH cohort, we analysed humoral immune response to HPV vaccination among women in relation to the phylogenetic relatedness of HPV genotypes. METHODS: We included 96 women aged 18-24 years attending college or university in Montreal, Canada. Participants provided blood samples at enrolment and five follow-up visits. Antibody response to bacterially expressed L1 and E6 glutathione S-transferase fusion proteins of multiple Alphapapillomavirus types, and to virus-like particles (VLP-L1) of HPV16 and HPV18 were measured using multiplex serology. We assessed correlations between antibody seroreactivities using Pearson correlations (r). RESULTS: At enrolment, 87.7% of participants were unvaccinated, 2.4% had received one, 3.2% two, and 6.7% three doses of HPV vaccine. The corresponding L1 seropositivity to any HPV was 41.2%, 83.3%, 100%, and 97.0%. Between-type correlations for L1 seroreactivities increased with the number of vaccine doses, from one to three. Among the latter, the strongest correlations were observed for HPV58-HPV33 (Pearson correlation [r] = 0.96; α9-species); HPV11-HPV6 (r = 0.96; α10-species); HPV45-HPV18 (r = 0.95; α7-species), and HPV68-HPV59 (r = 0.95; α7-species). CONCLUSIONS: Correlations between HPV-specific antibody seroreactivities are affected by phylogenetic relatedness, with anti-L1 correlations becoming stronger with the number of vaccine doses received.

Genetics of migraine: Delineation of contemporary understanding of the genetic underpinning of migraine.

Migraine is a disabling episodic brain disorder with an increased familial relative risk, an increased concordance in monozygotic twins, and an estimated heritability of approximately 50%. Various genetic approaches have been applied to identify genetic factors conferring migraine risk. Initially, candidate gene associations studies (CGAS) have been performed that test DNA variants in genes prioritized based on presumed a priori knowledge of migraine pathophysiology. More recently, genome-wide association studies (GWAS) are applied that test genetic variants, single-nucleotide polymorphisms (SNPs), in a hypothesis-free manner. To date, GWAS have identified ~40 genetic loci associated with migraine. New GWAS data, which are expected to come out soon, will reveal over 100 loci. Also, large-scale GWAS, which have appeared for many traits over the last decade, have enabled studying the overlap in genetic architecture between migraine and its comorbid disorders. Importantly, other genetic factors that cannot be identified by a GWAS approach also confer risk for migraine. First steps have been taken to determine the contribution of these mechanisms by investigating mitochondrial DNA and epigenetic mechanisms. In addition to typical epigenetic mechanisms, that is, DNA methylation and histone modifications, also RNA-based mechanisms regulating gene silencing and activation have recently gotten attention. Regardless, until now, most relevant genetic discoveries related to migraine still come from investigating monogenetic syndromes with migraine as a prominent part of the phenotype. Experimental studies on these syndromes have expanded our knowledge on the mechanisms underlying migraine pathophysiology. It can be envisaged that when all (epi)genetic and phenotypic data on the common and rare forms of migraine will be integrated, this will help to unravel the biological mechanisms for migraine, which will likely guide decision-making in clinical practice in the future.

A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache.

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.

Imaging of muscle injuries in soccer.

Accurate diagnosis of muscle injuries is a challenge in everyday clinical practice and may have profound impact on the recovery and return-to-play decisions of professional athletes particularly in soccer. Imaging techniques such as ultrasound and magnetic resonance imaging (MRI), in addition to the medical history and clinical examination, make a significant contribution to the timely structural assessment of muscle injuries. The severity of a muscle injury determined by imaging findings has a decisive influence on therapy planning and affects prognosis. Imaging is of high importance when the diagnosis or grade of injury is unclear, when recovery is taking longer than expected, and when interventional or surgical management may be needed. This narrative review will discuss ultrasound and MRI for the assessment of sports-related muscle injuries in the context of soccer, including advanced imaging techniques, with the focus on the clinical relevance of imaging findings for the prediction of return to play.

Emerging Quantitative Imaging Techniques in Sports Medicine.

This article describes recent advances in quantitative imaging of musculoskeletal extremity sports injuries, citing the existing literature evidence and what additional evidence is needed to make such techniques applicable to clinical practice. Compositional and functional MRI techniques including T2 mapping, diffusion tensor imaging, and sodium imaging as well as contrast-enhanced US have been applied to quantify pathophysiologic processes and biochemical compositions of muscles, tendons, ligaments, and cartilage. Dual-energy and/or spectral CT has shown potential, particularly for the evaluation of osseous and ligamentous injury (eg, creation of quantitative bone marrow edema maps), which is not possible with standard single-energy CT. Recent advances in US technology such as shear-wave elastography or US tissue characterization as well as MR elastography enable the quantification of mechanical, elastic, and physical properties of tissues in muscle and tendon injuries. The future role of novel imaging techniques such as photon-counting CT remains to be established. Eventual prediction of return to play (ie, the time needed for the injury to heal sufficiently so that the athlete can get back to playing their sport) and estimation of risk of repeat injury is desirable to help guide sports physicians in the treatment of their patients. Additional values of quantitative analyses, as opposed to routine qualitative analyses, still must be established using prospective longitudinal studies with larger sample sizes.

Added Predictive Value of Female-Specific Factors and Psychosocial Factors for the Risk of Stroke in Women Under 50.

BACKGROUND AND OBJECTIVES: Female-specific factors and psychosocial factors may be important in the prediction of stroke but are not included in prediction models that are currently used. We investigated whether addition of these factors would improve the performance of prediction models for the risk of stroke in women younger than 50 years. METHODS: We used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20-49 years without a history of cardiovascular disease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportional hazards models to predict stroke risk were developed, including traditional cardiovascular factors, and compared with models that additionally included female-specific and psychosocial factors. We compared the risk models using the c-statistic and slope of the calibration curve at a follow-up of 10 years. We developed an age-specific stroke risk prediction tool that may help communicating the risk of stroke in clinical practice. RESULTS: We included 409,026 women with a total of 3,990,185 person-years of follow-up. Stroke occurred in 2,751 women (incidence rate 6.9 [95% CI 6.6-7.2] per 10,000 person-years). Models with only traditional cardiovascular factors performed poorly to moderately in all age groups: 20-29 years: c-statistic: 0.617 (95% CI 0.592-0.639); 30-39 years: c-statistic: 0.615 (95% CI 0.596-0.634); and 40-49 years: c-statistic: 0.585 (95% CI 0.573-0.597). After adding the female-specific and psychosocial risk factors to the reference models, the model discrimination increased moderately, especially in the age groups 30-39 (Δc-statistic: 0.019) and 40-49 years (Δc-statistic: 0.029) compared with the reference models, respectively. DISCUSSION: The addition of female-specific factors and psychosocial risk factors improves the discriminatory performance of prediction models for stroke in women younger than 50 years.

Chronic prednisone, metformin, and nonsteroidal anti-inflammatory drug use and clinical outcome in a cohort of bladder cancer patients undergoing radical cystectomy in Québec, Canada.

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.

Role of imaging for eligibility and safety of a-NGF clinical trials.

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).

Transient side shift of cluster headache attacks after unilateral greater occipital nerve injection.

Attacks of cluster headache (CH) are usually side-locked in most, but not all, patients. In a few patients, the side may alternate between or, rarely, within cluster episodes. We observed seven cases in whom the side of CH attacks temporarily shifted immediately or shortly after unilateral injection of the greater occipital nerve (GON) with corticosteroids. In five patients with previously side-locked CH attacks and in two patients with previously side-alternating CH attacks, a side shift for several weeks occurred immediately (N = 6) or shortly (N = 1) after GON injection. We concluded that unilateral GON injections might cause a transient side shift of CH attacks through inhibition of the ipsilateral hypothalamic attack generator causing relative overactivity of the contralateral side. The potential benefit of bilateral GON injection in patients who experienced a side shift after unilateral injection should be formally investigated.

Safety and Efficacy of 2D Brachytherapy vs. 3D Image-Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer-A Single Institution Retrospective Study.

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.

Strategic application of imaging in DMOAD clinical trials: focus on eligibility, drug delivery, and semiquantitative assessment of structural progression.

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.

Seasonal dependent suitability of physical parameterizations to simulate precipitation over the Himalayan headwater.

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.