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OBJECTIVE Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Purpose To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. Design Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). Participants Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. Methods Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. Main Outcome Measures The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. Results Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non–adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. Conclusions A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non–adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.

Background The German clinical guideline on tobacco addiction recommends that general practitioners (GPs) provide brief stop-smoking advice to their patients according to the “5A” or the much briefer “ABC” method, but its implementation is insufficient. A lack of training is one barrier for GPs to provide such advice. Moreover, the respective effectiveness of a 5A or ABC training regarding subsequent delivery of stop-smoking advice has not been investigated. We developed a training for GPs according to both methods, and conducted a pilot study with process evaluation to optimize the trainings according to the needs of GPs. This study aims at evaluating the effectiveness of both trainings. Methods A pragmatic 2-arm cluster randomised controlled trial with a pre-post data collection will be conducted in 48 GP practices in North Rhine-Westphalia (Germany). GPs will be randomised to receive a 3.5-h-training in delivering either 5A or ABC, including peer coaching and intensive role plays with professional actors. The patient-reported primary outcome (receipt of GP advice to quit: yes/no) and secondary outcomes (recommendation rates of smoking cessation treatments, group comparison (5A versus ABC): receipt of GP advice to quit) will be collected in smoking patients routinely consulting their GP within 4 weeks prior, and 4 weeks following the training. Additional secondary outcomes will be collected at 4, 12 and 26 weeks following the consultation: use of cessation treatments during the last quit attempt (if so) since the GP consultation, and point-prevalence abstinence rates. The primary data analysis will be conducted using a mixed-effects logistic regression model with random effects for the cluster variable. Discussion If the training increases the rates of delivery of stop-smoking advice, it would offer a low-threshold strategy for the guideline implementation in German primary care. Should one method prove superior, a more specific guideline recommendation can be proposed. Trial registration German Clinical Trials Register (DRKS00012786); registered on 22th August 2017, prior to the first patient in. Open-Access-Publikationsfonds 2019

Objective This study aimed to identify and validate the diagnostic utility of a set of clinical and laboratory criteria (early warning criteria [EWC]) that portend a clinical deterioration event (escalated care event [ECE]) in neonatal intensive care unit (NICU) patients. Study Design Using the RAND appropriateness method, we first established a consensus on seven ECE, that is, events that require additional monitoring, treatment, or stay in the NICU or that were associated with morbidity. We then established consensus on EWC that could portend an ECE from an initial set of 32 potential EWC items to a final set of 10 items. The occurrence and nonoccurrence of EWC and ECE were prospectively identified and tracked over 9 weeks. Results Among 170 NICU patients studied (2,502 patient-days), the frequency of an EWC was 53 per 1,000 patient-days. Of these patients, 41% had an EWC and 16% had an ECE. An EWC was followed by an ECE within 72 hours, 37% of the time, and within a median time interval of 113 minutes. The sensitivity, specificity, positive predictive values, and negative predictive values of EWC in identifying an ECE were 0.96, 0.69, 0.37, and 0.99, respectively. Conclusion A simple bedside NICU-specific EWC identifies neonates likely to develop ECEs in the NICU.

Daily sperm production in bulls is determined by the size of the testicular Sertoli cell (SC) population established before puberty. Fine needle aspiration (FNA) is currently used as a diagnostic tool, but its value to determine SC and germ cell (GC) counts remains unexplored. The objectives were to compare three sampling techniques [(smears produced via 22G fine needle aspiration (SMR) vs. tissue sections collected via 14G aspiration (FNS) vs. conventional tissue sections (HIS)] and two stains [immunohistochemistry with GATA4 (IHC) and HE] to determine SC density in prepubertal bulls. Fourteen age-matched Angus bulls were surgically castrated. Testicular parenchyma samples and smears were stained using anti-GATA4 as a specific SC marker and HE. For stain comparison, mirrored tissue cuts were produced allowing cell counts of complementary seminiferous tubule (ST) cross sections. All data were analyzed using Pearson’s product moment correlations and linear regression. Testicular weights were correlated with IHC SC density (P = 0.018). High correlations existed for SC and GC counts done on ST cross sections using IHC (P < .0001) and HE (P < .0001). Within HIS and FNS, high correlations (r = 0.955; P ≤ 0.0001) existed between SC and automated GATA4+ cell densities. However, when comparing IHC SC density across techniques, no significant correlations (P ≤ 0.587) existed. The high correlation observed between SC counts done on mirrored ST cross sections for HE and IHC underlines the value of GATA4 as a specific SC marker in prepubertal bulls. Furthermore, the high correlation established between SC and GATA4+ cell densities within IHC HIS and FNS collection methods infers SC density determination can be automated. However, lack of correlation for SC density among techniques indicates that aspiration and conventional methods lead to different results. Research supported by North Dakota EPSCoR Doctoral Dissertation Assistantship (DDA) program.

Procarbazine hydrochloride is an oral alkylating agent primarily used as a component of chemotherapy regimens for Hodgkin's lymphoma, as well as in regimens for primary central nervous system lymphoma and high-grade gliomas. Although the prescribing information for procarbazine lists hepatic dysfunction as a potential adverse reaction, we found only one published report with a probable link between procarbazine and liver injury. We describe a 65-year-old man who developed liver injury due to procarbazine during salvage chemotherapy for non-Hodgkin's lymphoma. The patient had no preexisting liver disease, his lymphoma was without hepatic involvement, and no liver injury developed after initial chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Due to relapse of his non-Hodgkin's lymphoma, salvage chemotherapy with C-MOPP-R (cyclophosphamide, vincristine, procarbazine, prednisone, and rituximab) was administered, and the patient developed fever and aminotransferase level elevation during the second cycle. After discontinuation of all drug therapy, exclusion of other potential etiologies, and resolution of hepatic injury, the patient was rechallenged with procarbazine and again experienced fever with aminotransferase level elevation. His aminotransferase levels promptly returned to normal after discontinuation of procarbazine, and he experienced no further evidence of liver disease. Use of validated scoring systems of drug-induced liver injury indicated a definitive association between the patient's hepatic injury and procarbazine. Based on our experience with this patient, periodic assessment of hepatic function, as suggested in the package insert, is recommended in patients receiving procarbazine.