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BACKGROUND: Diagnosis of MALT lymphoma in the oral cavity is challenging. There is a great overlap in the histopathologic, immuno-histochemical and molecular features of MALT lymphoma with reactive lymphoid proliferations. The literature shows a very few case reports of primary MALT lymphoma of oral cavity. METHODS: We discuss the histopathologic, immuno-histochemical, cytogenetic features, treatment and behavior of 3 cases of primary MALT lymphoma oral cavity along with review of literature. RESULTS: The age ranged from 40 to 57 years (male to female ratio = 2:1). The sites involved were hard palate, bilateral gingivobuccal sulcus and right buccal mucosa. The most common histology was centrocyte-like (2 cases). Lymphoepithelial lesions were absent. On immunohistochemistry, all tumors showed diffuse strong CD20 and bcl2 expression with strong and diffuse MNDA staining in one case. IgH; MALT1 translocation was not seen in any of these cases. One patient received local radiotherapy, one received steroids; while the case 3 received RCHOP (Rituximab, cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine and prednisone) chemotherapy. Two patients had complete remission while one had recurrence. CONCLUSION: MALT lymphoma of oral cavity shows a wide spectrum of morphology with presence of transformed cells, that may lead to misdiagnosis of DLBL. Treatment guidelines are not well established but a tendency to excise MALT lymphomas of oral cavity has been observed. Nevertheless, MALT lymphoma of oral cavity appears to be an indolent disease.

Triple negative Breast tumor (TNBC) is an aggressive tumor with sparse data worldwide.We analyzed non-metastatic TNBC from 2013 to 2019 for demographics, practice patterns, and survival by the Kaplan Meir method. Prognostic factors for OS and DFS were evaluated using Cox Proportional Hazard model estimator for univariate and multivariable analysis after checking for collinearity among the variables.There were 1297 patients with median age of 38 years; 41 (33.3%) among 123 tested were BRCA-positives. Among these 593 (45.7%) had stage III disease, 1279 (98.6%) were grade III, 165 (13.0%) had peri-nodal extension (PNE), 212 (16.0%) lympho-vascular invasion (LVI), and 21 (1.6%) were metaplastic; 1256 (96.8%) received chemotherapy including 820 (63.2%) neoadjuvant with 306 (40.0%) pCR. Grade ≥3 toxicities occurred in 155 (12.4%) including two deaths and 3 s-primaries. 1234 (95.2%) underwent surgery [722 (55.7%) breast conservations] and 1034 (79.7%) received radiotherapy. At a median follow-up of 54 months, median disease-free (DFS) was 92.2 months and overall survival (OS) was not reached. 5-year estimated DFS and OS was 65.9% and 80.3%. There were 259 (20.0%) failures; predominantly distant (204, 15.7%) - lung (51%), liver (31.8%). In multivariate analysis presence of LVI (HR-2.00, p-0.003), PNE (HR-2.09 p-0.003), older age (HR-1.03, p-0.002) and stage III disease (HR-4.89, p-0.027), were associated with poor OS.Relatively large contemporary data of non-metastatic TNBC confirms aggressive biology and predominant advanced stage presentation which adversely affects outcomes. The data strongly indicate the unmet need for early detection to optimize care.

Background Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. Methods CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. Results VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 μg/mL and 3.86 μg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 μg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 μg/mL and 0.22 μg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected. Conclusions Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

Background Young (≤40 years) breast cancers (YBC) are uncommon, inadequately represented in trials and have unique concerns and merit studying. Methods The YBC treated with a curative intent between 2015 and 2016 at our institute were analysed. Results There were 1228 patients with a median age of 36 (12–40) years; 38 (3.1%) had Stage I, 455 (37.1%) - II, 692 (56.3%) –III, and remaining 43 (3.5%) Stage IV (oligo-metastatic) disease; 927 (75.5%) were node positive; 422 (34.4%) were Triple negatives (TNBC), 331 (27%) were HER-2 positive. There were 549 (48.2%) breast conservations and 591 (51.8%) mastectomies of which 62 (10.4%) underwent breast reconstruction. 1143 women received chemotherapy, 617 (53.9%) received as neoadjuvant and 142 (23.1%) had pathological complete response; 934 (81.9%) received adjuvant radiotherapy. At the median follow-up of 48 (0–131) months, 5-year overall and disease-free survival was 79.6% (76.8–82.5) and 59.1% (55.8–62.6). For stage I, II, III and IV, the 5-year overall-survival was 100%, 86.7% (82.8–90.6), 77.3% (73.4–81.2), 69.7% (52.5–86.9) and disease-free survival was 94% (85.9–100), 65.9% (60.3–71.5), 55% (50.5–59.5), and 29.6% (14–45.2) respectively. On multivariate analysis, TNBC and HER-2+ subgroups had poorer survival (p = 0.0035). 25 patients had BRCA mutations with a 5-year DFS of 65.1% (95% CI:43.6–86.6). Fertility preservation was administered in 104 (8.5%) patients; seven women conceived and 5 had live births. Significant postmenopausal symptoms were present in 153 (13%) patients. Conclusion More than half of the YBC in India were diagnosed at an advanced stage with aggressive features leading to suboptimal outcomes. Awareness via national registry and early diagnosis is highly warranted. Menopausal symptoms and fertility issues are prevalent and demand special focus., Highlights • Largest data of young breast cancer from India analysing demographics, outcomes and fertility. • Higher proportion of YBC with advanced stage and aggressive features compared to western data. • Inferior survival in HER-2+ not receiving Trastuzumab, need access of life saving drugs to all. • Scope of improvement and collaboration in challenges like fertility, pregnancy and quality of life.

Inflammatory factors have been considered to contribute to keratoconus (KC) pathogenesis. This study aims to determine the immune cells subsets and soluble inflammatory factor profile on the ocular surface of KC patients. 32 KC subjects (51 eyes) across different grades of severity and 15 healthy controls (23 eyes) were included in the study. Keratometry and pachymetry measurements were recorded. Ocular surface immune cells (collected by ocular surface wash) immunophenotyped using flow cytometry include leukocytes, neutrophils, macrophages, natural killer (NK) cells, pan-T cells, gamma delta T (gamma delta T) cells and NKT cells. Tear fluid collected using Schirmer's strip was used to measure 50 soluble factors by multiplex ELISA. Proportions of activated neutrophils, NK cells and gamma delta T cells were significantly increased in KC patients. Significantly higher levels of tear fluid IL-1 beta, IL-6, LIF, IL-17A, TNF alpha, IFN alpha/beta/gamma, EPO, TGF beta 1, PDGF-BB, sVCAM, sL-selectin, granzyme-B, perforin, MMP2, sFasL and IgE, along with significantly lower levels of IL-1 alpha and IL-9 were observed in KC patients. Alterations observed in few of the immuno-inflammatory parameters correlated with grades of disease, allergy, eye rubbing and keratometry or pachymetry measurements. The observation implies a distinct immuno-inflammatory component in KC pathogenesis and its potential as an additional therapeutic target in KC management.

PURPOSE There are sparse data in patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer with brain metastases from real-world settings, especially where access to newer targeted therapies is limited. METHODS This was a single institution, retrospective cohort study of patients with HER2-positive breast cancer diagnosed between January 2013 and December 2017 to have brain metastases and treated with any HER2-targeted therapy. The main objectives were to estimate progression-free survival (PFS) and overall survival (OS) from the time of brain metastases. RESULTS A total of 102 patients with a median age of 52 (interquartile range, 45-57) years were included, of whom 63 (61.8%) had received one line and 14 (13.7%) had received two lines of HER2-targeted therapies before brain metastasis, 98 (96.1%) were symptomatic at presentation, 22 (25.3%) had solitary brain lesion, 22 (25.3%) had 2-5 lesions, and 43 (49.4%) had ≥ 5 lesions. Local treatment included surgical resection in nine (8.9%) and radiotherapy in all (100%) patients. The first HER2-targeted therapy after brain metastasis was lapatinib in 71 (68.6%), trastuzumab in 19 (18.6%), lapatinib and trastuzumab in three (2.9%), trastuzumab emtansine in four (3.9%), and intrathecal trastuzumab in five (4.9%) patients. At a median follow-up of 13.9 months, the median PFS and OS were 8 (95% CI, 6.2 to 9.8) months and 14 (95% CI, 10.8 to 17.2) months, respectively, with a 2-year OS of 25% (95% CI, 16.7 to 34.4). The median PFS in patients who received lapatinib-capecitabine regimen (n = 62) was 9.0 (95% CI, 7.3 to 10.7) months. CONCLUSION There was a substantial clinical benefit of local and systemic therapy in patients with brain metastases and HER2-positive disease in a real-world setting with limited access to newer HER2-targeted drugs.

Background Overexpression of anti-apoptotic MCL-1 protein in oral squamous cell carcinoma (OSCC) is linked to disease progression, therapy resistance and poor outcome. Despite its characteristic short half-life owing to ubiquitin-proteasome-dependent degradation, oral tumours frequently show elevated MCL-1 protein expression. Hence, we investigated the role of deubiquitinase USP9X in stabilising MCL-1 protein and its contribution to oral tumorigenesis. Methods Expression of MCL-1 and USP9X was assessed by immunoblotting and immunohistochemistry in oral cancer cell lines and tissues. The association between MCL-1 and USP9X was confirmed by coimmunoprecipitation and immunofluorescence. Cell death assessment was performed by MTT, flow cytometry and clonogenic assays. Results Both USP9X and MCL-1 are significantly elevated in oral premalignant lesions and oral tumours versus normal mucosa. USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it. Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo. The elevated expression of USP9X and MCL-1 correlated with poor prognosis in OSCC patients. Conclusion We demonstrate the oncogenic role of USP9X in driving early-to-late stages of oral tumorigenesis via stabilisation of MCL-1, suggesting its potential as a prognostic biomarker and therapeutic target in oral cancers.

Surgery is the primary treatment of phyllodes tumor of the breast, and margins are the most important risk factor associated with local recurrence. We conducted a retrospective audit of 433 patients treated at our center.Women who presented with phyllodes tumors between 1999 and 2017 were included in the analysis. Data was collected from the hospital medical records, telephonic interviews, and electronic mail.Of the 433 women included in this study, 177 (40.9%) had benign phyllodes tumors, 84 (19.4%) were borderline, 131 (30.3%) were malignant, and 41 (9.5%) had sarcoma. A history of previous excision was noted in 154 (35.6%) patients, of which 104 presented with local recurrence. Of the total patients, 209 (48.3%) underwent breast conservation surgery; the median pT was 6 cm. At a median follow-up of 37.9 months, the 5-year disease-free survival (DFS) was 82.9%. On multivariate analysis, the factors that impacted DFS were histology (hazard ratio, 4.1; 95% confidence interval [CI], 1.5-10.9; P = .005) and history of previous excision biopsy (hazard ratio, 3.39; 95% CI, 1.76-6.52; P .001). We analyzed 231 women who presented without any prior excision separately, wherein at a median follow-up of 44.1 months, the DFS was 92.1% (95% CI, 92.05%-92.15%). In addition, less recurrences were noted in this cohort (5.6% [13/231] in no-excision biopsy vs. 12.5% with surgery done prior to presentation to our institute).A previous history of excision and the histologic subtype of phyllodes tumor are factors that have an impact on DFS, thus emphasizing the need for appropriate surgical planning and en bloc excision of the phyllodes at presentation.

We present the findings of 18 F-FDG PET and 68 Ga-fibroblast activation protein PET scans done in a case of bilateral breast carcinoma with 2 different histopathology, left breast tubulolobular carcinoma and right breast invasive breast carcinoma of no special type.

Background: It is unknown how individuals with multiple sclerosis (MS) age compared to unaffected peers. Objectives: The objective of the study is to describe the impact of MS on health and functioning in aging women. Methods: We used 10-item Physical Functioning Scale (PF10) scores (from the Short Form-36 (SF-36)) and other indicators of general, physical, mental health, and memory collected repeatedly over 25 years with self-administered questionnaires among participants in the Nurses’ Health Study ( n = 121,700 recruited at ages 30–55) and Nurses’ Health Study II ( n = 116,429 recruited at ages 25–42) to compare women with MS ( n = 733) to unaffected peers in their health and disability, and describe/quantify the burden of aging with MS. Results: Women with MS had a consistently lower PF10 by 0.9–1.7 standard deviations with greater overall variability than unaffected women. PF10-scores gradually decreased with increasing age in both groups, but MS cases declined 3–4 times faster in midlife, while decline was similar in old age. The physical function score of 45-year-old women with MS was comparable to that of 75-year-old unaffected women; 70-year-old women with MS scored similarly to 85-year-old unaffected women. MS cases also reported worse health/more disability throughout adulthood on the other indicators. Conclusion: The age-related decline in physical health is accelerated by 15–30 years in MS patients compared to unaffected peers.

Objective No relapse risk prediction tool is currently available to guide treatment selection for multiple sclerosis (MS). Leveraging electronic health record (EHR) data readily available at the point of care, we developed a clinical tool for predicting MS relapse risk. Methods Using data from a clinic‐based research registry and linked EHR system between 2006 and 2016, we developed models predicting relapse events from the registry in a training set (n = 1435) and tested the model performance in an independent validation set of MS patients (n = 186). This iterative process identified prior 1‐year relapse history as a key predictor of future relapse but ascertaining relapse history through the labor‐intensive chart review is impractical. We pursued two‐stage algorithm development: (1) L1‐regularized logistic regression (LASSO) to phenotype past 1‐year relapse status from contemporaneous EHR data, (2) LASSO to predict future 1‐year relapse risk using imputed prior 1‐year relapse status and other algorithm‐selected features. Results The final model, comprising age, disease duration, and imputed prior 1‐year relapse history, achieved a predictive AUC and F score of 0.707 and 0.307, respectively. The performance was significantly better than the baseline model (age, sex, race/ethnicity, and disease duration) and noninferior to a model containing actual prior 1‐year relapse history. The predicted risk probability declined with disease duration and age. Conclusion Our novel machine‐learning algorithm predicts 1‐year MS relapse with accuracy comparable to other clinical prediction tools and has applicability at the point of care. This EHR‐based two‐stage approach of outcome prediction may have application to neurological disease beyond MS.

Background Pregnancy associated breast cancer (PABC) is a rare entity and defined as breast cancer diagnosed during pregnancy or one-year post-partum. There is sparse data especially from low and middle-income countries (LMIC) and merits exploration. Methods The study (2013–2020) evaluated demographics, treatment patterns and outcomes of PABC. Results There were 104 patients, median age of 31 years; 43 (41%) had triple-negative disease, 31(29.8%) had hormone-receptor (HR) positive and HER2 negative, 14 (13.5%) had HER2-positive and HR negative and 16(15.4%) had triple positive disease. 101(97%) had IDC grade III tumors and 74% had delayed diagnosis. 72% presented with early stage (24, EBC) or locally advanced breast cancer (53, LABC) and received either neoadjuvant (n = 49) or adjuvant (n = 26) chemotherapy and surgery. Trastuzumab, tamoxifen, and radiotherapy were administered post-delivery. At a median follow up of 27 (IQR:19–35) months, the estimated 3-year event-free survival (EFS) for EBC and LABC was 82% (95% CI: 65.2–100) and 56% (95% CI: 42–75.6%) and for metastatic 24% (95% CI: 10.1%–58.5%) respectively. Of the 104 patients, 34 were diagnosed antepartum (AP) and 15 had termination, 2 had preterm and 16 had full-term deliveries(FTDs). Among postpartum cohort (n = 70), 2 had termination, 1 had preterm, 67 had FTDs. 83(including 17 from AP) children from both cohorts were experiencing normal milestones. Conclusion Data from the first Indian PABC registry showed that the majority had delayed diagnosis and aggressive features(TNBC, higher grade). Treatment was feasible in majority and stage matched outcomes were comparable to non-PABCs., Highlights • Pregnancy associated breast cancer (PABC) is a rare and Challenging entity with lack of data from low-middle income countries. • First Indian data showed that stage matched oncologic outcomes were comparable to non-PABC. • Obstetric outcomes were similar to non-cancer associated pregnancies with normal cognitive development. • Creating awareness and early diagnosis is of utmost importance to improve prognosis in this unique entity

Objective Serum neurofilament light (sNfL) is a promising new biomarker in multiple sclerosis (MS). We explored the relationship between sNfL and health outcomes and resource use in MS patients. Methods MS patients with serum samples and health‐outcome measurements collected longitudinally between 2011 and 2016 were analyzed. sNfL values were evaluated across age and gender. Data were analyzed using correlation with log‐transformed sNfL values. Results A total of 304 MS patients with a mean age of 32.9 years, average EDSS of 1.6 (SD = 1.5) and baseline sNfL of 8.8 (range 1.23–78.3) pg/mL were studied. Baseline sNFL values increased with age and were higher in females. Baseline sNfL correlated with baseline Multiple Sclerosis Quality of Life physical composite (mean = 49.4 (9.1), P = 0.035) and baseline EDSS (P = 0.002). Other PRO measures at baseline did not show a significant relationship with baseline sNfL. Average of baseline and follow‐up sNfL correlated with MSQoL physical‐role limitations (mean = 48.9 (10.8), P = 0.043) and social‐functioning (mean = 52.3 (7), P = 0.034) at 24‐month follow‐up. We found a trend for numerically higher sNfL levels in nonpersistent patients compared to those who were persistent to treatment (11.13 vs. 8.53 pg/mL, P = 0.093) measured as average of baseline and 24‐month values. Baseline NfL was associated with number of intravenous steroid infusions (mean = 0.2; SD = 3.0, P = 0.013), whereas the average of baseline and 12 months NfL values related to inpatient stays at 12 months (mean = 0.2; SD = 3.0 P = 0.053). Conclusion Serum NfL is a patient‐centric biomarker that correlated with MS patient health‐outcomes and healthcare utilization measures in a real‐world cohort.

Extra-nodal natural killer (NK)/T-cell lymphoma is a rare, distinctive clinicopathologic entity with an aggressive clinical course. High expression of multidrug-resistant (MDR) P-gp on NK lymphoma cells renders this disease resistant to anthracycline-based chemotherapy regimens. Over the years, based on retrospective analysis and phase II studies, regimens with L-asparaginase and non-MDR drugs have been used.To evaluate the outcome of patients with extra-nodal NK/T-cell lymphoma treated in a tertiary cancer care center in India from 2012 to 2021.Retrospective, observational, single-center study.Hematolymphoid Department, Tata Memorial Hospital.From January 2010 to December 2021, all consecutive patients with NK/T-cell lymphoma were analyzed.Relapse-free survival and overall survival.A total of 78 patients with a diagnosis of extra-nodal NK/T-cell lymphoma were treated from 2010 to 2021. Amongst them, 56 (71.8%) were male, with a median age of 40 years (15-71 years). The most common presenting symptom was nasal swelling (9%), followed by dysphagia (3.8%). B symptoms were present in 35 patients (45%). Only 5% had HLH anytime during the treatment. One-third of the patients had an ECOG performance status1. Nasal type constituted 80% of the cohort, regional node was involved in 60%, distant node was involved in 28%, 33% had more than 1 extra-nodal site involved, 23% had bulky disease, and 40% had advanced stage (stage 3-4) at presentation. EBV LMP1 was positive in 19 patients (24%). EBERISH was available in 9 patients, of which 7 were positive. Fifteen patients received treatment prior to presentation to our center (CHOP in 10 patients). At our center, the SMILE chemotherapy protocol was administered to 52 patients (66.7%). Consolidative radiation therapy was administered in 43 patients (55.1%). The best radiological response of CR was achieved in 49 patients (62.8%). After a median follow-up of 30 months, 30 (38.5%) patients relapsed and 30 (38.5%) died. Median relapse-free survival was 45 (95%CI: 5.1-84.8) months. Overall survival at 36 months was 53.4% (95%CI: 41.7%-68.4%).The outcome of NK/T-cell lymphoma in our cohort is comparable to the outcomes found in the literature.

The present study aimed to evaluate the safety and prophylactic efficacy of add-on Comprehensive Ayurveda and mindfulness-based Yoga (CAY) regimen to standard care among HealthCare Workers (HCWs) against COVID-19.This prospective single-blind (outcome assessor-blinded) RCT was conducted in tertiary care hospital in Delhi during July 2020-April 2021. HCWs of both sexes were randomized to add-on CAY intervention or control group. The primary outcomes were the incidence of confirmed COVID-19 positive cases and influenza-like illness events (ILI). Secondary outcomes were anxiety (GAD-7), depression (PHQ-9), and quality of life (SF-36) at the end of 12 weeks.Three hundred fifty-six participants (181 in intervention and 175 in the control group) were randomized. With the modified intention to treat approach, we analyzed 309 participants. The mean age for the intervention and control group was 39.3 ± 10.1 and 36.6 ± 10 years, respectively. Incidence of COVID-19 event was higher in control group compared to CAY group (16 of 164 [9.8%] vs. 11 of 145 [7.6%]; P = 0.50). The incidence of ILI events was also higher in the control group as compared to the CAY group (14 of 164 [8.5%] vs 9 of 145 [6.2%]). The health change domain of the SF-36 questionnaire showed statistically significant improvement in the CAY group as compared to the control group (P 0.01).Incidence of COVID-19 and ILI events was lower in the CAY group compared with the contr ol group, though the difference is not statistically significant.

Background Therapeutic decisions in breast carcinoma are being made on the basis of tumor cell proliferation using exorbitant genomic tests. The 2013 St Gallen meeting advocated surrogate definitions for classifying tumors into luminal subtypes on the basis of immunohistochemical (IHC) markers. We studied the classification of estrogen receptor (ER)-positive tumors using these definitions as well as different methods for Ki-67 labeling index (LI) estimation. Patients and Methods A total of 541 ER+ invasive breast carcinoma cases from January 2012 to December 2012 were evaluated for Ki-67 LI by the average and hot spot methods. The IHC results of ER, PR, and human epidermal growth factor receptor 2 (HER2) were noted. HER2 IHC equivocal (2+) samples were subjected to HER2 fluorescence in-situ hybridization testing. Luminal subgroups created on the basis of the 2013 St Gallen meeting guidelines were correlated with clinicopathologic variables and disease-free survival. Results The distribution of luminal subtypes was as follows: luminal A–like, 13.3%; luminal B–like (HER2−), 57.9%; and luminal B–like (HER2+), 28.8%. Approximately 6% of cases were recategorized into different subgroups when the average method was used instead of the hot spot method for Ki-67 LI assessment. Younger patients (≤ 50 years), grade 3 tumors, positive axillary nodes, recurrence, and distant metastasis had a positive statistical correlation with luminal B–like (HER2−) subtype. Patients with luminal B–like (HER2−) tumors had a shorter disease-free survival compared to patients with luminal A–like tumors. Conclusion Ki-67 LI, irrespective of the method of assessment, along with PR, can be efficiently used to divide ER+ tumors into prognostic subgroups in Indian patients.

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P

OBJECTIVE: To correlate uterine artery Doppler findings with maternal and neonatal outcomes in early- and late-onset preeclampsia with severe features. METHODOLOGY: Doppler scan was done in both uterine arteries. Maternal and neonatal outcomes in women with abnormal and normal Doppler results were compared. RESULTS: Abnormal Doppler results were present in 45 women (75%). Thirty-four (56.7%) women had abnormal RI, 19 (31.6%) had abnormal PI, and 36 (60%) had diastolic notch. Of the women who participated in the study, 21.6% developed maternal complications, and the majority belonged to the early-onset severe preeclampsia group. Diastolic notch was twofold more frequent in the early group. RI was abnormal in 63% of the early-onset and 50% of the late-onset group. CONCLUSION: Pregnancies with early-onset preeclampsia who had abnormal uterine artery Doppler findings were at high risk for both maternal and neonatal complications, whereas those who had late-onset preeclampsia with abnormal Doppler findings only had an increased risk of perinatal complications.

Objectives We describe the presentation, treatment and outcome of children with multisystem inflammatory syndrome with COVID-19 (MIS-C) in Mumbai metropolitan area in India. Methods This is an observational study conducted at four tertiary hospitals in Mumbai. Parameters including demographics, symptomatology, laboratory markers, medications and outcome were obtained from patient hospital records and analyzed in patients treated for MIS-C (as per WHO criteria) from 1 May, 2020 to 15 July, 2020. Results 23 patients (11 males) with median (range) age of 7.2 (0.8–14) years were included. COVID-19 RT-PCR or antibody was positive in 39.1% and 30.4%, respectively; 34.8% had a positive contact. 65% patients presented in shock; these children had a higher age (P=0.05), and significantly higher incidence of myocarditis with elevated troponin, NT pro BNP and left ventricular dysfunction, along with significant neutrophilia and lymphopenia, as compared to those without shock. Coronary artery dilation was seen in 26% patients overall. Steroids were used most commonly for treatment (96%), usually along with intravenous immunoglobulin (IVIg) (65%). Outcome was good with only one death. Conclusion Initial data on MIS-C from India is presented. Further studies and longer surveillance of patients with MIS-C are required to improve our diagnostic, treatment and surveillance criteria.

ObjectiveTo characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS).MethodsThis was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005.ResultsIn total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score.ConclusionsPersons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual.

Objective Multiple sclerosis (MS) is an autoimmune demyelinating disorder, which is characterized by relapses and remissions. Serum neurofilament light chain (sNfL) is an emerging biomarker of disease activity but its clinical use is still limited. In this study, we aim to characterize the temporal association between sNfL and new clinical relapses and new gadolinium‐enhancing (Gd+) lesions. Methods Annual sNfL levels were measured with a single‐molecule array (SIMOA) assay in 94 patients with MS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital (CLIMB) study. We used a multivariable linear mixed‐effects model to test the temporal association of sNfL with clinical relapses and/or new Gd+ lesions. We adjusted this model for age, disease duration, sex, and disease‐modifying therapies (DMTs) use. Results In the 3 months after a Gd+ lesion, we observed an average 35% elevation in sNfL (P

Neuromyelitis optica spectrum disorders (NMOSD) are a type of neurological autoimmune disease characterized by attacks of CNS inflammation that are often severe and predominantly affect the spinal cord and optic nerve. The majority of individuals with NMOSD are women, many of whom are of childbearing age. Although NMOSD are rare, several small retrospective studies and case reports have indicated that pregnancy can worsen disease activity and might contribute to disease onset. NMOSD disease activity seems to negatively affect pregnancy outcomes. Moreover, some of the current NMOSD treatments are known to pose risks to the developing fetus and only limited safety data are available for others. Here, we review published studies regarding the relationship between pregnancy outcomes and NMOSD disease activity. We also assess the risks associated with using disease-modifying therapies for NMOSD during the course of pregnancy and breastfeeding. On the basis of the available evidence, we offer recommendations regarding the use of these therapies in the course of pregnancy planning in individuals with NMOSD. Neuromyelitis optica spectrum disorders (NMOSD) are a type of neurological autoimmune disease characterized by attacks of CNS inflammation. In this Review, the authors discuss the relationship between pregnancy outcomes and NMOSD disease activity, and outline potential treatment approaches.

Stem cell therapies (SCT) have not received formal regulatory approval for the treatment of people with multiple sclerosis (PwMS), but PwMS may seek various options on their own accord. The current literature largely focuses on the efficacy and safety of SCT in PwMS in clinical trials, in particular autologous hematopoietic stem cell transplantation (aHSCT), in carefully selected participants. There is little reported on the MS disease modifying therapy (DMT) management of PwMS who choose to undergo SCT outside of these trials.We identified PwMS from two academic centers who had MS diagnosis fulfilling 2017 McDonald criteria and received SCT (methodologies permitted: aHSCT, umbilical-derived mesenchymal stem cells and/or adipose-derived mesenchymal stem cells (AdMSC)), with the goal to treat MS, between 1/1/2015 and 11/30/2021.Nine PwMS (five females; age range at SCT treatment 25-69 years old; MS disease duration 1-12 years; six relapsing-remitting, three secondary progressive, one primary progressive) underwent a total of eleven SCTs (nine aHSCT, two AdMSC, one umbilical-derived MSC) with the goal to treat MS. Two of six PwMS who underwent SCT10 years from MS diagnosis, and one of three PwMS who underwent stem cell therapies10 years from MS diagnosis were clinically stable thereafter. An MS DMT was resumed in five PwMS afterwards, including rituximab, ocrelizumab, siponimod, and glatiramer acetate: one remained clinically stable, whereas four clinically progressed. Four PwMS remained off of a DMT: three were clinically stable, whereas one clinically progressed. All nine patients demonstrated radiographic stability by MRI after SCT. Only one met formal criteria to consider aHSCT for MS.We demonstrate the heterogeneous real-world experience of treating MS after patient-chosen experimental SCTs, detailing the range of DMT management in various patient circumstances. Limitations of our study include its small sample size and the variety of stem cell therapies received.

Preventing new HIV infections, especially amongst young women, is key to ending the HIV epidemic especially in sub-Saharan Africa. Potent antiretroviral (ARV) drugs used as pre-exposure prophylaxis (PrEP) are currently being formulated as long-acting implantable devices, or nanosuspension injectables that release drug at a sustained rate providing protection from acquiring HIV. PrEP as implants (PrEP Implants) offers an innovative and novel approach, expanding the HIV prevention toolbox. Feedback from providers and future users in the early clinical product development stages may identify modifiable characteristics which can improve acceptability and uptake of new technologies. Healthcare workers (HCWs) perspectives and lessons learned during the rollout of contraceptive implants will allow us to understand what factors may impact the roll-out of PrEP implants. We conducted eighteen interviews with HCWs (9 Nurses and 9 Community Healthcare Workers) in rural KwaZulu-Natal, South Africa. HCWs listed the long-acting nature of the contraceptive implant as a key benefit, helping to overcome healthcare system barriers like heavy workloads and understaffing. However, challenges like side effects, migration of the implant, stakeholder buy-in and inconsistent training on insertion and removal hampered the roll-out of the contraceptive implant. For PrEP implants, HCWs preferred long-acting products that were palpable and biodegradable. Our findings highlighted that the characteristics of PrEP implants that are perceived to be beneficial by HCWs may not align with that of potential users, potentially impacting the acceptability and uptake of PrEP implants. Further our data highlight the need for sustained and multi-pronged approaches to training HCWs and introducing new health technologies into communities. Finding a balance between the needs of HCWs that accommodate their heavy workloads, limited resources at points of delivery of care and the needs and preferences of potential users need to be carefully considered in the development of PrEP implants.

Oral tolerance is defined as the specific suppression of cellular and/or humoral immune responses to an Ag by prior administration of the Ag through the oral route. Although the investigation of oral tolerance has classically involved Ag feeding, we have found that oral administration of anti-CD3 mAb induced tolerance through regulatory T (Treg) cell generation. However, the mechanisms underlying this effect remain unknown. In this study, we show that conventional but not plasmacytoid dendritic cells (DCs) are required for anti-CD3–induced oral tolerance. Moreover, oral anti-CD3 promotes XCL1 secretion by small intestine lamina propria γδ T cells that, in turn, induces tolerogenic XCR1+ DC migration to the mesenteric lymph node, where Treg cells are induced and oral tolerance is established. Consistent with this, TCRδ−/− mice did not develop oral tolerance upon oral administration of anti-CD3. However, XCL1 was not required for oral tolerance induced by fed Ags, indicating that a different mechanism underlies this effect. Accordingly, oral administration of anti-CD3 enhanced oral tolerance induced by fed MOG35–55 peptide, resulting in less severe experimental autoimmune encephalomyelitis, which was associated with decreased inflammatory immune cell infiltration in the CNS and increased Treg cells in the spleen. Thus, Treg cell induction by oral anti-CD3 is a consequence of the cross-talk between γδ T cells and tolerogenic DCs in the gut. Furthermore, anti-CD3 may serve as an adjuvant to enhance oral tolerance to fed Ags.

Near miss occurs in far greater numbers than maternal deaths and allows a more robust quantification on risk factors and determinants of life-threatening complications. A 'Three delay model' has been proposed in identification of causes of near miss and maternal deaths. There may be delay in seeking and obtaining health care: delay in recognising danger signs and deciding to reach source of care, delay in reaching appropriate source of care and delay in obtaining appropriate and adequate treatments. We compared various delays between near miss cases (

Neurogenic lower urinary tract dysfunction (LUTD) results in lower urinary tract symptoms (LUTS) that impact quality of life in people with multiple sclerosis (PwMS). The risk factors and the contribution of LUTD to multiple sclerosis (MS) disease progression are under-researched.To identify clinical and demographic predictors of LUTS in PwMS and gaps in clinical ascertainment.Participants were adults with MS enrolled in a prospective, multicenter study (SUMMIT, N=802), including a subset of N = 258 patients in the UCSF EPIC study for whom medical records were further reviewed. Demographic (age, sex, race, ethnicity), clinical (disease duration, MS type), and female-specific reproductive factors (e.g., parity) were evaluated to determine associations with bowel/bladder functional system score. Participants' medical records were analyzed to understand the patterns of LUTS ascertainment by physicians and the specific contribution of LUTS to overall bowel/bladder functional system scores.802 participants (71.3% female) contributed to these analyses. Higher bowel/bladder functional system scores, indicating worsening symptoms and function, were significantly associated with female sex (p=0.001) and progressive MS type (p≤ 0.001). In the EPIC participants, female-specific reproductive exposures (parity, menopause) were not significantly associated with worse bowel/bladder functional system scores. Most (98%) bowel/bladder functional system scores reflected the severity of LUTS (relative to bowel dysfunction). LUTS were under-ascertained clinically, and more so in women (XFemale sex and MS type are predictive of worsening LUTS. Symptoms may be less likely to be ascertained by clinicians in females compared to males.

Key Points Question In the management of multiple sclerosis, is there a difference in relapse outcomes associated with commonly prescribed, standard-efficacy medications as well as with common higher-efficacy medications? Findings This comparative effectiveness study integrated electronic health records with research registry data and found no significant differences in relapse outcomes between dimethyl fumarate and fingolimod after correcting for confounding biases. Rituximab was associated with a lower relapse rate when compared with natalizumab after bias correction. Meaning The study illustrates the value of incorporating electronic health record data as high-dimensional covariates in real-world comparative effectiveness analysis of multiple sclerosis medications., Importance As disease-modifying treatment options for multiple sclerosis increase, comparisons of the options based on real-world evidence may guide clinical decision-making. Objective To compare the relapse outcomes between 2 pairs of disease-modifying treatments: dimethyl fumarate vs fingolimod and natalizumab vs rituximab. Design, Setting, and Participants This comparative effectiveness study integrated data from a clinic-based multiple sclerosis research registry and its linked electronic health records (EHR) system between January 1, 2006, and December 31, 2016, and built treatment groups for each pairwise disease-modifying treatment comparison according to both registry records and electronic prescriptions. Parallel analyses were conducted from October 11, 2019, to July 7, 2021. Main Outcomes and Measures The main outcomes were the 1-year and 2-year relapse rates as well as the time to relapse. To compare relapse outcomes, the study adjusted for covariates from 2 sources (registry and EHR) and corrected for confounding biases among the covariates by the doubly robust estimation. Results The study included 4 treatment groups: dimethyl fumarate (n = 260; 198 women [76.2%]; 227 non-Hispanic White individuals [87.3%]; mean [SD] age at diagnosis, 41.7 [10.4] years), fingolimod (n = 267; 190 women [71.2%]; 222 non-Hispanic White individuals [83.1%]; mean [SD] age at diagnosis, 37.9 [9.9] years), natalizumab (n = 204; 160 women [78.4%]; 172 non-Hispanic White individuals [84.3%]; mean [SD] age at diagnosis, 37.2 [10.6] years), and rituximab (n = 115; 83 women [72.2%]; 99 non-Hispanic White individuals [86.1%]; mean [SD] age at diagnosis, 44.1 [11.1] years). No significant differences were found in the relapse outcomes between dimethyl fumarate and fingolimod after correcting for confounding biases and multiple testing (difference in 1-year relapse rate, 0.028 [95% CI, –0.031 to 0.084]; difference in 2-year relapse rate, 0.071 [95% CI, 0.008-0.128]; relative risk of 2-year non-relapse, 0.957 [95% CI, 0.884-1.035] with dimethyl fumarate as reference). When compared with rituximab, natalizumab was associated with a higher relapse rate for all 3 outcomes after bias correction and multiple testing (difference in 1-year relapse rate, 0.080 [95% CI, 0.013-0.137]; difference in 2-year relapse rate, 0.132 [95% CI, 0.043-0.189]; relative risk of 2-year non-relapse, 0.903 [95% CI, 0.822-0.944]). Confounders were identified from EHR data not recorded in the registry data through data-driven feature selection. Conclusions and Relevance This study reports real-world evidence of equivalent relapse outcomes between dimethyl fumarate and fingolimod and relapse reduction in favor of rituximab relative to natalizumab. This approach illustrates the value of incorporating EHR data as high-dimensional covariates in real-world treatment comparison., This comparative effectiveness study uses data from a multiple sclerosis registry and linked electronic health records to compare the relapse outcomes between 2 disease-modifying treatment pairs: dimethyl fumarate vs fingolimod and natalizumab vs rituximab.

To investigate patient-reported outcome (PRO) measures in patients with relapsing-remitting multiple sclerosis (RRMS) who transition to secondary progressive multiple sclerosis (SPMS).Subjects enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) who completed PRO measures in the RRMS and SPMS phases were identified (n = 52). The PRO measures were Medical Outcomes Study Short-Form 36 Health Survey (SF-36), the Modified Fatigue Impact Scale (MFIS), and the Center for Epidemiologic Studies Depression Scale (CESD). Two control groups of RRMS CLIMB patients who did not progress to SPMS were identified based on different matching criteria related to age, sex, disease duration and Expanded Disability Status Scale (EDSS). Summary statistics for each PRO were calculated at the last RRMS measurement and first SPMS measurement, and the change over this transition was calculated using a paired t-test. Patients who transitioned were compared to the control groups using linear regression to adjust for age, disease duration and EDSS and a mixed model to further account for the matching with a random effect for matched group.Patients who transitioned from RRMS to SPMS had noticeable deficits in terms of Quality of Life (QOL) and fatigue at the visit prior to the transition. Patients worsened in terms of SF-36 Role Physical (- 3.6 [- 6.6, - 0.7]), Social Functioning (- 3.7 [- 6.4, - 1.0]), and Physical Component Summary (- 2.3 [- 4.5, - 0.1]) during the transition from RRMS to SPMS. When patients who transitioned were compared to the matched subjects, they had worse scores on several outcomes, including Physical Functioning (adjusted mean difference = - 10.8 [- 14.1, - 7.5]), Physical Component Summary (- 5.2 [- 9.3, - 1.0]), fatigue (8.9 [1.7, 16.1]), and depression (3.1 [0.3, 5.9]).Patients in the period closely preceding transition from RRMS to SPMS have worse physical QOL and fatigue compared to subjects who remain RRMS.

Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood.In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected.254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p0.001), and longer time since last anti-CD20 therapy infusion (p0.001). 92.8% (13/14) vaccine responders (spike antibody titer100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody20 ug/dL. No patients required ICU care or died.Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered.

Adnexal torsion is the fifth leading cause of gynaecological emergencies (Tandulwadkar et al. 2009). It refers to complete or partial rotation of the adnexal supporting organ, which if untreated re...