Topical review: Lactation and use of DMTs in women with MS.

One in three females with multiple sclerosis (MS) becomes pregnant after diagnosis. In the postpartum period, there is a risk of rebound inflammatory activity. This risk can likely be reduced with breastfeeding, as well as with early initiation of effective therapies that have low therapeutic lag. To guide patients in their choices surrounding breastfeeding and MS therapies, clinicians must be familiar with how best to protect against relapses, to ensure infant safety, and to support breastfeeding choices. This topical review provides a broad framework on lactation in women with MS. It seeks to reframe guidelines around caring for the maternal-infant dyad, and for diverse populations living with MS. It also provides updated data on the effects of lactation in women with MS and the limited data on transfer of disease-modifying therapies (DMTs) into breastmilk. The ultimate goal is to support informed shared decision-making between clinicians and patients regarding breastfeeding during the high-risk postpartum period.

ISG15/GRAIL1/CD3 axis influences survival of patients with esophageal adenocarcinoma.

Immunosuppression is a common feature of esophageal adenocarcinoma (EAC) and has been linked to poor overall survival (OS). We hypothesized that upstream factors might negatively influence CD3 levels and T cell activity, thus promoting immunosuppression and worse survival. We used clinical data and patient samples of those who progressed from Barrett's to dysplasia to EAC, investigated gene (RNA-Seq) and protein (tissue microarray) expression, and performed cell biology studies to delineate a pathway impacting CD3 protein stability that might influence EAC outcome. We showed that the loss of both CD3-ε expression and CD3+ T cell number correlated with worse OS in EAC. The gene related to anergy in lymphocytes isoform 1 (GRAIL1), which is the prominent isoform in EACs, degraded (ε, γ, δ) CD3s and inactivated T cells. In contrast, isoform 2 (GRAIL2), which is reduced in EACs, stabilized CD3s. Further, GRAIL1-mediated CD3 degradation was facilitated by interferon-stimulated gene 15 (ISG15), a ubiquitin-like protein. Consequently, the overexpression of a ligase-dead GRAIL1, ISG15 knockdown, or the overexpression of a conjugation-defective ISG15-leucine-arginine-glycine-glycine mutant could increase CD3 levels. Together, we identified an ISG15/GRAIL1/mutant p53 amplification loop negatively influencing CD3 levels and T cell activity, thus promoting immunosuppression in EAC.

"Self-care selfies": Patient-uploaded videos capture meaningful changes in dexterity over 6 months.

OBJECTIVE: Upper extremity function reflects disease progression in multiple sclerosis (MS). This study evaluated the feasibility, validity, and sensitivity to change of remote dexterity assessments applying human pose estimation to patient-uploaded videos. METHODS: A discovery cohort of 50 adults with MS recorded "selfie" videos of self-care tasks at home: buttoning, brushing teeth, and eating. Kinematic data were extracted using MediaPipe Hand pose estimation software. Clinical comparison tests were grip and pinch strength, 9 hole peg test (9HPT), and vibration, and patient-reported dexterity assessments (ABILHAND). Feasibility and acceptability were evaluated (Health-ITUES framework). A validation cohort (N = 35) completed 9HPT and videos. RESULTS: The modality was feasible: 88% of the 50 enrolled participants uploaded ≥3 videos, and 74% completed the study. It was also usable: assessments easy to access (95%), platform easy to use (97%), and tasks representative of daily activities (86%). The buttoning task revealed four metrics with strong correlations with 9HPT (nondominant: r = 0.60-0.69, dominant: r = 0.51-0.57, P < 0.05) and ABILHAND (r = -0.48, P = 0.05). Retest validity at 1 week was stable (r > 0.8). Cross-sectional correlations between video metrics and 9HPT were similar at 6 months, and in the validation cohort (nondominant: r = 0.46, dominant: r = 0.45, P < 0.05). Over 6 months, pinch strength (5.8-5.0 kg/cm2 , P = 0.05) and self-reported pinch (ABILHAND) decreased marginally. While only 15% of participants worsened by 20% on 9HPT, 70% worsened in key buttoning video metrics. INTERPRETATION: Patient-uploaded videos represent a novel, patient-centered modality for capturing dexterity that appears valid and sensitive to change, enhancing its potential to be disseminated for neurological disease monitoring and treatment.

Anti-CD20 monoclonal antibody therapy in postpartum women with neurological conditions.

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients' questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 µg/mL, range 0.05-0.4; RTX: 0.03 µg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was <1% (OCR: 0.1%, range 0.07-0.7; RTX: 0.04%, range 0.005-0.3). Forty-three participants continued to breastfeed post-infusion. At 8-12 months, the proportion of infants' growth between the 3rd and 97th World Health Organization percentiles did not differ for breastfed (36/40) and non-breastfed (14/16, p > 0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.