Abstract In response to the evolving treatment landscape for new‐onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative ...analysis of NORSE management over time. Seventy‐seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second‐line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second‐line immunotherapies (odds ratio OR = 1.4, 95% CI = 1.1–1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3–2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second‐line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3–8.9)—particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3–21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5–20.1)—than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus ( ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second‐line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.
Febrile infection‐related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status ...epilepticus. It is unclear whether FIRES and non‐FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non‐FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non‐FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non‐infection‐related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein‐1 alpha (MIP‐1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non‐FIRES NORSE are very similar conditions.
Background
One year into the pandemic, published data on hematopoietic cell transplantation (HCT) recipients with coronavirus disease 2019 (COVID‐19) remain limited.
Methods
Single‐center ...retrospective cohort study of adult HCT recipients with polymerase chain reaction (PCR)‐confirmed severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection.
Results
Twenty‐eight consecutive transplantation and cellular therapy patients (autologous, n = 12; allogeneic, n = 15; chimeric antigen receptor T‐cell therapy CAR‐T, n = 1) with COVID‐19 were identified. The median age was 57 years. The median time from HCT to COVID‐19 diagnosis was 656 days (interquartile range IQR, 33‐1274). Patients were followed for a median of 59 days (IQR, 40‐88). Among assessable patients (n = 19), 10 (53%) had documented virological clearance; median time to clearance was 34 days (range, 21‐56). Out of 28, 12 (43%), 6 (21%), and 10 (36%) patients had mild, moderate, and severe/critical disease, respectively. Overall mortality was 25%, nearly identical for autologous and allogeneic HCT, and exclusively seen in hospitalized patients, older than 50 years of age with severe COVID‐19. None of the patients with mild (n = 12) or moderate (n = 6) COVID‐19 died whereas 7/10 patients (70%) with severe/critical COVID‐19 died (P = .0001). Patients diagnosed with COVID‐19 within 12 months of HCT exhibited higher mortality (57% vs 14%; P = .04). All‐cause 30‐day mortality (n = 4) was 14%. A higher proportion of patients who died within 30 days of COVID‐19 diagnosis (3/4) were receiving ≥2 immunosuppressants, compared with patients who survived beyond 30 days after COVID‐19 diagnosis (2/24; 75% vs. 8%; P = .01).
Conclusions
Mortality in COVID‐19 HCT patients is higher than that of the age‐comparable general population and largely dependent on age, disease severity, timing from HCT, and intensity of immunosuppression.
The thermal microenvironment of corals and the thermal effects of changing flow and radiation are critical to understanding heat-induced coral bleaching, a stress response resulting from the ...destruction of the symbiosis between corals and their photosynthetic microalgae. Temperature microsensor measurements at the surface of illuminated stony corals with uneven surface topography (Leptastrea purpurea and Platygyra sinensis) revealed millimetre-scale variations in surface temperature and thermal boundary layer (TBL) that may help understand the patchy nature of coral bleaching within single colonies. The effect of water flow on the thermal microenvironment was investigated in hemispherical and branching corals (Porites lobata and Stylophora pistillata, respectively) in a flow chamber experiment. For both coral types, the thickness of the TBL decreased exponentially from 2.5 mm at quasi-stagnant flow (0.3 cm s−1), to 1 mm at 5 cm s−1, with an exponent approximately 0.5 consistent with predictions from the heat transfer theory for simple geometrical objects and typical of laminar boundary layer processes. Measurements of mass transfer across the diffusive boundary layer using O2 microelectrodes revealed a greater exponent for mass transfer when compared with heat transfer, indicating that heat and mass transfer at the surface of corals are not exactly analogous processes.
Background
Adenovirus (AdV) is a serious infection following hematopoietic cell transplantation (HCT). Little is known about AdV viral kinetics and optimal threshold for initiation of pre‐emptive ...therapy.
Methods
Single‐center retrospective study of 16 consecutive adult HCT recipients with detectable AdV identified over a 5‐year period.
Results
Median time to AdV reactivation after HCT was 176 days (IQR 86–408). Nine patients received cidofovir, although 14/16 had no tissue‐invasive disease. Among treated patients, median duration of viremia was shorter when initiating treatment at viral loads < 10,000 copies/ml (28 vs. 52 days). All‐cause mortality in this cohort was 44%. All six patients (five of which were untreated) with peak viral loads < 10,000 copies/ml survived; whereas only 30% (3/10) of patients with peak viral loads greater than this threshold survived, despite most (n = 8; 80%) of them receiving cidofovir (P = .01). Three‐month survival following diagnosis of AdV viremia was significantly lower with peak viremia > 10,000 copies/ml (100 vs. 17%; P = .005).
Conclusion
AdV is associated with high all‐cause mortality, especially for viremia > 10,000 copies/ml. Delaying therapy until viremia reaches AdV levels ≥10,000 copies/ml was associated with more protracted infection and poor outcomes. Larger studies are needed.
We studied the diel variation of in situ coral temperature, irradiance and photosynthetic performance of hemispherical colonies of
Porites
lobata
and branching colonies of
Porites
cylindrica
during ...different bulk water temperature and tidal scenarios on the shallow reef flat of Heron Island, Great Barrier Reef, Australia. Our study presents in situ evidence that coral tissue surface temperatures can exceed that of the surrounding water under environmental conditions typically occurring during low tide in shallow reef or lagoon environments. Such heating may be a regular occurrence on shallow reef flats, triggered by the combined effects of high irradiance and low water flow characteristic of low Spring tides. At these times, solar heating of corals coincides with times of maximum water temperature and high irradiance, where the slow flow and consequent thick boundary layers impede heat exchange between corals and the surrounding water. Despite similar light-absorbing properties, the heating effect was more pronounced for the hemispherical
P. lobata
than for the branching
P. cylindrica
. This is consistent with previous laboratory experiments showing the evidence of interspecific variation in coral thermal environment and may result from morphologically influenced variation in convective heat transfer and/or thermal properties of the skeleton. Maximum coral surface warming did not coincide with maximum irradiance, but with maximum water temperature, well into the low-tide period with extremely low water flow in the partially drained reef flat, just prior to flushing by the rising tide. The timing of low tide thus influences the thermal exposure and photophysiological performance of corals, and the timing of tidally driven coral surface warming could potentially have different physiological impacts in the morning or in the afternoon.
•CMV reactivation is a common complication of CAR T-cell therapy and is associated with increased overall mortality.•Immunosuppression, particularly corticosteroids, for management of CAR T-cell ...toxicities is a major risk factor for CMV reactivation.
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Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation recipients; however, data on CMV reactivation after chimeric antigen receptor (CAR) T-cell therapy are limited. We report the incidence and outcomes of 95 adult CMV-seropositive patients who received CAR T-cell therapy between February 2018 and February 2023. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV infection (cs-CMV). Thirty-one patients (33%) had evidence of CMV reactivation (any viremia), and 10 patients (11%) had cs-CMV. The median time from CAR T-cell infusion to CMV reactivation was 19 days (interquartile range IQR, 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3 to 4 cytokine release syndrome (67 vs 28%; P = .01), and those who received corticosteroids (39 vs 21%; P = .03), anakinra (56 vs 28%; P = .02), or ≥2 immunosuppressants (41 vs 21%; P = .02). Receipt of corticosteroids (18 vs 0%; P = .004), tocilizumab (14 vs 0%; P = .04), anakinra (33 vs 7%; P = .008), and ≥2 immunosuppressants (20 vs 0%; P = .001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a twofold increase in CMV reactivation in multivariate analyses (adjusted odds ratio aOR, 2.27; 95% confidence interval, 1.1-4.8; P = .03). Overall, the 1-year mortality was significantly higher in those with CMV reactivation (57% vs 23%; P = .001). Immunosuppression, particularly with corticosteroids, for the management of CAR T-cell toxicities, is a major risk factor for CMV reactivation.
The use of haploidentical or HLA-mismatched unrelated donors (MMUD) allows allogeneic hematopoietic cell transplantation in individuals without suitable matched donors. Post-transplantation ...cyclophosphamide (PTCy) is used routinely for prevention of graft-versus-host disease in recipients of haploidentical transplants, and its use has been recently explored in MMUD transplantation. We compared the incidence of cytomegalovirus (CMV) reactivation and rate of lymphocyte recovery between PTCy MMUD and alternative transplantation modalities. Single-center retrospective study of 22 consecutive PTCy MMUD recipients transplanted between April 2017 and January 2019. Patients undergoing anti-thymocyte globulin (ATG) MMUD (n = 37) and PTCy haploidentical transplantation (n = 19) between January 2015 and July 2018 served as historical controls. We assessed the incidence of CMV (any viremia) and clinically significant CMV reactivation (cs-CMVi; defined as CMV disease or CMV viremia leading to preemptive treatment) in these 3 groups. Immune reconstitution was assessed by absolute lymphocyte count (ALC) at days 30, 90, 180, and 360 after transplantation. Statistical analyses included Kaplan-Meier plots with a log-rank test, Kruskal-Wallis test, and Fisher's exact test where appropriate, and logistic regression analyses. For PTCy MMUD, PTCy haploidentical and ATG MMUD groups, the 100-day and 200-day incidence of CMV (any viremia) were 41%, 63%, and 77% (P = .02), and 64%, 68%, and 86% (P = .049), respectively. The rate of cs-CMVi was also lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (14% versus 53% and 54% at day 100 P = .01 and 25% versus 53% and 58% at day 200 P = .03). There was a trend toward lower 200-day incidence of cs-CMVi in PTCy MMUD compared to ATG MMUD, even after excluding letermovir-treated patients from the analysis (25% versus 58% P = .06). The association between PTCy MMUD and lower risk of cs-CMVi remained significant even after adjusting for letermovir prophylaxis (odds ratio = 0.23, 95% confidence interval, 0.07-0.81 P = .02). Day 30 ALC was lower in PTCy MMUD compared to PTCy haploidentical and ATG MMUD (0.14, 0.33, 0.44 × 10
/L, respectively P = .005) but similar across groups at other time points. PTCy MMUD transplantation was associated with lower incidence of CMV events, independent of the use of CMV prophylaxis. Larger studies are needed.
Reflectance spectroscopy and microscale temperature measurements were used to investigate links between optical and thermal properties of corals. Coral tissue heating showed a species-specific linear ...correlation to the absorptance of incident irradiance. Heat budgets estimated from absorptance and thermal boundary layer measurements indicated differences in the relative contribution of convection and conduction to heat loss in Porites lobata and Stylophora pistillata, and a higher heat conduction into the skeleton of the thin-tissued branching S. pistillata as compared to the massive thick-tissued P. lobata. Decreasing absorptance associated with bleaching resulted in decreased surface warming of coral tissue. Action spectra of coral tissue heating showed elevated efficiency of heating at wavelengths corresponding to absorption maxima of major zooxanthellae photopigments. Generally, energy-rich radiation (< 500 nm) showed the highest heating efficiency. Speciesspecific relationships between coral tissue heating and absorptance can be strongly affected by differences in the thermal properties of the skeleton and/or tissue arrangement within the skeletal matrix, indicating a yet unresolved potential for coral shape, size, and tissue thickness to affect heat dissipation and especially the conduction of heat into the coral skeleton.
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