Successful restoration of protective immunity against measles, mumps, and rubella following MMR vaccination in adult hematopoietic cell transplant recipients.

BACKGROUND: The optimal number of doses as well as the role for measurement of postvaccination titers after measles, mumps, rubella (MMR) vaccination in adult hematopoietic cell transplantation (HCT) recipients remains unknown. METHODS: In the present study, we assessed humoral immunity against measles, mumps and rubella before and after MMR vaccination in 187 adults who received at least one dose of the MMR vaccine after HCT. RESULTS: Among those with baseline titers, posttransplant prevaccination seroprotection rates were 56%, 30%, and 54% for measles, mumps, and rubella, respectively; and significantly lower in allogeneic versus autologous HCT recipients for measles (39% vs. 80%, p = .0001), mumps (22% vs. 41%; p = .02) and rubella (48% vs. 62%, p = .12). Among those who were seronegative at baseline, seroconversion rates after one dose of MMR were 69%, 56%, and 97% for measles, mumps, and rubella, respectively. Seronegative patients after one dose of MMR (i.e., nonresponders) seroconverted for measles and mumps after a second MMR vaccine dose. CONCLUSION: Our findings demonstrate successful restoration of protective immunity against measles, mumps, and rubella after vaccination in adult HCT recipients; one dose of MMR elicited protective titers in the majority of patients, and a second vaccine dose was immunogenic in nonresponders.

Early administration of SARS-CoV-2 monoclonal antibody reduces the risk of mortality in hematologic malignancy and hematopoietic cell transplant patients with COVID-19.

BACKGROUND: Data on severe acute respiratory distress syndrome coronavirus 2 monoclonal antibody (SARS-CoV-2-specific mAb) use in hematologic malignancy and hematopoietic cell transplantation (HM/HCT) patients are limited. Here, we describe our experience with the use of casirivimab-imdevimab or bamlanivimab for the treatment of coronavirus disease 2019 (COVID-19) in HM/HCT patients. METHODS: This was a retrospective chart review at the University of Miami Hospital and Sylvester Comprehensive Cancer Center for HM/HCT patients with COVID-19 who received casirivimab-imdevimab or bamlanivimab from November 21, 2020, to September 30, 2021. Outcomes measured were mortality, hospital admission, and infusion reaction to SARS-CoV-2-specific mAbs. RESULTS: We identified 59 HM/HCT patients with mild to moderate COVID-19 who received casirivimab-imdevimab or bamlanivimab. Median age was 57 years (interquartile range [IQR]: 45-65). Among the 59 patients, 25 (42%) received cellular therapy: 14 (24%) had undergone allogeneic HCT, nine (15%) autologous HCT, and two (3%) received chimeric antigen receptor T-cell therapy. The median time from COVID-19 symptom onset to SARS-CoV-2-specific mAb administration was 4 (IQR: 3-6) days. Forty-six (78%) patients received SARS-CoV-2-specific mAbs as outpatients and 13 (22%) patients received SARS-CoV-2-specific mAbs during hospitalization. Among patients who received SARS-CoV-2-specific mAbs as outpatients, only four (9%) visited the emergency department at days 10, 11, 15, and 35 after SARS-CoV-2-specific mAb administration. None of these four patients required hospital admission. Among the hospitalized patients, five (38%) were admitted to the hospital with neutropenic fever, four (31%) were already hospitalized for transplantation and cellular therapy, three (23%) were admitted for monitoring of COVID-19 symptoms, and one (8%) was admitted with acute kidney injury. Three hospitalized patients (23%) died at 14, 35, and 59 days after SARS-CoV-2-specific mAb administration; two of these three deaths were attributed to COVID-19 infection. One patient developed an immediate infusion reaction to bamlanivimab, and no infusion reactions were reported to casirivimab-imdevimab use. CONCLUSION: During the alpha and delta variant surges, early administration of bamlanivimab or casirivimab-imdevimab prevented hospitalization and death when given in the outpatient setting. Among patients who received mAbs at or after hospital admission, the risk of COVID-19 disease progression and death remains significant. Larger studies of the use of mAb therapy to treat COVID-19 in this population are needed.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Using Deep Learning Models to Predict Prosthetic Ankle Torque.

Inverse dynamics from motion capture is the most common technique for acquiring biomechanical kinetic data. However, this method is time-intensive, limited to a gait laboratory setting, and requires a large array of reflective markers to be attached to the body. A practical alternative must be developed to provide biomechanical information to high-bandwidth prosthesis control systems to enable predictive controllers. In this study, we applied deep learning to build dynamical system models capable of accurately estimating and predicting prosthetic ankle torque from inverse dynamics using only six input signals. We performed a hyperparameter optimization protocol that automatically selected the model architectures and learning parameters that resulted in the most accurate predictions. We show that the trained deep neural networks predict ankle torques one sample into the future with an average RMSE of 0.04 ± 0.02 Nm/kg, corresponding to 2.9 ± 1.6% of the ankle torque's dynamic range. Comparatively, a manually derived analytical regression model predicted ankle torques with a RMSE of 0.35 ± 0.53 Nm/kg, corresponding to 26.6 ± 40.9% of the ankle torque's dynamic range. In addition, the deep neural networks predicted ankle torque values half a gait cycle into the future with an average decrease in performance of 1.7% of the ankle torque's dynamic range when compared to the one-sample-ahead prediction. This application of deep learning provides an avenue towards the development of predictive control systems for powered limbs aimed at optimizing prosthetic ankle torque.

Successful Treatment of Disseminated Disease Due to Highly Resistant Aspergillus calidoustus with a Novel Antifungal Therapy.

Invasive aspergillosis is the most common invasive mold infection following a hematopoietic cell transplant. Widespread use of antifungal prophylaxis has led to the increasing incidence of cryptic Aspergillus species. Aspergillus calidoustus is one of those emerging species and is notorious for multidrug resistance to antifungals. Here, we report a case of disseminated A. calidoustus infection in a hematopoietic stem cell transplant recipient who was successfully treated with combination therapy that included a novel antifungal.

A case series to examine the perinatal outcomes of infants conceived by intravaginal culture (IVC).

PURPOSE: In vitro fertilization (IVF) has been a well-established method for treating infertility for over four decades. The mainstay method of culture of oocytes and embryos has been in gas incubators. More recently, the novel use of a gas-permeable closed vessel to culture oocytes and embryos in the vagina, intravaginal culture (IVC), has been introduced as a viable lower-cost option for infertility patients. Several studies have studied the efficacy of IVC; however, there is no data on the perinatal outcomes of the babies born using this newer technology. METHODS: Our study is a retrospective case series (n = 66) from a single center, uniquely examining the perinatal outcomes of infants born after IVC. RESULTS: There were 50 singleton and 16 twin gestations in this case series. For singleton infants conceived via IVC (n = 50), the mean gestational age at delivery was 38 weeks and 4 days, and the mean birth weight was 3159.1 + / - 501.5 g. Four infants were born with low birth weight, three were born preterm, and one was born macrosomic. The twin pregnancies had a mean gestational age at delivery of 33 weeks 4 days and a mean birth weight of 1992.9 + / - 620.7 g. Twenty-seven infants met the criteria for low birthweight, and twenty-four infants delivered preterm. No twin infants met the criteria for macrosomia. CONCLUSION: This case series provides an initial description of the perinatal outcomes of IVC conceived infants, which shows no concerning trends in adverse birth outcomes for singleton infants. As expected, IVC twin gestations had a high rate of low birth weight and preterm delivery. Continued larger studies are essential to provide more comprehensive data on perinatal outcomes of infants conceived by this new technology.

Viral kinetics and outcomes of adenovirus viremia following allogeneic hematopoietic cell transplantation.

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.

Clinical presentation and outcomes of COVID-19 following hematopoietic cell transplantation and cellular therapy.

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.

Achievement of clinical isavuconazole blood concentrations in transplant recipients with isavuconazonium sulphate capsules administered via enteral feeding tube.

BACKGROUND: Isavuconazole is a triazole antifungal available in IV and capsule formulation. Prescribing information states that capsules should not be chewed, crushed, dissolved or opened because the drug was not studied in this manner. However, considering the pharmacokinetics of the capsules, we theorized opening and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole. OBJECTIVES: To determine whether patients receiving isavuconazonium sulphate capsules via EFT would achieve clinical blood concentrations of isavuconazole. METHODS: Nineteen solid organ and HCT recipients receiving isavuconazole via EFT for prevention or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA. Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and therapeutic drug monitoring (TDM) was performed. RESULTS: TDM was performed after a median of 7 days (range 6-17) following EFT administration and 15 days (range 7-174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 µg/mL (range 0.3-5.2). Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 µg/mL (range 0.3-5.2) and 2.2 µg/mL (range 0.8-3.6; P = 0.896), respectively. Concentrations achieved with the EFT route were similar to or greater than the corresponding concentrations via the IV route in six patients who had TDM performed during both routes of administration. CONCLUSIONS: It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI.

Clinical "real-world" experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Letermovir was approved in 2017 for prevention of cytomegalovirus (CMV) infection in seropositive (R+) allogeneic hematopoietic cell transplantation (HCT) patients. Post-marketing data with this new agent are scarce. METHODS: We compared the incidence of both CMV reactivation (any viremia) and clinically significant CMV infection (CS-CMVi; CMV DNAemia leading to preemptive treatment or presence of CMV tissue invasive disease) at days +100 and +200 post-HCT in 25 adult allogeneic HCT patients who received letermovir prophylaxis (until day 100) and a historical control group of 106 CMV R+ allogeneic HCT recipients who underwent CMV preemptive therapy. RESULTS: CMV reactivation within 100 days post-HCT was lower in the letermovir group vs control group (20% vs 72% respectively, P < .001). The 100-day cumulative incidence of CS-CMVi was significantly lower in the letermovir group vs control group (4% vs 59% respectively, P < .001). Significantly reduced incidence of CMV reactivation and CS-CMVi was also observed at 200 days in the letermovir group. No difference in mortality was observed between the two groups. CONCLUSION: This study confirms the efficacy of letermovir in preventing CMV reactivation in CMV R+ allogeneic HCT recipients in first 100 days post-HCT and suggests sustained efficacy after discontinuation of prophylaxis.

Successful Treatment of Invasive Fungal Infection Due to Highly Resistant Aspergillus calidoustus in an Allogeneic Hematopoietic Cell Transplant Recipient.

Invasive aspergillosis (IA) is the most common invasive fungal infection following a hematopoietic cell transplant, with emerging cryptic species exhibiting resistance to commonly used antifungals such as azoles. These species have been increasingly found after the introduction of anti-mold prophylaxis. We report a case of a 56-year-old female with primary myelofibrosis whose allogeneic hematopoietic cell transplant was complicated by disseminated fungal infection (skin, lung) due to Aspergillus calidoustus, a cryptic specie. Treatment of Aspergillus species remains challenging as these cryptic species are usually resistant to azoles including voriconazole which is the first line of treatment of IA. Infection was successfully treated with surgical excision and combination antifungal therapy based on in vitro susceptibility and synergy testing. Therapy included isavuconazole, a drug that has been shown to be non-inferior to voriconazole in the treatment of invasive mold infections.

Use of maintenance therapy and incidence of recurrent Cytomegalovirus DNAemia among allogeneic hematopoietic cell transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is the most common infection following hematopoietic cell transplantation (HCT). Preemptive antiviral therapy is highly effective at halting viral replication and preventing CMV disease; however, recurrence rates after clearance of CMV DNAemia are high (50-70%). Current treatment guidelines recommend maintenance therapy after initial clearance. Yet, the effectiveness of this intervention to prevent recurrence is not well defined. OBJECTIVES: We aimed to assess the impact of maintenance therapy on the probability of recurrent CMV in allogeneic HCT recipients with early CMV reactivation. STUDY DESIGN: Sixty-six patients with an initial episode of early CMV reactivation who achieved viral clearance in response to preemptive therapy were included. We compared the incidence of recurrent CMV DNAemia in patients who received maintenance therapy vs those who underwent early discontinuation of antiviral therapy. RESULTS: Recurrence occurred in 47/64 (73%) patients, including 11/14 (79%) patients without maintenance therapy and 36/50 (72%) of patients who received maintenance therapy (P = 0.74). The propensity score adjusted risk ratio for the effect of maintenance therapy on recurrence was 0.89 (95% CI 0.64-1.25; P = 0.41). In a time to event analysis using the unweighted cohort, the 90-day probability of CMV recurrence was similar between patient groups independent of maintenance therapy administration (54% vs 64% for maintenance vs non-maintenance groups, respectively; log-rank P = 0.37). CONCLUSION: These data suggest that maintenance antiviral therapy does not reduce the incidence of CMV recurrence while off therapy and is of limited value in HCT recipients who have successfully eradicated CMV DNAemia in response to preemptive therapy. Larger studies in this area are needed.

Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies.

BACKGROUND: Voriconazole is an azole antifungal utilized for prophylaxis and treatment of invasive fungal infections in hematologic patients. Previous studies have revealed decreased efficacy and increased toxicity with subtherapeutic <1 mcg/mL and supratherapeutic > 4 mcg/mL levels. A voriconazole dose modification guideline was introduced in July 2014 based on a retrospective analysis. OBJECTIVE: The primary objective was to evaluate the voriconazole dose modification guideline. Secondary objectives were to identify patient-specific characteristics that contribute to inadequate levels, adverse effects, and breakthrough invasive fungal infections. METHODS: This prospective study included 128 patients with 250 admissions who received voriconazole from July 2014 to February 2016. Eligible adult patients receiving voriconazole for prophylaxis or treatment with at least one trough level, drawn appropriately, were included. Demographics, adverse effects, and breakthrough invasive fungal infections were documented. RESULTS: Voriconazole use was categorized as: new start, new start with loading dose, or continuation of home therapy. The median initial levels were 1.5, 3.5, and 1.7 mcg/mL with 62% (73/119), 55% (6/11), and 60% (72/120) within the therapeutic range, respectively. Using the voriconazole dose modification guideline, 80% were within goal by the second dose adjustment. Age ≤ 30 and BMI ≤ 25 kg/m2 had higher rates of subtherapeutic levels in the new start cohorts (p = 0.024 and p = 0.009). Approximately 7.6% of patients experienced an adverse effect with neurologic/psychological being the most common. A total of 8.5% of patients had a possible, probable or proven breakthrough invasive fungal infections while on voriconazole. CONCLUSION: Using the voriconazole dose modification guideline, the number of patients that reached therapeutic range improved from 36% to 80% by the second dose adjustment (p = 0.007). This voriconazole dose modification guideline can be utilized to help dose and adjust voriconazole in order to achieve therapeutic levels.

Postoperative falls after total knee arthroplasty in patients with a femoral nerve catheter: can we reduce the incidence?

A femoral nerve catheter (FNC) is often used to minimize pain following total knee arthroplasty (TKA), but complications including inpatient falls, may increase as a result, despite fall prevention protocols. We evaluated the rate of falls in 707 primary TKAs performed with an FNC at a major academic center from May 2009 to September 2012. Despite a formalized fall prevention protocol, we found 19 falls (2.7%). Three patients required further operative intervention. At a rate of 2.7%, postoperative fall is one of the most common complications of TKA at our institution. While pain control may be good with the use of FNCs following primary TKA, improvements in fall prevention strategies or the use of alternative postoperative pain control modalities may need to be considered.

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy.

Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, data regarding CMV reactivation after chimeric antigen receptor T (CAR T) cell therapy are limited. In this single-center retrospective study, 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, viremia requiring antiviral treatment). 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 (IQR, 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3-4 cytokine release syndrome (67 vs. 28%; P=0.01), and those who received corticosteroids (39 vs. 21%; P=0.03), anakinra (56 vs. 28%; P=0.02), or ≥2 immunosuppressants (41 vs. 21%; P=0.02). Receipt of corticosteroids (18 vs. 0%; P=0.004), tocilizumab (14 vs. 0%; P=0.04), anakinra (33 vs. 7%; P=0.008), and ≥2 immunosuppressants (20 vs. 0%; P=0.001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a 2-fold increase in CMV reactivation in multivariate analyses (aOR 2.27, 95%CI 1.1-4.8, P=0.03). Overall, 1-year mortality was significantly higher in those with CMV reactivation (57% vs. 23%, P=0.001). Immunosuppression, particularly corticosteroids, for the management of CAR T cell toxicities is a major risk factor for CMV reactivation. CMV preventive strategies in high-risk CAR T recipients might improve outcomes.

Indigenous lands, protected areas, and slowing climate change.

Recent climate talks in Copenhagen reaffirmed the crucial role of reducing emissions from deforestation and degradation (REDD). Creating and strengthening indigenous lands and other protected areas represents an effective, practical, and immediate REDD strategy that addresses both biodiversity and climate crises at once.

Role of Brazilian Amazon protected areas in climate change mitigation.

Protected areas (PAs) now shelter 54% of the remaining forests of the Brazilian Amazon and contain 56% of its forest carbon. However, the role of these PAs in reducing carbon fluxes to the atmosphere from deforestation and their associated costs are still uncertain. To fill this gap, we analyzed the effect of each of 595 Brazilian Amazon PAs on deforestation using a metric that accounts for differences in probability of deforestation in areas of pairwise comparison. We found that the three major categories of PA (indigenous land, strictly protected, and sustainable use) showed an inhibitory effect, on average, between 1997 and 2008. Of 206 PAs created after the year 1999, 115 showed increased effectiveness after their designation as protected. The recent expansion of PAs in the Brazilian Amazon was responsible for 37% of the region's total reduction in deforestation between 2004 and 2006 without provoking leakage. All PAs, if fully implemented, have the potential to avoid 8.0 +/- 2.8 Pg of carbon emissions by 2050. Effectively implementing PAs in zones under high current or future anthropogenic threat offers high payoffs for reducing carbon emissions, and as a result should receive special attention in planning investments for regional conservation. Nevertheless, this strategy demands prompt and predictable resource streams. The Amazon PA network represents a cost of US$147 +/- 53 billion (net present value) for Brazil in terms of forgone profits and investments needed for their consolidation. These costs could be partially compensated by an international climate accord that includes economic incentives for tropical countries that reduce their carbon emissions from deforestation and forest degradation.