Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD.We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies.Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P?=?.009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P?=?.037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD.An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.     

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.     

Evidence Base Update on the Treatment of Early Childhood Anxiety and Related Problems

The controlled evaluation of treatments for early childhood anxiety and related problems has been a relatively recent area of investigation, and accordingly, trials examining early childhood anxiety treatment have not been well represented in existing systematic reviews of youth anxiety treatments. This Evidence Base Update provides the first systematic review of evidence supporting interventions specifically for the treatment of early childhood anxiety and related problems. Thirty articles testing 38 treatments in samples with mean age < 7.9 years (N = 2,228 children) met inclusion criteria. We applied Southam-Gerow and Prinstein’s (2014) review criteria, which classifies families of treatments according to one of five levels of empirical support—Well-Established, Probably Efficacious, Possibly Efficacious, Experimental, and of Questionable Efficacy. We found family-based cognitive-behavioral therapy (CBT) to be a Well-Established treatment, and Group Parent CBT and Group Parent CBT + Group Child CBT to both be Probably Efficacious treatments. In contrast, play therapy and attachment-based therapy are still only Experimental treatments for early childhood anxiety, relaxation training has Questionable Efficacy, and there is no evidence to date to speak to the efficacy of individual child CBT and/or medication in younger anxious children. All 3 currently supported interventions for early childhood anxiety entail exposure-based CBT with significant parental involvement. This conclusion meaningfully differs from conclusions for treating anxiety in older childhood that highlight the well-established efficacy of individual child CBT and/or medication and that question whether parental involvement in treatment enhances outcomes.     

Epidermal growth factor receptor 2 immunoexpression in gastric cells of domestic cats with H. heilmannii infection

The aim of this study was to evaluate the immunoexpression of HER-2 in gastric cells of cats infected with Non H. pylori Helicobacter (NHPH) and to investigate an association with the presence of inflammatory infiltrate. Forty-eight paraffin-embedded gastric samples were retrieved from the archives of the Veterinary Anatomic Pathology Laboratory that had previously been shown to be positive for NHPH with the rapid urease test and cytology. Infection by NHPH was confirmed by histopathology using the Warthin-Starry staining. Hematoxylin-eosin stained sections were reviewed to evaluate inflammatory cell infiltrates. Immunohistochemical analysis was done using anti- H. pylori antibody and anti-HER-2 antibody. Molecular analysis was performed by PCR to confirm the presence of Helicobacter. Statistical analysis was performed to determine whether there was an association between the presence of H. Heilmannii and HER-2 expression in gastric samples. All samples were positive for NHPH, by immunohistochemistry, and confirmed by PCR as H. Heilmannii. On histopathologic analysis, 56,3% of the samples had lymphocytes and plasma cells infiltrates, 52,1% of which were mild and 4,2% moderate. The intensity of the inflammatory infiltrate in the gastric mucosa was significantly greater in the complete plasma membrane of parietal cells of gastric glands that had greater HER-2 immunoexpression (p = 0.0001). A statistically significant association (p = 0.007) between the H. Heilmannii infection score and the expression of HER-2 in the lateral membrane of gastric surface cells was observed. HER-2 expression may be increased in feline gastric cells infected by H. Heilmannii and in parietal cells of gastric glands with an increased inflammatory infiltrate.     

Hypergammaglobulinemia sustains the development of regulatory responses during chronic Leishmania donovani infection in mice

Visceral leishmaniasis, a chronic, potentially fatal disease, is characterized by high production of low‐affinity antibodies. In humans, hypergammaglobulinemia is prediction of disease progression. Nevertheless, the contribution of hypermutated and/or class‐switched immunoglobulins to disease pathogenesis has never been studied. Using Aicda^?/? mice and the experimental model of Leishmania donovani infection, we demonstrate that the absence of hypermutated and/or class‐switched antibodies was associated with increased resistance to disease, stronger protective Th1 responses, and a lower frequency of regulatory IFNγ⁺IL‐10⁺ CD4 T cells. Interestingly, stronger Th1 responses and the absence of IFNγ⁺IL‐10⁺ CD4 T cells during chronic infection in infected Aicda^?/? mice were not caused by a T‐cell intrinsic effect of AID, but by changes in the cytokine environment during chronic disease. Indeed TNF, IL‐10 and IFN‐ß expressions were only upregulated in the presence of hypermutated, class‐switched antibodies and hypergammaglobulinemia at later stages of infection. Taken together, our results suggest that hypergammaglobulinemia sustains inhibitory responses during chronic visceral leishmaniasis.     

Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology

3‐Methylglutaconic aciduria (3‐MGA‐uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole‐exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3‐MGA‐uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High‐resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50‐deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild‐type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity.     

Deleterious de novo variants of X‐linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita

Pathogenic variants in the X‐linked gene ZC4H2, which encodes a zinc‐finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo‐/akinesia and/or (neurogenic) AMC.     

Mutations in PLS1, encoding fimbrin,cause autosomal dominant nonsyndromic hearing loss

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1^?/? mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.