A Longitudinal RCT of P-ESDM With and Without Parental Mindfulness Based Stress Reduction: Impact on Child Outcomes.

This randomized controlled trial (NCT03889821) examined Mindfulness Based Stress Reduction (MBSR) in conjunction with the Parent-implemented Early Start Denver Model (P-ESDM). A previous report described improved metrics of parental distress (Weitlauf et al. in Pediatrics 145(Supplement 1):S81-S92, 2020). This manuscript examines child outcomes. 63 children with ASD (< 36 months) and their parents received 12 P-ESDM sessions. Half of parents also received MBSR. Longitudinal examination of whole sample means revealed modest improvements in autism severity, cognitive, and adaptive skills. There was not a significant time × group interaction for children whose parents received MBSR. Future work should examine more proximal markers of child or dyadic change to enhance understanding of the impact of providing direct treatment for parents as part of early intervention initiatives.

CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication.

BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.

Two Cases of Crystal-storing Histiocytosis Diagnosed by Morphology, Immunohistochemistry, and Ultrastructural Examination.

Crystal-storing histiocytosis (CSH) is a non-neoplastic histiocytic proliferation containing crystalline material, usually associated with an underlying lymphoproliferative or plasmacytic disorder. The crystalline structures are typically derived from kappa light chain immunoglobulins. The lesions of CSH are comprised of sheets of histiocytes with abundant eosinophilic cytoplasm containing variably prominent, elongated crystals. This rare phenomenon is important to recognize, as it is known to morphologically obscure an underlying neoplasm. Histologically, the cells of CSH may closely mimic Gaucher cells, as well as the "pseudo-Gaucher" cells sometimes encountered in chronic myeloid leukemia. The distinction between the cells of CSH and that of histologic mimics may be made more definitively through the use of electron microscopy, as the crystalline inclusions seen in CSH display characteristic size, shape, and localization within the cells. Here, we report 2 rare cases of CSH diagnosed by morphology, immunohistochemistry, and ultrastructural examination. The first case presented was diagnosed concurrently with plasma cell myeloma, and the second case discussed was diagnosed in association with marginal zone lymphoma.

Imitators of chronic pancreatitis: diffuse neuroendocrine tumour of the pancreas.

We report a rare case of diffuse replacement of the pancreas with neuroendocrine tumour mimicking chronic pancreatitis. A 55-year-old female with no significant past medical history initially presented with abdominal pain in 2006. A CT of the abdomen and pelvis was performed, revealing diffuse pancreatic parenchymal calcifications with mild pancreatic ductal dilatation and no discrete mass. She was diagnosed with chronic pancreatitis and followed clinically until 2015, where she presented with recurrent abdominal pain. A repeat CT and MRI of the abdomen were performed which revealed new hypoenhancing masses within the pancreas, particularly in the pancreatic tail. There was a persistent background of pancreatic parenchymal calcifications. The possibility of pancreatic neuroendocrine tumour was raised, and an indium-111 Octreotide scan was recommended. Diffuse intense uptake was identified throughout the pancreas on the indium-111 imaging. Given the concern for neuroendocrine tumour, a total pancreatectomy was performed, with histopathology revealing replacement of the pancreas with coalescing well-circumscribed nodules. Many of the nodules had numerous calcifications and localized amyloid deposition. Immunohistochemical stains of the neoplastic cells were strong for neuroendocrine markers chromogranin A and synaptophysin. Overall the findings were consistent with numerous neuroendocrine tumours of the pancreas, Grade II, as per the 2010 WHO criteria for neuroendocrine tumours of the pancreas. Neuroendocrine tumours of the pancreas are lesions that arise from the islet cells, with an approximate incidence of five cases per million people per year. Only one other case report has been documented in the literature by Singh et al demonstrating diffuse pancreatic neuroendocrine tumour replacing the entire pancreas. As diffuse pancreatic neuroendocrine tumour can look similar on imaging to chronic pancreatitis or other infiltrative processes, we wanted to present this case and some of the more specific imaging findings in distinguishing these entities.

Cholesterol granulomas presenting as sellar masses: a similar, but clinically distinct entity from craniopharyngioma and Rathke's cleft cyst.

PURPOSE: Cholesterol granulomas in the sella are rare and can mimic the appearance of craniopharyngioma or Rathke's cleft cysts. Information regarding the clinical presentation, imaging characteristics, and clinical course of sellar cholesterol granulomas can help clinicians to differentiate these lesions from other sellar cystic lesions. METHODS: We present three cases of sellar cholesterol granulomas. A literature review was performed for all cases of sellar cholesterol granulomas with individual patient data reported. RESULTS: We identified 24 previously reported cases in addition to our three cases. Mean age was 36.6 years (range 5-68). There were 16 (59%) females. The most common (74%) presenting symptom was endocrinological deficits, typically either isolated diabetes insipidus (DI) or panhypopituitarism. Location was intrasellar in 3 (11%), suprasellar in 6 (22%), and intrasellar/suprasellar in 18 (67%) patients. Lesions were most commonly (83%) T1 hyperintense. Gross total resection was achieved in 16 (64%) and subtotal resection in 9 (36%) patients. Of the seventeen (63%) patients presenting with varying degrees of bitemporal hemianopsia, all had improvement in vision postoperatively. It is worth noting that no cases of preoperative hypopituitarism or DI improved postoperatively. Even though gross total resection was only achieved in 64%, there was only one recurrence reported. CONCLUSION: Sellar cholesterol granulomas are characterized by T1 hyperintensity, younger age, and more frequent and severe endocrinological deficits on presentation. Our review demonstrates high rates of improvement of visual deficits, but poor rates of endocrine function recovery. Recurrence is uncommon even in cases of subtotal resection.

Non-linearity within the primary measurement range of a lipase assay as the cause of a gap in the interpatient lipase results distribution.

OBJECTIVES: Interpatient distribution data for lipase (Roche Cobas® assay) showed an unexpected data gap, where no results were reported. This gap occurred beginning at a point just above the assay's primary measurement range (i.e., above the cutoff (300U/L) for automated repeat-on-dilution). Calculation or other errors within the automated dilution process were ruled out. Linearity of assay results was investigated. DESIGN AND METHODS: Linearity of experimental sample dilution series data was assessed by correlation coefficient, intercept, and constancy of slope. RESULTS: Dilution experiment data demonstrated a discontinuity of results between 300 and 400U/L consistent with the observed gap in patient data. Although data within the presumed linear range of the assay had a high linear correlation coefficient (r2>0.99), a non-zero intercept and progressively variable slope were inconsistent with linearity. Although the assay was assessed as linear by the College of American Pathology linearity survey, survey data also demonstrated non-linearity for this assay when analyzed for slopes and intercept. CONCLUSIONS: Non-linearity in the presumed linear range of an assay can produce gaps in patient data above a repeat-on-dilution cutoff. As in this instance, CAP linearity surveys may not identify certain forms of non-linearity.

Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells.

The success of adoptive T cell gene transfer for treatment of cancer and HIV is predicated on generating a response that is both durable and safe. We report long-term results from three clinical trials to evaluate gammaretroviral vector-engineered T cells for HIV. The vector encoded a chimeric antigen receptor (CAR) composed of CD4 linked to the CD3ζ signaling chain (CD4ζ). CAR T cells were detected in 98% of samples tested for at least 11 years after infusion at frequencies that exceeded average T cell levels after most vaccine approaches. The CD4ζ transgene retained expression and function. There was no evidence of vector-induced immortalization of cells; integration site distributions showed no evidence of persistent clonal expansion or enrichment for integration sites near genes implicated in growth control or transformation. The CD4ζ T cells had stable levels of engraftment, with decay half-lives that exceeded 16 years, in marked contrast to previous trials testing engineered T cells. These findings indicate that host immunosuppression before T cell transfer is not required to achieve long-term persistence of gene-modified T cells. Further, our results emphasize the safety of T cells modified by retroviral gene transfer in clinical application, as measured in >500 patient-years of follow-up. Thus, previous safety issues with integrating viral vectors are hematopoietic stem cell or transgene intrinsic, and not a general feature of retroviral vectors. Engineered T cells are a promising form of synthetic biology for long-term delivery of protein-based therapeutics. These results provide a framework to guide the therapy of a wide spectrum of human diseases.

Innate immune responses and permissiveness to ranavirus infection of peritoneal leukocytes in the frog Xenopus laevis.

Ranaviruses such as frog virus 3 ([FV3] family Iridoviridae) are increasingly prevalent pathogens that infect reptiles, amphibians, and fish worldwide. Whereas studies in the frog Xenopus laevis have revealed the critical involvement of CD8 T-cell and antibody responses in host resistance to FV3, little is known about the role played by innate immunity to infection with this virus. We have investigated the occurrence, composition, activation status, and permissiveness to infection of peritoneal leukocytes (PLs) in Xenopus adults during FV3 infection by microscopy, flow cytometry, and reverse transcription-PCR. The total number of PLs and the relative fraction of activated mononucleated macrophage-like cells significantly increase as early as 1 day postinfection (dpi), followed by NK cells at 3 dpi, before the peak of the T-cell response at 6 dpi. FV3 infection also induces a rapid upregulation of proinflammatory genes including arginase 1, interleukin-1beta, and tumor necrosis factor alpha. Although PLs are susceptible to FV3 infection, as evidenced by apoptotic cells, active FV3 transcription, and the detection of viral particles by electron microscopy, the infection is weaker (fewer infectious particles), more transitory, and involves a smaller fraction (less than 1%) of PLs than the kidney, the main site of infection. However, viral DNA remains detectable in PLs for at least 3 weeks postinfection, past the point of viral clearance observed in the kidneys. This suggests that although PLs are actively involved in anti-FV3 immune responses, some of these cells can be permissive and harbor quiescent, asymptomatic FV3.