Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; ...cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.
We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.
We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.
Objectives
We evaluated the impact of a 2014 New York City health code change requiring laboratories to indicate if a patient is pregnant or probably pregnant in the electronic laboratory report ...(ELR) when reporting syphilis and hepatitis B virus (HBV) cases to the New York City Department of Health and Mental Hygiene (DOHMH).
Methods
We calculated the number of pregnant persons with syphilis or HBV infection reported to DOHMH from January 1, 2013, through June 30, 2018. We compared the proportion in which the first report to DOHMH was an ELR with pregnancy indicated before and after the policy change. We calculated time between first ELR with pregnancy indicated and subsequent reporting by a method other than ELR and the proportion of cases in which ELR with pregnancy indicated was the only report source.
Results
A total of 552 new syphilis and 8414 HBV-infected cases were reported to DOHMH. From January 2013–June 2014 (pre-change) to January 2017–June 2018 (post-change), the proportion of cases in which ELR with pregnancy indicated was the first report to DOHMH increased significantly (14.7% 23/156 to 46.2% 80/173 for syphilis; 8.0% 200/2498 to 45.3% 851/1879 for HBV infection P < .001). Median time between first ELR with pregnancy indicated and subsequent reporting by a method other than ELR was 9.0 days for syphilis and 51.0 days for HBV infection. ELR with pregnancy indicated was the only report for 43.1% (238/552) of syphilis cases and 23.4% (1452/6200) of HBV cases during the study period.
Conclusion
Including pregnancy status with ELR can increase the ability of public health departments to conduct timely interventions to prevent mother-to-child transmission.
ABSTRACTThere is significant variability in the design and management of pediatric endoscopy units. Although there is information on adult endoscopy units, little guidance is available to the ...pediatric endoscopy practitioner. The purpose of this clinical report, prepared by the NASPGHAN Endoscopy and Procedures Committee, is to review the important considerations for setting up an endoscopy unit for children. A systematic review of the literature was undertaken in the preparation of this report regarding the design, management, needed equipment, motility setup, billing and coding, and pediatric specific topics.
The Bureau of Communicable Disease at the New York City Department of Health and Mental Hygiene receives an average of more than 1000 reports daily via electronic laboratory reporting. Rapid ...recognition of any laboratory reporting drop-off of test results for 1 or more diseases is necessary to avoid delays in case investigation and outbreak detection.
We modified our outbreak detection approach using the prospective space-time permutation scan statistic in SaTScan. Instead of searching for spatiotemporal clusters of high case counts, we reconceptualized "space" as "laboratory" and instead searched for clusters of recent low reporting, overall and for each of 52 diseases and 10 hepatitis test types, within individual laboratories. Each analysis controlled for purely temporal trends affecting all laboratories and accounted for multiple testing.
A SAS program automatically created input files, invoked SaTScan, and further processed SaTScan analysis results and output summaries to a secure folder. Analysts reviewed output weekly and reported concerning drop-offs to coordinators, who liaised with reporting laboratory staff to investigate and resolve issues.
During a 42-week evaluation period, October 2017 to July 2018, we detected 62 unique signals of reporting drop-offs. Of these, 39 (63%) were verified as true drop-offs, including failures to generate or transmit files and programming errors. For example, a hospital laboratory stopped reporting influenza after changing a multiplex panel result from "positive" to "detected." Six drop-offs were detected despite low numbers of expected reports missing (<10 per drop-off).
Our novel application of SaTScan identified a manageable number of possible electronic laboratory reporting drop-offs for investigation. Ongoing maintenance requirements are minimal but include accounting for laboratory mergers and referrals. Automated analyses facilitated rapid identification and correction of electronic laboratory reporting errors, even with small numbers of expected reports missing, suggesting that our approach might be generalizable to smaller jurisdictions.
Therapeutic strategies with proven efficacy for chronic cutaneous graft-versus-host disease (GvHD) are limited, with long-term oral glucocorticoids remaining the first-line treatment. Prolonged ...treatment with glucocorticoids contributes to the significantly increased risk of nonrelapse mortality and substantial deficit in quality of life reported in paediatric transplant patients with chronic GvHD. We report a case of atopic dermatitis-like chronic cutaneous GvHD responding to dupilumab, allowing for the eventual withdrawal of oral glucocorticoids.
Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the ...emergence of autoimmunity, although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTAs). At the initiation of GVHD, LN fibroblastic reticular cells (FRCs) rapidly reduced expression of genes regulated by DEAF1, an autoimmune regulator-like transcription factor required for intranodal expression of PTAs. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRCs during GVHD resulted in the activation of autoaggressive T cells and gut injury. Finally, we show that FRCs normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging autoreactive T cells from the repertoire.
Relapsed disease and infection continue to be the leading causes of treatment failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT). The pathophysiology, common to both, ...is impaired donor T cell immune reconstitution and/or T cell exhaustion. Therapeutic strategies aimed at improving donor T cell immune reconstitution and preventing T cell exhaustion are required in order to improve patient outcomes. The research presented provides evidence that acute graft-versus-host-disease (aGVHD) impairs T cell recovery and function by damaging the stromal architecture of secondary lymphoid organs. Radio-resistant host non-haematopoietic antigen presenting cells (APCs) are emerging as key players in dictating tissue-specific cytotoxic T lymphocyte (CTL) responses and initiating aGVHD. The fibroblastic reticular cell (FRC) is a subset that plays a central role in every stage of the T cell life cycle in the periphery and is necessary for the generation of protective anti-pathogen immunity. Normally, these cells proliferate and repair the peripheral lymph node following viral damage or hypoxia, by initiating a ‘reorganisational programme’ through interaction with lymphoid tissue inducer (LTi)-like cells, in a mechanism akin to that which occurs during embryogenesis. I show that both the FRC and LTi-like cell populations are targeted by the allogeneic T cell response in aGVHD. Disruption of the FRC-LTi axis results in profound damage to the lymph node structure and persistent hypoplasia of peripheral T cell niches. FRCs are targeted by naïve donor T cells in a CD8+ T cell-dependent model of aGVHD, through a mechanism that requires cognate interactions between FRCs and T cells. In contrast to viral infection, lymph nodes in aGVHD are unable to mount a reorganisational programme involving LTi-like cell influx and proliferation. Sustained damage to the FRC network impairs T cell homing to lymph nodes, T cell survival and the capacity to mount a response to 3rd party antigen. These data indicate that future research should focus upon efforts to protect the FRC-LTi axis following transplantation.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA) associated bone marrow failure (BMF)/aplastic anemia (AA) and hematological ...malignancy. We performed a retrospective multicenter study on 813 FA children undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years (interquartile range, 3.4-4.0). Median age at transplant was 8.8 years (6.5-18.1). Overall survival (OS), event-free survival (EFS) and GvHD-free, relapse-free survival (GRFS) at 5 years were 83% (80-86%), 78% (75-81%) and 70% (67-74%) respectively. OS was comparable between matched family donor (MFD, n=441, 88%) and matched unrelated donor (MUD, n=162, 86%) and was superior to that of mismatched family or unrelated donor (MMFD/MMUD, n=144, 72%) and haploidentical donor (HID) (n=66, 70%, p<0.001). In multivariable analysis, a transplant indication of acute myeloid leukaemia/myelodysplastic syndrome compared to AA/BMF, use of MMFD/MMUD and HID compared to MFD, Fludarabine-Cyclophosphamide (FluCy) + other conditioning compared to FluCy independently predicted inferior OS, while alemtuzumab compared to ATG was associated with better OS. Age 10 years was associated with worse EFS and GRFS. Cumulative incidences (CIN) of primary and secondary graft failure were 2% (1-3%) and 3% (2-4%) respectively. CIN of grade II-IV acute GvHD, grade III-IV acute GvHD and chronic GvHD were 23% (20-26%), 12% (10-15%) and 8% (6-10%) respectively. The 5-year CIN of secondary malignancy was 2% (1-3%). These data suggest that HSCT should be offered to Fanconi Anemia patients with AA/BMF at a younger age in the presence of a well-matched donor.
At a single U.S. Army installation from 1997 to 2005, domestic violence volunteer victim advocates assisted 1,417 clients in 1,380 physical and 301 verbal abuse incidents. The average soldier and ...spouse population during this time was slightly less than 10,000. Advocates went to the scene of the incident to talk to the victim to ensure that her/his rights were observed, to determine whether the victim was safe, was referred to the hospital social work service for assessment, and had the information necessary to negotiate the complex military and community systems. The advocate inquired of the victim the characteristics of the incident and risk factors in the history of the relationship. In many incidents, risk factors indicated a history of serious violence by the offender including an increasing level of violence, stalking, and assaults. Frequently reported precipitants of incidents were relationship problems, jealously, and infidelity. Spouses often reported previous attempts to leave and to get help. Advocates play an important role in gathering information uniquely available at the scene that can be useful in planning education and intervention programs to reduce domestic violence in the Army, the military services, and civilian society.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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