A diagnosis of mycosis fungoides in a pediatric patient with recurrent Langerhans cell histiocytosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141250/1/pbc26835.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141250/2/pbc26835_am.pd

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Sexism in the management of bleeding disorders

Sexism has been an issue in bleeding disorders for centuries. Women with bleeding disorders have been underrecognized and underdiagnosed. Those who are diagnosed often experience delays in diagnosis and feel that their symptoms are dismissed or minimized. Several factors contribute to this sexism. Historically, the clinical and research focus within the bleeding disorder community has been on men and hemophilia. Von Willebrand disease, a disease that has long been recognized as affecting women, is much more common than hemophilia, yet has significantly fewer resources devoted to it. The lack of knowledge and comfort that patients and health care providers have regarding menstruation compounds the issue, as heavy menstrual bleeding is one of the most common symptoms seen in women with bleeding disorders. Stemming from the universal stigmatization of periods, this lack of comfort and knowledge results in fewer women seeking care, fewer health care providers addressing the issue, and fewer women getting the care they deserve. Progress has been made, with many organizations dedicating resources to improving the care of these women. The road is long, and much more work is needed to ensure that women with bleeding disorders receive the care they deserve.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166285/1/rth212468.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166285/2/rth212468_am.pd

Health issues in women and girls affected by haemophilia with a focus on nomenclature, heavy menstrual bleeding, and musculoskeletal issues

IntroductionWomen and girls affected by haemophilia, including haemophilia carriers (WGH) are at risk of bleeding symptoms that may go unrecognized, including heavy menstrual bleeding (HMB) and musculoskeletal bleeding. Terminology continues to evolve.AimTo describe the current recommendations for nomenclature surrounding WGH, and the current understanding of HMB, iron deficiency, and musculoskeletal complaints in these patients.MethodsLiterature was reviewed and summarized.ResultsWith regards to nomenclature, women with factor levels less than 50% should be classified as having haemophilia, while carriers with normal levels should be characterized accordingly to symptomatology. HMB and resultant iron deficiency are common among WGH, have a multitude of downstream effects, and maybe overlooked due to stigma around menstruation. Musculoskeletal bleeding and resultant joint changes are increasingly recognized in this population but do not necessarily correlate with factor levels.ConclusionAlthough progress has been made in the care of WGH, much work remains to further improve their care.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172841/1/hae14535.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172841/2/hae14535_am.pd

Is ≥ 100% the magic number to rule out the laboratory diagnosis of von Willebrand disease based on initial testing?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/170804/1/ajh26343_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/170804/2/ajh26343.pd

Management of anticoagulation associated reproductive tract bleeding in adolescent and young adult females - Results of a multinational survey

Introduction: Reproductive tract bleeding (RTB) is an important outcome in menstruating females on anticoagulant therapy (AC). The diagnosis and management of AC-RTB in adolescent and young adult (AYA) females is unknown. Aims: The aim of this study was to survey the contemporary patterns of diagnosis and management of AC-RTB in AYA females. Methods: SurveyMonkey® questions were sent to members of 1) Pediatric and Neonatal Thrombosis Hemostasis Subcommittee and Women\u27s Health Subcommittee of the International Society on Thrombosis and Haemostasis and 2) Hemostasis and Thrombosis Research Society. Results are reported using descriptive statistics. Results: Response rate was 33% (251 out of 753). AC-RTB was infrequently reported. Menstrual history was not routinely reviewed prior to initiation of AC. Respondents indicated a differential risk of AC-RTB, most frequently with Rivaroxaban. Respondents continued hormonal therapy (HT) if an AYA female was on it at the start of AC. When AC-RTB occurred, management strategies were variable with initiation of HT or antifibrinolytic therapy being the most frequent. The timing of AC-RTB after the thrombotic event influenced the respondents\u27 choice of therapy. Differences were seen in the management strategies between US and non-US participants, with more US respondents initiating HT while more non-US respondents modifying the AC regimen. Respondents uniformly reported complications with AC-RTB and with its treatment. Conclusion: This survey highlights the need to review menstrual history at the start of and during AC and for future research into choosing the optimal AC in AYA females. The results can inform the design of future studies

Does a Bleeding Disorder Lessen the Efficacy of the 52-mg Levonorgestrel-Releasing Intrauterine System for Heavy Menstrual Bleeding in Adolescents? A Retrospective Multicenter Study

PURPOSE: The aim of this study is to compare the patient-reported bleeding outcomes and complication rates with the use of the 52-mg levonorgestrel-releasing intrauterine system (52-LNG-IUS) for treatment of heavy menstrual bleeding (HMB) among adolescents with and without a diagnosed inherited bleeding disorder (BD) within the first 12 months after insertion. METHODS: Retrospective chart review was conducted of adolescents ages 14-21 years, with and without an inherited BD, who underwent 52-LNG-IUS insertion between September 2013 and February 2020 for the treatment of HMB. RESULTS: One hundred forty-four 52-LNG-IUS insertions among 139 subjects were evaluated. Fifty-nine (41%) of these were among adolescents with a diagnosed inherited BD, and 85 (59%) were among those without a BD. Among subjects with follow-up, documentation of patient-reported bleeding outcome, and a retained IUS (92/144), both groups subjectively reported improvement in bleeding outcome, with 91.7% (33/36) of those with a BD and 94.6% (53/56) of those without a BD reporting that bleeding outcome was better than prior to IUS insertion (p = .675). There was no statistically significant difference in the rate of spontaneous expulsion (p = .233), with the rate of expulsion in the first 12 months after placement among those with a BD of 13.7% (7/51) and 6.8% for those without a BD (5/72). DISCUSSION: Adolescents with HMB both with and without an inherited BD benefit from the 52-LNG-IUS for the treatment of HMB. Rates of spontaneous IUS expulsion are not statistically different regardless of the presence of a BD and are similar to rates found in other studies of intrauterine device use in adolescents

Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A.

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.)