Venetoclax for pediatric patients with newly diagnosed acute myeloid leukemia.

This retrospective study at the University of Texas MD Anderson Cancer Center evaluated frontline venetoclax combination therapy in 11 pediatric/adolescent patients with acute myeloid leukemia (AML). Despite the small sample size and retrospective nature, the treatment demonstrated safety and potential efficacy, with most patients achieving early complete remission. Adverse events were consistent with other AML therapies, and no discontinuations due to toxicity occurred. While acknowledging study limitations, including selection bias and diverse concurrent therapies, this research underscores the promising role of venetoclax in pediatric AML. Further investigation is crucial to validate its long-term efficacy in this population.

Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

Birth outcomes following in utero co-exposure to tobacco and marijuana.

BACKGROUND: With recent changes in tobacco and marijuana use patterns, it becomes crucial to understand how the prenatal co-use of these substances impacts birth outcomes. The goal of this study was to examine the risk of adverse birth outcomes among infants born to women who used tobacco and marijuana concurrently throughout pregnancy compared to infants of women who used tobacco alone. METHODS: This study involved a retrospective chart review of pregnant women identified via self-report or biochemical testing who used tobacco products alone (N = 71) or tobacco and marijuana simultaneously (N = 127) at any point throughout pregnancy. Differences in birth outcomes between these groups, including APGAR (appearance, pulse, grimace, activity, and respiration) scores, respiratory distress, neonatal intensive care unit admission, intrauterine growth restriction, birth weight, birth length, head circumference, gestational age, and length of hospital stay, were analyzed using linear regression and odds ratio analysis. RESULTS: There were no significant differences in outcomes for infants of women who used tobacco and marijuana compared to infants of women who used tobacco alone during pregnancy. Rates of adverse birth outcomes were high among women who used tobacco compared to what would be expected in unexposed pregnancies. CONCLUSIONS: Tobacco and marijuana co-use during pregnancy was not associated with an additional risk of adverse birth outcomes compared to tobacco use alone. Women should be educated on potential risks of marijuana, and especially, tobacco use during pregnancy. These results will inform clinical recommendations for pregnant women using tobacco and marijuana, aiming to decrease preventable adverse outcomes for patients and infants.

Cardiopulmonary resuscitation in low-resource settings: a statement by the International Liaison Committee on Resuscitation, supported by the AFEM, EUSEM, IFEM, and IFRC.

Most recommendations on cardiopulmonary resuscitation were developed from the perspective of high-resource settings with the aim of applying them in these settings. These so-called international guidelines are often not applicable in low-resource settings. Organisations including the International Liaison Committee on Resuscitation (ILCOR) have not sufficiently addressed this problem. We formed a collaborative group of experts from various settings including low-income, middle-income, and high-income countries, and conducted a prospective, multiphase consensus process to formulate this ILCOR Task Force statement. We highlight the discrepancy between current cardiopulmonary resuscitation guidelines and their applicability in low-resource settings. Successful existing initiatives such as the Helping Babies Breathe programme and the WHO Emergency Care Systems Framework are acknowledged. The concept of the chainmail of survival as an adaptive approach towards a framework of resuscitation, the potential enablers of and barriers to this framework, and gaps in the knowledge are discussed, focusing on low-resource settings. Action points are proposed, which might be expanded into future recommendations and suggestions, addressing a large diversity of addressees from caregivers to stakeholders. This statement serves as a stepping-stone to developing a truly global approach to guide resuscitation care and science, including in health-care systems worldwide.

In utero effects of opioids on fetal growth.

BACKGROUND: Studies indicate antenatal opioid use is associated with birth size deficits, as evidenced by reductions in birth weight and head circumference. However, there remains a limited understanding of how early this growth restriction occurs, and what specific parameters are affected. This novel study evaluated global and specific growth deficits associated with prenatal opioid exposure between 18-22 weeks' gestation as assessed during anatomy ultrasounds. METHODS: Pregnant women who completed an anatomy ultrasound were identified via electronic medical records from a large academic obstetric practice. The study group used opioids, with tobacco and/or marijuana use permitted (n = 41). The control group could have used tobacco and/or marijuana, but not opioids (n = 308). Neither group had alcohol or other drug exposure. Records were reviewed for medical history and ultrasound size parameters, coded as percentiles for gestational age. RESULTS: Demographics and medical histories were compared with several significant differences noted. After controlling for these differences, significant (p < 0.05) growth deficits were identified in opioid-exposed fetuses. Specifically, reductions >10 percentile points were observed in head circumference, biparietal diameter, and humerus length for opioid-exposed fetuses compared to controls. Additionally, intrauterine growth restriction (IUGR) was diagnosed five times more often. Femur length was significantly reduced in opioid-exposed fetuses prior to adjustment for confounding (p = .016), but this reduction was not significant (p = .072) after controlling for background differences. Estimated fetal weight (p = .274) and abdominal circumference (p = .633) were not significantly different between exposure groups. CONCLUSION: Fetal opioid exposure predicted various bone growth deficits during routine anatomy ultrasound, indicating the effects of opioid exposure on size deficits may be evident as early as 18-22 weeks' gestation. These findings may also suggest that in utero opioid exposure negatively impacts bone growth specifically rather than weight or fat/muscle mass. Additional studies with larger sample sizes may also reveal significantly reduced femur length, further supporting a negative impact on bone growth. Future studies evaluating bone health and immune function in children after antenatal opioid exposure may help clarify this specific effect of opioids on bone development.

Dynamin and reverse-mode sodium calcium exchanger blockade confers neuroprotection from diffuse axonal injury.

Mild traumatic brain injury (mTBI) is a frequently overlooked public health concern that is difficult to diagnose and treat. Diffuse axonal injury (DAI) is a common mTBI neuropathology in which axonal shearing and stretching induces breakdown of the cytoskeleton, impaired axonal trafficking, axonal degeneration, and cognitive dysfunction. DAI is becoming recognized as a principal neuropathology of mTBI with supporting evidence from animal model, human pathology, and neuroimaging studies. As mitochondrial dysfunction and calcium overload are critical steps in secondary brain and axonal injury, we investigated changes in protein expression of potential targets following mTBI using an in vivo controlled cortical impact model. We show upregulated expression of sodium calcium exchanger1 (NCX1) in the hippocampus and cortex at distinct time points post-mTBI. Expression of dynamin-related protein1 (Drp1), a GTPase responsible for regulation of mitochondrial fission, also changes differently post-injury in the hippocampus and cortex. Using an in vitro model of DAI previously reported by our group, we tested whether pharmacological inhibition of NCX1 by SN-6 and of dynamin1, dynamin2, and Drp1 by dynasore mitigates secondary damage. Dynasore and SN-6 attenuate stretch injury-induced swelling of axonal varicosities and mitochondrial fragmentation. In addition, we show that dynasore, but not SN-6, protects against H2O2-induced damage in an organotypic oxidative stress model. As there is currently no standard treatment to mitigate cell damage induced by mTBI and DAI, this work highlights two potential therapeutic targets for treatment of DAI in multiple models of mTBI and DAI.

A Role for Postsynaptic Density 95 and Its Binding Partners in Models of Traumatic Brain Injury.

Postsynaptic density 95 (PSD-95), the major scaffold protein at excitatory synapses, plays a major role in mediating intracellular signaling by synaptic N-methyl-d-aspartate (NMDA) type glutamate receptors. Despite the fact that much is known about the role of PSD-95 in NMDA-mediated toxicity, less is known about its role in mechanical injury, and more specifically, in traumatic brain injury (TBI). Given that neural circuitry is disrupted after TBI and that PSD-95 and its interactors end-binding protein 3 (EB3) and adenomatous polyposis coli (APC) shape dendrites, we examined whether changes to these proteins and their interactions occur after brain trauma. Here, we report that total levels of PSD-95 and the interaction of PSD-95 with EB3 increase at 1 and 7 days after moderate controlled cortical impact (CCI), but these changes do not occur after mild injury. Because changes occur to PSD-95 following brain trauma in vivo, we next considered the functional consequences of PSD-95 alterations in vitro. Rapid deformation of cortical neurons leads to neuronal death 72 h after injury, but this outcome is not dependent on PSD-95 expression. However, disruptions in dendritic arborization following stretch injury in vitro require PSD-95 expression, and these changes in arborization can be mimicked with expression of PSD-95 mutants lacking the second PDZ domain. Thus, PSD-95 and its interactors may serve as therapeutic targets for repairing dendrites after TBI.

Cypin: A novel target for traumatic brain injury.

Cytosolic PSD-95 interactor (cypin), the primary guanine deaminase in the brain, plays key roles in shaping neuronal circuits and regulating neuronal survival. Despite this pervasive role in neuronal function, the ability for cypin activity to affect recovery from acute brain injury is unknown. A key barrier in identifying the role of cypin in neurological recovery is the absence of pharmacological tools to manipulate cypin activity in vivo. Here, we use a small molecule screen to identify two activators and one inhibitor of cypin's guanine deaminase activity. The primary screen identified compounds that change the initial rate of guanine deamination using a colorimetric assay, and secondary screens included the ability of the compounds to protect neurons from NMDA-induced injury and NMDA-induced decreases in frequency and amplitude of miniature excitatory postsynaptic currents. Hippocampal neurons pretreated with activators preserved electrophysiological function and survival after NMDA-induced injury in vitro, while pretreatment with the inhibitor did not. The effects of the activators were abolished when cypin was knocked down. Administering either cypin activator directly into the brain one hour after traumatic brain injury significantly reduced fear conditioning deficits 5 days after injury, while delivering the cypin inhibitor did not improve outcome after TBI. Together, these data demonstrate that cypin activation is a novel approach for improving outcome after TBI and may provide a new pathway for reducing the deficits associated with TBI in patients.

Physical, Complementary, and Alternative Medicine in the Treatment of Pelvic Floor Disorders.

PURPOSE OF REVIEW: The purpose of the study was to catalog the most recent available literature regarding the use of conservative measures in treatment of pelvic floor disorders. RECENT FINDINGS: Pelvic floor disorders encompass abnormalities of urination, defecation, sexual function, pelvic organ prolapse, and chronic pain, and can have significant quality of life implications for patients. Current guidelines recommend behavioral modifications and conservative treatments as first-line therapy for pelvic floor disorders. We have reviewed the literature for articles published on physical, complementary, and alternative treatments for pelvic floor disorders over the past 5 years. Review of pelvic floor muscle physiotherapy (PFMT) and biofeedback (BF) shows a benefit for patients suffering from bladder dysfunction (incontinence, overactive bladder), bowel dysfunction (constipation, fecal incontinence), pelvic organ prolapse, and sexual dysfunction (pelvic pain). Combination of PFMT and BF has shown improved results compared to PFMT alone, and some studies find that electrical stimulation can augment the benefit of BF and PFMT. Additionally, acupuncture and cognitive behavioral therapy has shown to be an effective treatment for pelvic floor disorders, particularly with respect to pelvic pain. This update highlights beneficial conservative treatments available for pelvic floor dysfunction, and supplements the current literature on treatment options for patients suffering from these disorders.