Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Azacitidine treatment for myeloid leukemia associated with Down syndrome: A nationwide retrospective study in Japan.

Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.

Survival time analysis of remaining teeth following replacement of unilateral free-end missing teeth: A comparison between fixed implant-supported prostheses and removable partial dentures.

OBJECTIVES: This retrospective study aimed to investigate the differences in tooth loss rate between fixed implant-supported prostheses (FISPs) and removable partial dentures (RPDs) in cases of unilateral free-end missing teeth. MATERIALS AND METHODS: The data of 324 patients who underwent treatment with FISPs or RPDs for unilateral free-end missing teeth and satisfied the applicable criteria, were evaluated (47 in the FISPs group and 277 in the RPDs group). After propensity score (PS) matching, which was used to extract patients with similar background factors related to prosthetic selection at baseline, survival time analyses were performed with tooth loss as the endpoint. The adjusted variables were age, sex, number of restored teeth, periodontal status, and the practicing dentist's experience in years. The remaining teeth were classified into subcategories in relation to the missing molars. RESULTS: Overall, 58 patients (29 in each group) selected by PS matching were evaluated in the final analysis. The total number of lost teeth was 35 (FISPs group: n = 10; RPDs group: n = 25). The mean (±SD) period to tooth loss and the 10-year survival rates in the FISPs and RPDs groups were 51.6 (±30.1) months and 42.3 (±29.7) months, 70.5% and 16.4%, respectively. The log-rank test showed that significantly longer survival time in FISPs compared with RPDs. CONCLUSIONS: After adjustments for confounding factors using PS matching, replacing unilateral free-end missing teeth with FISPs may exhibit a lower tooth loss rate in adjacent and contralateral teeth compared to replacing with RPDs.

Suspected malnutrition-induced reversible feline skin fragility syndrome in a cat with congenital axial deformities.

A stray cat, an intact female Japanese domestic shorthair cat of unknown age (suspected to be a young adult), was rescued. The cat was lethargic and thin and had marked skin fragility, delayed wound healing without skin hyperextensibility, and hind limb proprioceptive ataxia and paresis. Survey radiography, computed tomography, and magnetic resonance imaging revealed congenital vertebral anomalies, including thoracolumbar transitional vertebrae, scoliosis resulting from a thoracic lateral wedge-shaped vertebra, and a kinked tail, and a dilated spinal cord central canal. Through nutritional support, the cat's general condition normalized, followed by a gradual and complete improvement of skin features. Whole-genome sequencing was completed; however, no pathogenic genetic variant was identified that could have caused this phenotype, including congenital scoliosis. A skin biopsy obtained 7 y after the rescue revealed no remarkable findings on histopathology or transmission electron microscopy. Based on clinical course and microscopic findings, malnutrition-induced reversible feline skin fragility syndrome (FSFS) was suspected, and nutritional support was considered to have improved the skin condition. Key clinical message: This is the second reported case of presumed malnutrition-induced reversible FSFS and was accompanied by long-term follow-up.

Syndrome de fragilité cutanée réversible induit par la malnutrition soupçonné chez un chat avec des difformités axiales congénitales. Un chat errant, une femelle intacte de race japonaise à poil court et d'âge inconnu (suspecté être une jeune adulte), a été secourue. La chatte était léthargique et maigre, et avait une fragilité marquée de la peau, un retard dans la guérison de plaies sans hyperextensibilité de la peau, et une ataxie proprioceptive et parésie des membres postérieurs. Des radiographies, un examen par tomodensitométrie, et de l'imagerie par résonnance magnétique ont révélé des anomalies congénitales des vertèbres, incluant des vertèbres transitionnelles thoraco-lombaires, une scoliose résultant d'une vertèbre thoracique en forme de coin, une queue pliée, et un canal central de la moelle épinière dilaté. Grâce à un soutien nutritionnel, la condition générale du chat s'est stabilisée, suivi d'une amélioration graduelle et complète des caractéristiques de la peau. Le séquençage du génome complet a été effectué; toutefois, aucune variation génétique pathogénique n'a été identifiée qui aurait pu causer ce phénotype, incluant la scoliose congénitale. Une biopsie cutanée obtenue 7 j après le sauvetage n'a révélé aucune trouvaille spéciale à l'histopathologie ou par microscopie électronique à transmission. Basé sur le déroulement clinique et l'examen microscopique, le syndrome de fragilité cutanée réversible félin induit par la malnutrition (FSFS) était suspecté, et le soutien nutritionnel a été considéré comme ayant amélioré la condition cutanée.Message clinique clé :Ce cas est le deuxième cas rapporté de FSFS induit par la malnutrition soupçonné et a fait l'objet d'un suivi à long terme.(Traduit par Dr Serge Messier).

Developing and evaluating a cancer communication picture book for children, families, and health care professionals: A mixed-methods feasibility study.

Objective: Effective communication about cancer with children is a significant challenge for healthcare professionals and families. This study aimed to create a picture book as a tool for facilitating communication about cancer and to assess its feasibility. It also demonstrated the use of mixed methods and convergent designs for intervention development. Methods: The study included healthcare professionals (n = 14), children without cancer (aged 4-8 years; n = 21) and their families (n = 18), as well as children with various types of cancer, undergoing maintenance therapy or follow-up (aged 4-12 years; n = 3) and their families (n = 3). Quantitative and qualitative data were separately analyzed, and meta-inferences were made using a joint display. The picture book was refined based on feedback from healthcare professionals, and a similar iterative process was carried out with children and their families. Results: Over 85% of the participants considered the picture book, along with a side book, feasible. The picture book was found to be helpful for discussing the topic of cancer with children. It also significantly improved the knowledge of children without cancer (P < 0.01). Most children expressed interest in reading it and believed it was useful for talking to others about cancer. However, some concerns were raised regarding the context and expressions in the picture book. Conclusions: This study successfully assessed the feasibility of the developed picture book using a mixed methods approach, offering valuable insights into its implementation and refinement. Further research is needed to evaluate the effectiveness of its use and gather user feedback.

INVASIVE HEMODYNAMIC MONITORING WITH PULMONARY ARTERY CATHETER IN SEPSIS-ASSOCIATED CARDIOGENIC SHOCK.

ABSTRACT: Background: Both sepsis-induced cardiomyopathy and worsening of preexisting cardiac disease can contribute to circulatory shock in septic patients. The early use of pulmonary artery catheter (PAC) could play a pivotal role in the management of sepsis-associated cardiogenic shock. In this study, we aimed to evaluate the impact of early invasive hemodynamic monitoring with PAC in patients with sepsis-associated cardiogenic shock. Method: We performed a retrospective study using the National Inpatient Sample data from January 2017 to December 2019. The early use of PAC was defined as the use of PAC within 2 days from the admission. We performed the multivariable logistic regression analysis to investigate the association between the early use of PAC and in-hospital mortality in patients with sepsis-associated cardiogenic shock and sepsis without cardiogenic shock, respectively. Results: There was no difference in in-hospital mortality between PAC and no PAC groups in sepsis without cardiogenic shock (adjusted odds ratio [aOR] = 1.05, 95% confidence interval [CI] = 0.82-1.35, P = 691). On the other hand, the early use of PAC was independently associated with lower in-hospital mortality in patients with sepsis-associated cardiogenic shock (aOR = 0.58, 95% confidence interval [CI] = 0.46-0.72, P < 0.001). The use of PAC was also associated with increased use of mechanical circulatory support in those with sepsis-associated cardiogenic shock (aOR = 12.26, 95% CI = 9.37-16.03, P < 0.001). For patients with sepsis-associated cardiogenic shock, the use of PAC after 2 days of admission was associated with significantly higher in-hospital mortality and decreased use of mechanical circulatory support. Conclusion: The use of pulmonary artery catheters in sepsis-associated cardiogenic shock was associated with significantly lower in-hospital mortality and increased use of mechanical circulatory supports in patients with sepsis-associated cardiogenic shock.

Prevalence and prognosis of hyperdynamic left ventricular systolic function in septic patients: a systematic review and meta-analysis.

PURPOSE: The prevalence of hyperdynamic left ventricular (LV) systolic function in septic patients and its impact on mortality remain controversial. In this systematic review and meta-analysis, we investigated the prevalence and association of hyperdynamic LV systolic function with mortality in patients with sepsis. METHODS: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. Primary outcomes were the prevalence of hyperdynamic LV systolic function in adult septic patients and the associated short-term mortality as compared to normal LV systolic function. Hyperdynamic LV systolic function was defined using LV ejection fraction (LVEF) of 70% as cutoff. Secondary outcomes were heart rate, LV end-diastolic diameter (LVEDD), and E/e' ratio. RESULTS: Four studies were included, and the pooled prevalence of hyperdynamic LV systolic function was 18.2% ([95% confidence interval (CI) 12.5, 25.8]; I2 = 7.0%, P < 0.0001). Hyperdynamic LV systolic function was associated with higher mortality: odds ratio of 2.37 [95%CI 1.47, 3.80]; I2 = 79%, P < 0.01. No difference was found in E/e' (P = 0.43) between normal and hyperdynamic LV systolic function, while higher values of heart rate (mean difference: 6.14 beats/min [95%CI 3.59, 8.69]; I2 = 51%, P < 0.0001) and LVEDD (mean difference: - 0.21 cm [95%CI - 0.33, - 0.09]; I2 = 73%, P < 0.001) were detected in patients with hyperdynamic LV systolic function. CONCLUSION: The prevalence of hyperdynamic LV systolic function is not negligible in septic patients. Such a finding is associated with significantly higher short-term mortality as compared to normal LV systolic function.

Effect of single-photon emission computed tomography acquisition method and sampling angles on image quality and quantitative accuracy in xSPECT-reconstructed images.

OBJECTIVE: The aim of this study was to evaluate the effects of the single-photon emission computed tomography (SPECT) acquisition method and sampling angles on the qualitative and quantitative interpretations of xSPECT-reconstructed images. METHODS: The spatial resolution was evaluated using a JSP phantom, and the uniformity and quantitative accuracy were verified with a NEMA IEC Body Phantom using an SIEMENS Symbia Intevo SPECT/computed tomography system. SPECT was performed using three acquisition methods (step-and-shoot, continuous, and acquire during the step), and the sampling angles were set to 2, 3, 4, 5, and 6°. The xSPECT-reconstruction technology which is used with ordered subset-conjugated gradient minimization was used for image reconstruction. RESULTS: Full width of half maximum, an evaluation index of spatial resolution, varied up to 2.73 mm with different sampling angles and up to 2.06 mm with different acquisition methods. Uniformity, as assessed by the coefficient of variation, improved with increasing sampling angles. The accuracy of the quantification of the hot sphere showed an error rate of approximately 10% depending on the sampling angle, and an error rate of approximately 5% depending on the different acquisition methods. CONCLUSIONS: In xSPECT-reconstructed images, the difference in sampling angle has a greater impact on image quality and quantitativity than the difference in the acquisition method. For tests in which uniformity is important, a larger sampling angle is recommended.

Clinical efficacy and tolerability of zonisamide monotherapy in dogs with newly diagnosed idiopathic epilepsy: Prospective open-label uncontrolled multicenter trial.

BACKGROUND: Zonisamide (ZNS) is a newer generation antiseizure medication (ASM) used to treat epilepsy in dogs and cats. However, scientific and clinical information, particularly regarding monotherapy, is limited. OBJECTIVES: To evaluate the antiseizure efficacy and tolerability of ZNS monotherapy in dogs with newly diagnosed idiopathic epilepsy (IE). ANIMALS: Study included 56 client-owned dogs newly diagnosed with IE. METHODS: This was a prospective multicenter, open-label, uncontrolled study. All dogs were ASM-naïve and had ≥2 seizures within 12 weeks. Dogs were administered 2.7-14.4 mg/kg ZNS PO q12h and followed up for ≥12 weeks. Data from the 12-week maintenance treatment period were compared with those from the 4- to 12-week pretreatment period for efficacy evaluation. Data from the entire ZNS administration period were used to assess tolerability. RESULTS: Fifty-six dogs were included in our study. Of the dogs, 53 were assessed for efficacy; 40 (76%) had a ≥ 50% reduction in seizure frequency, and 29 (55%) achieved seizure freedom. For 90% of the dogs with ≥50% reduction in seizure frequency, the mean ZNS dose was 4.8 (range, 2.7-8.6) mg/kg q12h and the mean trough plasma ZNS concentration was 18.9 (range, 8.0-48.0) µg/mL. In 7 of the 56 dogs (13%), reduced activity, decreased appetite, vomiting, hindlimb weakness, soft stools, or constipation was observed, albeit mild and temporary. Laboratory tests revealed no relevant changes. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that ZNS monotherapy is effective and well-tolerated in dogs with newly diagnosed IE.

Comparison of Central and Peripheral Arterial Blood Pressure Gradients in Critically Ill Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Measurement of blood pressure taken from different anatomical sites, are often perceived as interchangeable, despite them representing different parts of the systemic circulation. We aimed to perform a systematic review and meta-analysis on blood pressure differences between central and peripheral arterial cannulation in critically ill patients. DATA SOURCES: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and Embase from inception to December 26, 2023, using Medical Subject Headings (MeSH) terms and keywords. STUDY SELECTION: Observation study of adult patients in ICUs and operating rooms who underwent simultaneous central (femoral, axillary, or subclavian artery) and peripheral (radial, brachial, or dorsalis pedis artery) arterial catheter placement in ICUs and operating rooms. DATA EXTRACTION: We screened and extracted studies independently and in duplicate. We assessed risk of bias using the revised Quality Assessment for Studies of Diagnostic Accuracy tool. DATA SYNTHESIS: Twenty-four studies that enrolled 1598 patients in total were included. Central pressures (mean arterial pressure [MAP] and systolic blood pressure [SBP]) were found to be significantly higher than their peripheral counterparts, with mean gradients of 3.5 and 8.0 mm Hg, respectively. However, there was no statistically significant difference in central or peripheral diastolic blood pressure (DBP). Subgroup analysis further highlighted a higher MAP gradient during the on-cardiopulmonary bypass stage of cardiac surgery, reperfusion stage of liver transplant, and in nonsurgical critically ill patients. SBP or DBP gradient did not demonstrate any subgroup specific changes. CONCLUSIONS: SBP and MAP obtained by central arterial cannulation were higher than peripheral arterial cannulation; however, clinical implication of a difference of 8.0 mm Hg in SBP and 3.5 mm Hg in MAP remains unclear. Our current clinical practices preferring peripheral arterial lines need not change.

The prevalence, risk factors, and outcomes of acute pulmonary embolism complicating sepsis and septic shock: a national inpatient sample analysis.

The study aimed to evaluate the prevalence, risk factors, and clinical outcomes of pulmonary embolism in patients diagnosed with sepsis with and without shock. The National Inpatient Sample was used to identify adults with sepsis with and without shock between 2017 and 2019. The prevalence of acute pulmonary embolism and the association of acute pulmonary embolism with in-hospital mortality, hospital length of stay for survivors, and overall costs of hospitalization were evaluated. Multivariable logistic and linear regression analyses, adjusted for various parameters, were used to explore these associations. Of the estimated 5,019,369 sepsis hospitalizations, 1.2% of patients with sepsis without shock and 2.3% of patients with septic shock developed pulmonary embolism. The odds ratio for in-hospital mortality was 1.94 (95% confidence interval (CI) 1.85-2.03, p < 0.001). The coefficient for hospital length of stay was 3.24 (95% CI 3.03-3.45, p < 0.001). The coefficient for total costs was 46,513 (95% CI 43,079-49,947, p < 0.001). The prevalence of pulmonary embolism in patients diagnosed with sepsis with and without shock was 1.2 and 2.3%, respectively. Acute pulmonary embolism was associated with higher in-hospital mortality, longer hospital length of stay for survivors, and higher overall costs of hospitalization.