Intensive Therapy Research Articles

Reduction in Diabetes-Related Hospitalizations and Medical Costs After Dexcom G6 Continuous Glucose Monitor Initiation in People with Type 2 Diabetes Using Intensive Insulin Therapy.

Some people with type 2 diabetes (T2D) require intensive insulin therapy to manage their diabetes. This can increase the risk of diabetes-related hospitalizations. We hypothesize that initiation of real-time continuous glucose monitoring (RT-CGM), which continuously measures a user's glucose values and provides threshold- and trend-based alerts, will reduce diabetes-related emergency department (ED) and inpatient hospitalizations and concomitant costs. A retrospective analysis of US healthcare claims data using Optum's de-identified Clinformatics® Data Mart database was performed. The cohort consisted of commercially insured, CGM-naïve individuals with T2D who initiated Dexcom G6 RT-CGM system between August 1, 2018, and March 31, 2021. Twelve months of continuous health plan enrollment before and after RT-CGM initiation was required to capture baseline and follow-up rates of diabetes-related hospitalizations and associated healthcare resource utilization (HCRU) costs. Analyses were performed for claims with a diabetes-related diagnosis code in either (1) any position or (2) first or second position on the claim. A total of 790 individuals met the inclusion criteria. The average age was 52.8 (10.5) [mean (SD)], 53.3% were male, and 76.3% were white. For claims with a diabetes-related diagnosis code in any position, the number of individuals with ≥ 1 ED visit decreased by 30.0% (p = 0.01) and with ≥ 1 inpatient visit decreased by 41.5% (p < 0.0001). The number of diabetes-related visits and average number of visits per person similarly decreased by at least 31.4%. Larger relative decreases were observed for claims with a diabetes-related diagnosis code in the first or second position on the claim. Total diabetes-related costs expressed as per-person-per-month (PPPM) decreased by $341 PPPM for any position and $330 PPPM for first or second position. Initiation of Dexcom G6 among people with T2D using intensive insulin therapy was associated with a significant reduction in diabetes-related ED and inpatient visits and related HCRU costs. Expanded use of RT-CGM could augment these benefits and result in further cost reductions.

Predictive value of postprandial C-peptide for utilizing multiple daily injection therapy in type 2 diabetes.

Multiple daily injection (MDI) insulin therapy is an effective method of glycemic control and appropriate assignment to MDI therapy could minimize the risks of hypoglycemia and weight gain. The aim of the present study was to identify factors associated with indication for MDI therapy in type 2 diabetes (T2DM). We recruited 360 participants with T2DM that were admitted to the Endocrinology Department of Peking University People's Hospital between August 2017 and July 2018. They first underwent intensive insulin therapy, then were switched to an optimized, simpler insulin treatment that aimed to maintain fasting blood glucose between 4.4 and 7.2 mmol/L, without episodes of hypoglycemia. The baseline characteristics of groups administering either MDI or basal/premix insulin were compared and multivariable logistic regression analysis was used to determine the odds ratios (ORs) for factors associated with MDI therapy. Receiver operating characteristic (ROC) curves were then used to identify independent predictors of MDI insulin regimen efficacy. The mean age of the participants was 57.6 ± 12.9 years, and diabetes duration was 14.2 ± 8.2 years. Two hundred and sixty-seven participants administered basal/premix insulin and 93 underwent MDI therapy, of whom 61.8% and 46.2% were male, respectively (p = 0.01). The duration of diabetes was significantly longer in the MDI group (13.1 ± 7.7 years vs. 17.3 ± 8.7 years; p < 0.01). Fasting plasma glucose (FPG) was higher in the MDI group than in the basal/premix group (8.3 [6.7, 11.3] mmol/L vs. 7.2 [5.7, 9.3] mmol/L; p < 0.01), while the postprandial C-peptide concentration (PCP) was significantly lower in the MDI group (2.6 [1.8, 3.5] ng/mL) compared to the basal/premix group (3.6 [2.5, 6.2] ng/mL, p < 0.01. Multivariable logistic regression analysis suggested that diabetes duration and FPG were positively associated with MDI therapy: OR (95% confidence interval [CI]) 1.06 (1.02, 1.10) and 1.12 (1.02, 1.24), respectively. In addition, PCP was negatively associated with MDI therapy (0.72 [0.60, 0.86]). ROC analysis suggested that a PCP of < 3.1 ng/mL predicted MDI therapy with 59.6% sensitivity and 72.1% specificity. The results of our study suggest that longer diabetes duration, higher FPG, and lower PCP were associated with necessity for MDI insulin regimen. These findings should assist with the personalization of insulin treatment.

Empowering Families and Providers With a Lifestyle Medicine Approach to Pediatric Obesity

Pediatric overweight and obesity is a complex chronic medical condition with a multitude of contributing factors. Rates are now nearly double what they were before the COVID-19 pandemic and if the current trajectory holds it is anticipated that by 2050 one in every two US children will experience obesity before the age of thirty-five. Pediatric obesity guidelines emphasize referral to intensive health behavior and lifestyle therapy programs, but these are difficult to access. Front line providers caring for children can use a lifestyle medicine approach within the medical home to make lifestyle changes easier. Lifestyle Medicine can promote a family-oriented, weight-neutral approach by (1) Educating and equipping providers to assess readiness to change and providing high-quality motivational interviewing and lifestyle counseling, (2) Equipping patients and their families with tools involving the six lifestyle interventions to optimize health starting an early age, and (3) Offering a longitudinal uniform office approach to effectively prevent, manage and often reverse obesity and related comorbidities through healthy habit change.

Psychotropic Medication Use and Polypharmacy Among Children and Adolescents Initiating Intensive Behavioral Therapy for Severe Challenging Behavior

To evaluate the prevalence, trends, and factors associated with psychotropic medication use and polypharmacy among children and adolescents initiating intensive behavioral therapy for severe challenging behavior over a 10-year period. In this retrospective observational study, we examined data from caregiver interviews and patient medical records on the number and types of psychotropic medications prescribed to patients initiating intensive behavioral therapy between January 1, 2013, and December 31, 2022. Trends in medication use and polypharmacy across the 10-year period were analyzed using regression analysis, while differences in demographics and clinical factors for patients with use and polypharmacy were analyzed using nonparametric statistical analysis with odds ratios presented for significant factors. Data from all 302 pediatric patients initiating intensive behavioral therapy across the 10-year period were analyzed. Among all patients and all years, 83.8% were taking at least 1 psychotropic medication and 68.2% experienced polypharmacy. There were no changes in the prevalence of use, mean number of medications taken, or polypharmacy across the 10-year period. Patients diagnosed with attention-deficit/hyperactivity disorder or anxiety disorder, as well as those exhibiting self-injurious behavior had higher use of psychotropic medication and polypharmacy and were taking more medications overall. Psychotropic medication use and polypharmacy were extremely high for children and adolescents with severe challenging behavior, but use and polypharmacy did not change over the 10-year period of data collection. Further research is needed to establish the generality of these findings to other regions of the US.

Optimizing perinatal wellbeing in pregnancy with obesity: a clinical trial with a multi-component nutrition intervention for prevention of gestational diabetes and infant growth and neurodevelopment impairment.

Pregnancy complicated by obesity represents an increased risk of unfavorable perinatal outcomes such as gestational diabetes mellitus (GDM), hypertensive disorders in pregnancy, preterm birth, and impaired fetal growth, among others. Obesity is associated with deficiencies of micronutrients, and pregnant women with obesity may have higher needs. The intrauterine environment in pregnancies complicated with obesity is characterized by inflammation and oxidative stress, where maternal nutrition and metabolic status have significant influence and are critical in maternal health and in fetal programming of health in the offspring later in life. Comprehensive lifestyle interventions, including intensive nutrition care, are associated with a lower risk of adverse perinatal outcomes. Routine supplementation during pregnancy includes folic acid and iron; other nutrient supplementation is recommended for high-risk women or women in low-middle income countries. This study is an open label randomized clinical trial of parallel groups (UMIN Clinical Trials Registry: UMIN000052753, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000060194) to evaluate the effect of an intensive nutrition therapy and nutrient supplementation intervention (folic acid, iron, vitamin D, omega 3 fatty acids, myo-inositol and micronutrients) in pregnant women with obesity on the prevention of GDM, other perinatal outcomes, maternal and newborn nutritional status, and infant growth, adiposity, and neurodevelopment compared to usual care. Given the absence of established nutritional guidelines for managing obesity during pregnancy, there is a pressing need to develop and implement new nutritional programs to enhance perinatal outcomes.

Metabolic effects of testosterone added to intensive lifestyle intervention in older men with obesity and hypogonadism.

Whether testosterone replacement therapy (TRT) conveys additional cardiometabolic benefit to an intensive lifestyle therapy (LT) in older men with obesity and hypogonadism remains unclear. To determine whether TRT augments the effect of LT on metabolic outcomes in older men with obesity and hypogonadism. Secondary analysis of a randomized, double-blind, placebo-controlled trial. Veterans Affairs Medical Center. 83 older (age ≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and persistently low AM testosterone (< 10.4 nmol/L) associated with frailty. LT (weight management and exercise training) plus either testosterone (LT+TRT) or placebo (LT+Pbo) for six months. Primary outcome was change in glycated hemoglobin (HbA1c). Secondary outcomes included changes in other glucometabolic and lipid profile components, liver enzymes, inflammatory markers, adipokines; subcutaneous, visceral, intramuscular, and hepatic fat; blood pressure, and metabolic syndrome score. HbA1c decreased similarly in LT+TRT and LT+Pbo groups (-0.5% vs. -0.6%, respectively; p= 0.35). While TRT showed no synergistic effect with LT on ameliorating secondary outcomes, it eliminated the augmentative effect of LT on high-density lipoprotein cholesterol concentration (5.4 ± 1.0 mg/dL in LT+Pbo group vs. 0.2 ± 1.1 mg/dL in LT+TRT group, p= 0.01) and adiponectin levels (-408 ± 489 ng/mL in TRT+LT group vs 1832 ± 468 ng/mL in LT+Pbo group, p= 0.02). In older men with obesity and hypogonadism, adding TRT for six months to LT does not result in further improved cardiometabolic profiles, and could potentially blunt some of the metabolic benefits induced by LT.

Cost-Effectiveness of an Intensive Upper Limb Rehabilitation Therapy for Children With Unilateral Cerebral Palsy: An Economic Evaluation of a Randomized Controlled Trial

Background: Unilateral cerebral palsy is a major cause of childhood disability and a substantial economic burden. Intensive group-based therapy, consisting of hybrid constraint-induced movement and bimanual therapies, has been shown to be effective in improving specific quality-of-life domains in children with this disability. Our objective in this study was to assess if this intervention was cost-effective compared with standard care. Methods: An open-label, parallel, randomized controlled trial with an embedded economic evaluation of the intervention was conducted. A total of 47 children were randomized to either the intervention group (n = 27) or the standard care (n = 20) group. The effectiveness of the intervention was assessed using the Cerebral Palsy Quality of Life (Child) questionnaire across several domains. Nonparametric bootstrapping was used to quantify uncertainty intervals (UIs) for incremental cost-effectiveness ratios. Results: The incremental cost-effectiveness ratios for the intervention were $273 (95% UI: $107 to $945) for Pain and Impact of Disability, $1071 (95% UI: -$5718 to $4606) for Family Health and $1732 (95% UI: -$6448 to $8775) for Access to Services. For the 4 remaining domains, the intervention was dominated by standard care. At a willingness-to-pay threshold of $1000, only for the Pain and Impact of Disability domain was the intervention likely to have a probability of being cost-effective exceeding 0.75. Conclusions: Other than the Pain and Impact of Disability domain, there was insufficient evidence demonstrating the intervention to be cost-effective over a 13-week time horizon.

Real-world evidence on tagraxofusp for blastic plasmacytoid dendritic cell neoplasm - collected cases from a single center and case reports.

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare, aggressive hematologic malignancy. Until recently, the only curative treatment consisted of intensive chemotherapy, followed by hematopoietic cell transplantation (HCT) in eligible adult cases. Tagraxofusp, a CD123-targeted protein-drug conjugate and the first approved targeted treatment for BPDCN,might enhance outcomes especially in patients not eligible for intensive therapies. Here, we report real-world outcomes of five male patients with a median age of 79 years who received tagraxofusp as first-line treatment for BPDCN. Tagraxofusp was found to be well-tolerated in this elderly cohort, with only one patient requiring discontinuation. Three patients responded to the treatment (two patients achieved a CR and one patient achieved a partial response), of which two subsequently underwent allogeneic (allo) HCT. One patient is alive and well after ≥ 4 years after alloHCT, and one patient shows sustained CR after now 13 cycles of tagraxofusp. The other three patients died of progressive disease 4-11 months after initiation of treatment. In line with results from 13 published cases outside clinical trials in the literature, sustained responses were associated with CR after tagraxofusp treatment and subsequent alloHCT. Our results provide real-world evidence for safety and efficacy of tagraxofusp as first-line treatment for BPDCN.

Continuous glucose monitoring for the routine care of type 2 diabetes mellitus.

Although continuous glucose monitoring (CGM) devices are now considered the standard of care for people with type 1 diabetes mellitus, the uptake among people with type 2 diabetes mellitus (T2DM) has been slower and is focused on those receiving intensive insulin therapy. However, increasing evidence now supports the inclusion of CGM in the routine care of people with T2DM who are on basal insulin-only regimens or are managed with other medications. Expanding CGM to these groups could minimize hypoglycaemia while allowing efficient adaptation and escalation of therapies. Increasing evidence from randomized controlled trials and observational studies indicates that CGM is of clinical value in people with T2DM on non-intensive treatment regimens. If further studies confirm this finding, CGM could soon become a part of routine care for T2DM. In this Perspective we explore the potential benefits of widening the application of CGM in T2DM, along with the challenges that must be overcome for the evidence-based benefits of this technology to be delivered for all people with T2DM.

Short and prolonged fasting prior to the performance of tracheostomies in intensive therapy: a retrospective study

Short and prolonged fasting prior to the performance of tracheostomies in intensive therapy: a retrospective study

Neurostimulation for treatment of post-stroke impairments.

Neurostimulation, the use of electrical stimulation to modulate the activity of the nervous system, is now commonly used for the treatment of chronic pain, movement disorders and epilepsy. Many neurostimulation techniques have now shown promise for the treatment of physical impairments in people with stroke. In 2021, vagus nerve stimulation was approved by the FDA as an adjunct to intensive rehabilitation therapy for the treatment of chronic upper extremity deficits after ischaemic stroke. In 2024, pharyngeal electrical stimulation was conditionally approved by the UK National Institute for Health and Care Excellence for neurogenic dysphagia in people with stroke who have a tracheostomy. Many other approaches have also been tested in pivotal device trials and a number of approaches are in early-phase study. Typically, neurostimulation techniques aim to increase neuroplasticity in response to training and rehabilitation, although the putative mechanisms of action differ and are not fully understood. Neurostimulation techniques offer a number of practical advantages for use after stroke, such as precise dosing and timing, but can be invasive and costly to implement. This Review focuses on neurostimulation techniques that are now in clinical use or that have reached the stage of pivotal trials and show considerable promise for the treatment of post-stroke impairments.

Plasmapheresis as therapeutic option in a 16-year-old with EVALI: A case report.

Since 2019 when a cluster of cases with acute respiratory distress syndrome (ARDS) associated with e-cigarettes in the United States was reported, there have been increasing numbers of reports. Electronic-cigarette or Vaping Use-associated Lung Injury (EVALI) represents a recent entity of respiratory clinical syndromes, primarily in young adults. We report a previously healthy 16-year-old boy who developed severe ARDS following a brief nonspecific prodromal phase after excessive consumption of e-cigarettes. Despite maximum intensive care therapy, including several weeks of venovenous extracorporeal membrane oxygenation, plasmapheresis and repeated administration of immunoglobulins seemed the only way to achieve therapeutic success. Although many case reports have been published, to our knowledge, there are none to date on the therapeutic use of plasmaphoresis in severe EVALI. This case highlights the clinical features of EVALI and the diagnostic dilemma that can arise with EVALI occurring against the background of an expired SARS-CoV-2 infection, with a paediatric inflammatory syndrome (PIMS) as differential diagnosis. EVALI is a diagnosis of exclusion, and the medical history of vaping and e-cigarette use can provide valuable clues. Ethical approval for this case report (protocol number 23-145 RS) was provided by the Ethical Committee of the Department of Medicine, Philipps-Universität Marburg, Germany on 13th of June 2023. Written informed consent to publish this case and the associated images was obtained from the patient and his mother.

Effect of Intensive Insulin Therapy on Prognosis in Patients With Acute Myocardial Infarction

Objective To evaluate the clinical efficacy and safety of intensive insulin therapy in the patients with acute myocardial infarction and provide guidance for improving the prognosis. Methods The articles involving the randomized controlled trials(RCT)focusing on the effects of intensive versus conventional insulin therapy on the clinical outcomes of the patients with acute myocardial infarction were retrieved from Cochrane,Embase,PubMed,CNKI,Wanfang Data,VIP,and CBM with the time interval from inception to October 2022.The data of each RCT were extracted and used for meta-analysis in RevMan5.4. Results A total of 8 articles were included in this study,involving 726 patients(372 in the intensive insulin group and 354 in the normal insulin group).The meta-analysis results showed that the intensive insulin group had lower incidence of major cardiovascular adverse events (RR=0.53, 95%CI=0.44-0.64, P<0.001), lower all-cause mortality (RR=0.51, 95%CI=0.33-0.78, P=0.002),lower high-sensitivity C-reactive protein level on day 7(WMD=-2.00,95%CI=-2.17- -1.83,P<0.001),higher left ventricular ejection fraction on day 30 (WMD=3.94, 95%CI=2.45-5.43,P<0.001), and higher incidence of hypoglycemia events (RR=2.96, 95%CI=1.12-7.83,P=0.030) than the normal insulin group.There was no significant difference between the two groups in terms of no-reflow event after percutaneous coronary intervention(RR=0.39,95%CI=0.14-1.13,P=0.080). Conclusion Intensive insulin therapy might be associated with more clinical benefits in the patients with acute myocardial infarction,while the conclusion remains to be confirmed by more studies.

IJCM_276A: Determinants of Delayed Sputum Conversion among Tuberculosis Patients in Malappuram District: A Case Control Study

Background: Treatment of drug-sensitive TB consists of an intensive phase of 2 months followed by a continuation phase of 4 months. After completion of intensive phase of therapy, sputum AFB smear microscopy is repeated and presence of smear conversion is suggested as a significant early predictor of treatment effectiveness. Delay in sputum conversion will lead to prolongation of the period of time that patients remain contagious. Objectives: To study the determinants of delayed sputum conversion among Tuberculosis patients in Malappuram district Methodology: A Case control study was conducted among tuberculosis patients residing in Malappuram district of Kerala and registered under NTEP in District Tuberculosis Centre (DTC), Manjeri, Malappuram. After satisfying inclusion and exclusion criteria, 90 tuberculosis patients who failed to achieve sputum smear negativity after completion of 2 months of intensive phase multi drug therapy were taken as cases. Another 90 tuberculosis patients those who achieved sputum smear negativity after completion of 2 months of intensive phase therapy were selected as control group. Data was collected by interview method. Results: Patients with lower socio-economic status (OR = 3.59, 95% CI 1.92- 6.73), low BMI or underweight (OR = 1.98, 95% CI 1.1 - 3.6), multiple symptoms (OR= 5.50, 95% CI 1.98 - 15.28), increased duration of symptoms (OR=4.54, 95% 2.24-9.19), co-morbid condition of diabetes mellitus (OR = 2.25, 95% CI 1.24 - 4.09) are at statistically significant risk of delay in sputum smear conversion after intensive phase of anti-tubercular therapy. Conclusion: Patients with lower socio-economic status, low BMI or underweight, multiple symptoms, increased duration of symptoms, co-morbid condition of diabetes mellitus are at statistically significant risk of delay in sputum smear conversion after intensive phase of anti-tubercular therapy. Treating physicians and public health experts should give special attention to TB patients with these risk factors.

457 A Phase I Trial of Tazemetostat and Venetoclax in Relapsed and Refractory non-Hodgkin Lymphoma

OBJECTIVES/GOALS: Primary Objective: To evaluate the safety of venetoclax plus tazemetostat in patients with relapsed and refractory (R/R) Follicular lymphoma (FL) or Diffuse large B-cell lymphoma (DLBCL) Secondary Objectives: 1. To evaluate the tolerability of the combination of T+V using patient reported outcomes (PROs) 2. To evaluate the efficacy of T+V METHODS/STUDY POPULATION: Study design: A phase I trial in two parts: Part 1: a single-arm, open-label sequential dose escalation (3+3) of venetoclax in combination with tazemetostat, given at its recommended phase II dose (RP2D) of 800mg BID, to determine the maximum tolerated dose (MTD) of venetoclax. Part 2: two expansion cohorts (R/R DLBCL and R/R FL) to further characterize the safety and tolerability of the combination, and to estimate the preliminary efficacy. We will perform additional exploratory studies to determine if there are biologic features that correlate with responses. Eligibility: up to 38 patients aged &gt;/=18 years old with histologically confirmed diagnosis of FL or DLBCL who have received at least 2 prior lines of therapy for lymphoma with evidence of disease progression and meet inclusion criteria RESULTS/ANTICIPATED RESULTS: Primary Endpoints: 1. Incidence and severity of adverse events as per CTCAEv5 2. Dose-limiting toxicity (DLT) of T+V, and to establish the maximum tolerated dose (MTD) of V plus fixed dose T Secondary Endpoints: 1. Incidence and Severity of toxicity and quality of life as per PRO-CTCAE and FACT-Lym 2. Overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, as per Lugano criteria 3. Duration of response (DOR), progression-free survival (PFS), overall survival (OS)Exploratory Endpoints: 1. Characterization of tumor cells pre-treatment (including EZH2 mutations and BCL2 translocations) 2. Phenotypic analysis (including BCL2 expression) and quantification of the tumor microenvironment in pre-treatment samples (using image mass cytometry)Explorato DISCUSSION/SIGNIFICANCE: There is a need for novel therapeutic approaches to improve the prognosis for patients with R/R NHL. Preclinical data suggests synergism between the pair.5 Importantly, this represents a chemotherapy-free, oral regimen. If well tolerated, this could present an alternative therapeutic option for patients ineligible for more intensive therapies.

Lipid-Lowering Therapy after Acute Coronary Syndrome.

Achieving guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets remains a significant challenge in clinical practice. This review assesses the barriers to reaching LDL-C goals and explores the potential solutions to these issues. When aiming for the recommended LDL-C goal, strategies like "lower is better" and "strike early and strong" should be used. The evidence supports the safety and efficacy of intensive lipid-lowering therapy post-acute coronary syndrome (ACS), leading to improved long-term cardiovascular health and atherosclerotic plaque stabilization. Despite the availability of effective lipid-lowering therapies, such as high-intensity statins, ezetimibe, the combination of both, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a substantial proportion of patients do not meet their LDL-C targets. Contributing factors include systemic healthcare barriers, healthcare provider inertia, patient non-adherence, and statin intolerance. Statin intolerance, often rather statin reluctance, is a notable obstacle due to perceived or expected side effects, which can lead to discontinuation of therapy. In conclusion, while there are obstacles to achieving optimal LDL-C levels post-ACS, these can be overcome with a combination of patient-centric approaches, clinical vigilance, and the judicious use of available therapies. The safety and necessity of reaching lower LDL-C goals to improve outcomes in patients post-ACS are well-supported by current evidence.

Pursuing dynamics of minimal residual leukemic subclones in relapsed and refractory acute myeloid leukemia during conventional therapy.

Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied. Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored. Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse. In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones.

Justification of Intensive care management of children with severe COVID19 (а case study)

the unprecedented COVID-19 pandemic that spread across the world and lasted for more than 3 years had significant medical and social consequences. Despite the fact that in the children's population the coronavirus infection has a milder course and a much lower risk of mortality, there are individual cases with pre-existing comorbidities that cause severe acute respiratory distress syndrome. Thus, in most cases, severe COVID-19 developed in children with pre-existing conditions, including: immunodeficiency, diabetes mellitus, bronchial asthma, etc. Therefore, comorbidities disposed children to progress to severe Covid-19 which requires treatments with more aggressive therapeutic tactics and personalised management. The article presents a clinical case of severe acute respiratory distress syndrome caused by the SARS-CoV-2 virus in an early age child. The patient was observed in the Anesthesiology and Intensive Therapy Department of the Chernivtsi Regional Children's Clinical Hospital. Due to acute respiratory infection, the child has been developing signs of respiratory failure. The available instrumental findings confirmed right lung pneumonia, complicated by pneumothorax. Laboratory tests confirmed leukocytosis, thrombocytopenia, hypertransfusion, increased procalcitonin, increased level of C-reactive protein, D-dimer and interleukin-6 as well as circulating immune complexes. The treatment regimen included respiratory protection (oxygen therapy), support of hemodynamics (infusion of glucose-saline solutions), administration of intravenous normal human immunoglobulin, a short course of parenteral glucocorticosteroids, the use of step-by-step combined antibacterial therapy and a direct-acting antiviral drug (remdesivir), and thromboembolism prophylaxis (low-molecular-weight heparin). Following intensive treatment, the child's condition was characterised by a slow positive dynamics, leading to full recovery. This case demonstrates the need for timely detection of life-threatening conditions caused by COVID-19 and requires an aggressive management of child's condition using a complex intensive therapy.

Comparative analysis of clinical symptoms and biochemical alterations in women with polycystic ovary syndrome: assessing the impact of type 1 diabetes versus non-diabetic controls

BackgroundWomen with type 1 diabetes depend on insulin injections throughout their life. However, the recommendation for strict metabolic control of diabetes requires the administration of supra-physiological doses of insulin, which might result in insulin-mediated stimulation of androgen synthesis. Hyperandrogenism in women with type 1 diabetes may be associated with polycystic ovary syndrome (PCOS). This study was performed to investigate PCOS and its associated clinical symptoms and biochemical alterations in women with type 1 diabetes in the Palestinian Territories. This retrospective cohort study consists of 50 women with type 1 diabetes and 50 apparently healthy non-diabetic controls. Questionnaire interviews were conducted. The diagnosis of PCOS was based on chronic anovulation and biochemical evidence of hyperandrogenism. Serum total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and insulin were measured by ELISA.ResultsThe mean waist-to-hip ratio and age at menarche were significantly higher in diabetic women than in non-diabetic controls (81.9 ± 7.9 and 13.9 ± 1.6 years vs. 78.8 ± 5.7 and 13.2 ± 1.2 years, and P = 0.045, P = 0.020, respectively). Oligomenorrhea, acanthosis nigricans, seborrhea, and hirsutism were more frequent in diabetics. The levels of total testosterone and insulin were significantly higher in diabetics (0.58 ± 0.11 ng/ml and 15.8 ± 12.4 mlU/ml vs. 0.44 ± 0.11 ng/ml and 10.8 ± 4.5 mlU/ml, P < 0.001 and P = 0.010, respectively). PCOS was present in 11 (22.0%) of diabetic women compared to 3 (6.0%) in non-diabetics (P = 0.044). Diabetic women with PCOS received higher doses of insulin than non-PCOS women (72.7 ± 23.9 vs. 55.0 ± 19.8 UI.cc/ml/day, P = 0.023). PCOS women showed more frequent oligomenorrhea (100% vs. 15.4%, P < 0.001) and higher levels of total testosterone and insulin (0.64 ± 0.09 and 23.1 ± 13.0 vs. 0.53 ± 0.11 and 14.1 ± 11.8, P = 0.023 and P = 0.041, respectively). PCOS cases were significantly more frequent in diabetic women receiving intensive insulin therapy than their counterparts with non-intensive insulin therapy (40.9% vs. 7.1%, P = 0.012).ConclusionIntensive insulin treatment in type 1 diabetes potentiates the development of PCOS and its related clinical and biochemical features particularly oligomenorrhea, hyperinsulinemia, and hyperandrogenemia.

HER2-Positive Metastatic Colorectal Cancer.

Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.