Age Impacts Risk of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Non-Severe Combined Immune Deficiency Inborn Errors of Immunity.

Alemtuzumab, fludarabine, and melphalan containing-reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is an increased risk of mixed chimerism leading to secondary graft failure. This study evaluated factors associated with the risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-severe combined immune deficiency (SCID) IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine, and melphalan. We hypothesized that age would impact the incidence of mixed chimerism. We retrospectively reviewed records of patients who underwent HCT for non-SCID IEI with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to -10), fludarabine (150 mg/m2 or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg if weight <10 kg on day -3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor chimerism on 2 or more consecutive occasions in whole blood. Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were categorized into 3 groups: age <1 year, age 1 to 5 years, and age >5 years. Forty-nine patients (52.7%) developed mixed chimerism, at a median of 34 days post-HCT (range, 10 to 1396 days). Mixed chimerism developed in 88.9% (n = 16/18) of the age <1 year group, in 57.1% (n = 20/35) of the age 1 to 5 years group, and in 35% (n =14/40) of the age >5 years group. Patients age <5 years were significantly more likely to develop mixed chimerism (χ2 (3, N = 93) = 14.8; P = .001). We observed a significantly increased cumulative incidence of developing mixed chimerism associated with age <1 year (P = .0002). Competing risk regression analysis showed a 3-fold higher risk of developing mixed chimerism for age <1 year (subdistribution hazard ratio (HR), 3.05; 95% confidence interval [CI], 1.11 to 8.38; P = .031,) compared to age >5 years and a significantly decreased risk of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR, .24; 95% CI, .09 to .65; P = .005) There were no significant associations between mixed chimerism and graft source, graft type, CD34+ or CD3+ cell dose, HLA match, or underlying disease (hemophagocytic lymphohistiocytosis [HLH] versus non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required 1 or more secondary interventions (donor lymphocyte infusion, CD34 boost, or second HCT). Patients age <1 year with mixed chimerism were significantly more likely than patients age >5 years to require secondary intervention for mixed chimerism (P = .004). Our study demonstrates that age <5 years, especially age <1 year, is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate-schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children age <5 years, particularly those age <1 year, require a higher-intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.

Compassionate Use Narsoplimab for Severe Refractory Transplantation-Associated Thrombotic Microangiopathy in Children.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and potentially severe complication of hematopoietic cell transplantation. TA-TMA-directed therapy with eculizumab, a complement C5 inhibitor, has resulted in a survival benefit in some studies. However, children with TA-TMA refractory to C5 inhibition with eculizumab (rTA-TMA) have mortality rates exceeding 80%, and there are no other known therapies. Narsoplimab, an inhibitor of the MASP-2 effector enzyme of the lectin pathway, has been studied in adults with TA-TMA as first-line therapy with a response rate of 61%. Although there are limited data on narsoplimab use as a second-line agent in children, we hypothesized, that complement pathways proximal to C5 are activated in rTA-TMA, and that narsoplimab may ameliorate rTA-TMA in children. In this single-center study, children were enrolled on single-patient, Institutional Review Board-approved compassionate use protocols for narsoplimab treatment. Clinical complement lab tests were obtained at the discretion of the treating physician, although all patients were also offered participation in a companion biomarker study. Research blood samples were obtained at the time of TA-TMA diagnosis, prior to eculizumab treatment, at the time of refractory TA-TMA diagnosis prior to the first narsoplimab dose, and 2 weeks after the first narsoplimab dose. Single ELISA kits were used to measure markers of complement activation according to the manufacture's instructions. Five children with rTA-TMA received narsoplimab; 3 were in multiorgan failure and 2 had worsening multiorgan dysfunction at the time of treatment. Additional comorbidities at the time of treatment included sinusoidal obstructive syndrome (SOS; n = 3), viral infection (n = 3), and steroid-refractory stage 4 lower gut grade IV acute graft-versus-host disease (aGVHD, n = 3). Two infants with concurrent SOS and no aGVHD had resolution of organ dysfunction; 1 also developed transfusion-independence (complete response), and the other's hematologic response was not assessable in the setting of leukemia and chemotherapy (partial response). One additional patient achieved transfusion independence but had no improvement in organ manifestations (partial response), and 2 patients treated late in the course of disease had no response. Narsoplimab was well tolerated without any attributed adverse effects. Three patients consented to provide additional research blood samples. One patient with resolution of organ failure demonstrated evidence of proximal pathway activation prior to narsoplimab treatment with subsequent declines in Ba, Bb, C3a, and C5a and increases in C3 in both clinical and research lab tests. Otherwise, there was no clear pattern of other complement markers, including MASP-2 levels, after therapy. In this cohort of ill children with rTA-TMA and multiple comorbidities, 3 patients benefited from narsoplimab. Notably, the 2 patients with resolution of organ involvement did not have steroid-refractory aGVHD, which is thought to be a critical driver of TA-TMA. Additional studies are needed to determine which patients are most likely to benefit from narsoplimab and which markers may be most helpful for monitoring lectin pathway activation and inhibition.

DNA Directed Pro-Dopamine Regulation Coupling Subluxation Repair, H-Wave® and Other Neurobiologically Based Modalities to Address Complexities of Chronic Pain in a Female Diagnosed with Reward Deficiency Syndrome (RDS): Emergence of Induction of "Dopamine Homeostasis" in the Face of the Opioid Crisis.

Addiction is a complex multifactorial condition. Established genetic factors can provide clear guidance in assessing the risk of addiction to substances and behaviors. Chronic stress can accumulate, forming difficult to recognize addiction patterns from both genetic and epigenetic (environmental) factors. Furthermore, psychological/physical/chemical stressors are typically categorized linearly, delaying identification and treatment. The patient in this case report is a Caucasian female, aged 36, who presented with chronic pain and partial disability following a surgically repaired trimalleolar fracture. The patient had a history of unresolved attention deficit disorder and an MRI scan of her brain revealed atrophy and functional asymmetry. In 2018, the patient entered the Bajaj Chiropractic Clinic, where initial treatment focused on re-establishing integrity of the spine and lower extremity biomechanics and graduated into cognitive behavior stabilization assisted by DNA pro-dopamine regulation guided by Genetic Addiction Risk Severity testing. During treatment (2018-2021), progress achieved included: improved cognitive clarity, focus, sleep, anxiety, and emotional stability in addition to pain reduction (75%); elimination of powerful analgesics; and reduced intake of previously unaddressed alcoholism. To help reduce hedonic addictive behaviors and pain, coupling of H-Wave with corrective chiropractic care seems prudent. We emphasize the importance of genetic assessment along with attempts at inducing required dopaminergic homeostasis via precision KB220PAM. It is hypothesized that from preventive care models, a new standard is emerging including self-awareness and accountability for reward deficiency as a function of hypodopaminergia. This case study documents the progression of a patient dealing with the complexities of an injury, pain management, cognitive impairment, anxiety, depression, and the application of universal health principles towards correction versus palliative care.

Quality Improvement in Hematopoietic Stem Cell Transplant and Cellular Therapy: Using the Model for Improvement to impact Outcomes.

Quality improvement and quality assurance form a complementary and independent relationship. Quality assurance measures compliance against industry standards using audits, whereas quality improvement is a continuous process focused on processes and systems that can improve care. The Model for Improvement is a robust quality improvement tool that transplant and cellular therapy teams can use to redesign healthcare processes. The Model for Improvement uses several components addressed in sequence to organize and critically evaluate improvement activities. Unlike other health sciences clinical research, quality improvement projects, and research are based on dynamic hypotheses that develop into observable, serial tests of change with continuous collection and feedback of performance data to stakeholders.

Pulmonary Complications After Pediatric Stem Cell Transplant.

The number of disorders that benefit from hematopoietic stem cell transplantation (HSCT) has increased, causing the overall number of HSCT to increase accordingly. Disorders treated by HSCT include malignancy, benign hematologic disorders, bone marrow failure syndromes, and certain genetic diagnoses. Thus, understanding the complications, diagnostic workup of complications, and subsequent treatments has become increasingly important. One such category of complications includes the pulmonary system. While the overall incidence of pulmonary complications has decreased, the morbidity and mortality of these complications remain high. Therefore, having a clear differential diagnosis and diagnostic workup is imperative. Pulmonary complications can be subdivided by time of onset and whether the complication is infectious or non-infectious. While most infectious complications have clear diagnostic criteria and treatment courses, the non-infectious complications are more varied and not always well understood. This review article discusses pulmonary complications of HSCT recipients and outlines current knowledge, gaps in knowledge, and current treatment of each complication. This article includes some adult studies, as there is a significant paucity of pediatric data.

Urinary symptoms and infections among female garment factory workers in Bangladesh.

BACKGROUND: The prevalence of urinary symptoms and infections among female garment factory workers in Bangladesh - a large developing country - is largely unknown. Garment sector is this country's main economic growth engine. OBJECTIVES: This paper focuses on garment industry workers and compares the findings with another group of low socioeconomic status working women. METHODS: Urinary tract symptoms (UTS) were determined by self-reported survey including International Consultation on Incontinence Modular Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) and urinary tract infection (UTI) was determined among a subset population by urine dipstick tests. RESULTS: Data were collected from 310 garment workers and 297 comparison workers. About one third of garment workers (31.94%) and comparison workers (29.97%) could take up to 3 toilet breaks in a day. Garment workers reported to be more sexually active and menstruation was more common among them compared to comparison workers. They reported a significantly higher prevalence of malodorous urine and vaginal discharge. Garment workers were found to have a significantly higher ICIQ-FLUTS score of voiding than comparison workers (0.44 vs. 0.27; p-value = 0.0167).Among the study respondents, 148 garment workers and 134 other workers provided urine samples and 21 (7.45%) were found to have UTI. After considering all the risk factors in multivariate model, garment work had a significant impact on the probability of having UTI with Odds Ratio of 5.46 (p-value = 0.0374; 95% CI = 1.10, 26.97) compared to other workers. CONCLUSIONS: This study highlights the prevalence and burden of urinary symptoms and infections among female worker populations in Bangladesh.

Traumatic life events and development of post-traumatic stress disorder among female factory workers in a developing country.

BACKGROUND: Post-traumatic stress disorder (PTSD) may be more prevalent and burdensome in developing countries. AIMS: The goals of this study were to (1) determine the prevalence of PTSD, (2) identify types and number of traumas related to screening positive for PTSD and (3) determine other sociodemographic risk factors and health/medical conditions that may be correlated to PTSD among garment-factory workers and a comparable working population in Bangladesh. METHOD: A survey was administered to a convenient sample of 607 lower socio-economic status (SES) working women in Bangladesh, 310 of who were garment workers. The primary outcome PTSD was measured by the PTSD Checklist. The Life Events Checklist determined the number and type of traumatic events. RESULTS: The prevalence of PTSD was found to be 17.79% - 7.25% in garment workers and 21.55% in the comparison worker group. In multivariate analysis, PTSD was found to be significantly associated with age, income, chronic pain and number of stressful events. Participants between 45-50 years of age had the greatest odds of reporting PTSD - 15.68 fold (95% confidence interval (CI) = 4.08, 60.29) compared with those younger than 24 years. PTSD was more common in those with lower income (2,000-4,000 taka) (odds ratio (OR) = 1.60; 95% CI = 0.79, 3.26), who had chronic pain (OR = 2.48; 95% CI = 1.51, 4.07) and who experienced over three traumatic life events (OR = 11.25; 95% CI = 4.59, 27.59). The mean number of traumatic events experienced by this entire population was 4.9 with PTSD being more likely in those who experienced physical assault (OR = 6.35; 95% CI = 4.07, 9.90), who caused serious harm or death to someone else (OR = 4.80; 95% CI = 1.36, 16.87) and who had exposure to combat or war (OR = 4.76; 95% CI = 1.17, 19.34). CONCLUSION: Undiagnosed and untreated PTSD impacts the quality of life and decrease worker productivity among working-age women in this developing country.

Prevalence and risk factors of depression among garment workers in Bangladesh.

BACKGROUND: Depression is a growing health issue in both developed and developing countries. General unawareness at the population level, lack of training among health care providers and scarcity of resources including treatment opportunities may conceal the real burden of depression in developing countries, and more epidemiological studies on its prevalence and risk factors are critically needed. AIM: This study reports the prevalence of depression and its associated risk factors among female garment factory workers in Bangladesh - a major supplier country of clothes for the Western market. This research should generate useful evidence for national and international stakeholders who have an interest in improving health, safety and well-being of outsourced factory workers. METHODS: A survey was conducted on a sample of 600 lower socio-economic status working women including garment workers. This survey collected data on demographic and health profile of these workers. The primary outcome was depression as measured by Patient Health Questionnaire 9. It also obtained data on traumatic life events and post-traumatic stress disorder. RESULTS: The prevalence of depression was 23.5%: 20.9% among garment workers and 26.4% among others. Part-time employment (odds ratio-OR): 2.36, 95% confidence interval (95% CI): 1.01-5.51), chronic pain (OR: 1.67, 95% CI: 1.01-2.78), two or more traumatic life events (OR: 6.43, 95% CI: 2.85-14.55) and dysuria (OR: 2.50, 95% CI: 1.02-6.15) were found to be significantly associated with depression among these workers in multivariate regression model. Depression prevalene lowered by 11% among these workers for every additional monthly earning of 1,000 taka (US$12). CONCLUSION: Depression is a multifaceted health issue with many personal, social, economic and health determinants and consequences. This study demonstrates that the prevalence of moderate-to-severe depression among working women in Bangladesh is quite high. Prevention and treatment of depression in developing countries and societies can reduce suffering, lower incidence of suicide, and prevent economic loss. Creating awareness on outsourced workers' poor mental health may help in developing initiatives to protect and preserve their well-being.

Self-efficacy, disability level and physical strength in the injured workers: findings from a major factory disaster in Bangladesh.

INTRODUCTION: In 24 April 2013, Rana Plaza - a high-rise building in Bangladesh where garments were being made for the Western markets collapsed. In this study, we report on the surviving workers' physical strength, self-efficacy, and disability level one year after the disaster. METHODS: This cross-sectional study took place at the Centre for the Rehabilitation of the Paralysed (CRP) which provided care for more than 600 victims. For this study, upper extremity strength among the survivors was assessed by dynamometer hand grip (HG) and lower extremity strength by five time sit to stand test (FTSST). The WHODAS tool measured level of disability and General Self-Efficacy questionnaire measured self-efficacy. Post-traumatic stress disorder (PTSD) prevalence was determined by the PCL-scale. RESULTS: The study recruited 181 injured workers. The mean disability score among them was 49.8 (SD 17.5) and mean self-efficacy score was 24.9 (SD 6.9). In multivariate models, after adjusting for age, gender, education, injury profile, employment, marital status and job category, self-efficacy was found to be higher among those who scored above median HG test score [ß= -2.32 (95% CI: -4.63, -0.01)] and FTSST performance score [ß= -2.69 (95% CI: -4.93, -0.46)]. The disability level was found to be significantly associated with PTSD score [ß = 0.84 (95% CI: 0.62, 1.06)] and self-efficacy score [ß= -0.45 (95% CI: -0.78, -0.13)]. CONCLUSIONS: There is an immense need to develop and deliver effective post-injury recovery, rehabilitation and return-to-work programs for injured workers in resource poor countries. Implications for Rehabilitation The study findings suggest that one year after the factory disaster in Bangladesh, the injured workers are suffering from a high degree of disability, low physical performance and reporting low self-efficacy. The national and international stakeholders including Western buyers, aid agencies, NGOs, worker advocacy groups, consumer associations and the government of Bangladesh can be updated on the progress made so far. There is an immense need to develop and deliver effective post-injury recovery, rehabilitation and return-to-work programs for injured workers in resource poor countries. International organizations like ILO, WHO, World Bank can help developing countries in building these capacities.

The prevalence and risk factors of Post-Traumatic Stress Disorder among workers injured in Rana Plaza building collapse in Bangladesh.

OBJECTIVES: Prevalence and risk factors of PTSD among injured garment workers who survived a major factory collapse. METHODS: Survivors receiving treatment or rehabilitation care at one year post event were surveyed, which included Post Traumatic Stress Disorder Checklist Specific version. RESULTS: The respondents consisted of 181 people with a mean age of 27.8 years and a majority had less than high school education (91.2%). Multivariable logistic regression found that the odds of having PTSD was higher among married (OR: 3.2 [95% CI: 1.3-8.0]), those who used to work more than 70 hr/week (OR: 2.4 [1.1-5.3]), workers who used to hold higher job positions (OR: 2.6 [1.2-5.6]) or who had a concussion injury (OR: 3.7 [1.4-9.8]). Among the respondents, 83.4% remained unemployed, and only 57.3% (63 people) reported receiving a quarter or less of what they were promised as compensation. CONCLUSIONS: Probable PTSD was prevalent among surviving workers of the Rana Plaza building collapse in Bangladesh.