Noncoding mutations drive persistence of a founder preleukemic clone which initiates late relapse in T-ALL.

ABSTRACT: T-ALL relapse usually occurs early but can occur much later, which has been suggested to represent a de novo leukemia. However, we conclusively demonstrate late relapse can evolve from a pre-leukemic subclone harbouring a non-coding mutation that evades initial chemotherapy.

Substance use disorder and treatment in healthcare providers.

ABSTRACT: Substance use disorder (SUD) is associated with innumerable risk factors and patient presentations, and is a leading cause of preventable disease. Research continues to explore the role of biochemical and social constructs that may play a role in the foundation, perpetuation, and progression of SUD in at-risk populations. Healthcare providers develop SUD at lifetime rates similar to those of the general population, but detecting common signs and symptoms may be challenging, often delaying treatment until the course becomes more complicated. Compounding this are tangible and intangible reservations to care, including clinician fear of the financial cost for treatment, lost wages, and damage to professional esteem. Nonetheless, all clinicians must be able to recognize SUD and be aware of treatments for afflicted colleagues.

Complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS), formerly called reflex sympathetic dystrophy (RSD), is a chronic pain phenomenon associated with an alteration in peripheral and central pain perception in a localized body region. Because of the many risk factors associated with this phenomenon, the true nature of the disease risk and clinical course are a challenge to predict. After the diagnosis is confirmed and treatment is provided promptly, clinicians must consider patient health and function holistically to foster improvement in overall quality of life.

A patient with untreated preeclampsia and peripartum cardiomyopathy.

ABSTRACT: The pathophysiologic process of peripartum cardiomyopathy, a rare and potentially life-threatening condition, is not completely understood. One theory is a possible link between the development of preeclampsia and peripartum cardiomyopathy. These two conditions have been linked to significant mortality in peripartum or postpartum patients. Clinicians must be able to identify the two, their differences, and start appropriate therapies immediately.

Investigating how historical legacies of militarized violence can motivate COVID-19 vaccine hesitancy: Evidence from global dyadic survey.

BACKGROUND: In almost all countries, COVID-19 vaccines available for public use are produced outside of that country. Consistent with recent social science research, we hypothesize that legacies of violent conflict from vaccine-producing against vaccine-consuming countries may motivate vaccine hesitancy among people in targeted countries that purchase vaccines produced by the erstwhile aggressor. METHODS: Our analyses draw on data from the Correlates of War project and a large, representative survey of 18,291 adults that asked respondents in 16 countries to self-report their attitudes toward COVID-19 vaccines originating from 12 potential vaccine-producing countries in December 2020 (184 country-pairs, 208,422 ratings). For the main analysis, we used random-effect linear probability models and turned to Bayesian Model Averaging to probe the robustness of the main findings. RESULTS: We demonstrate that elevated levels of historical violence between vaccine-producing and vaccine-consuming countries are associated with increased negative feelings toward a COVID-19 vaccine produced by the vaccine producer. CONCLUSION: Global vaccine hesitancy may result, at least in part, from public perceptions of historical conflict between vaccine-producing and vaccine-consuming countries. These results can help public health practitioners better preempt and adjust for cross-national vaccine resistance.

Novice Accuracy in Ultrasound and Stethoscope Study (NAUSS).

INTRODUCTION: The purpose of this noninferiority study was the accurate determination of valvular heart disease, using bedside echocardiogram as compared to stethoscope, by a novice clinician examiner. METHODS: We conducted a single university, single program study to investigate the use of bedside ultrasound in the hands of a novice clinical user, defined as someone with fewer than 2 years of clinical education. We enrolled 8 examinees with evidence of valvular heart disease to be assessed by 13 subjects. RESULTS: Descriptive statistics revealed echocardiogram accuracy of 56% compared to 44% accuracy with stethoscope, though not statistically significant. Interestingly, 31% of subjects obtained equal measures with both instruments. Correlation proficiency between both modalities was also observed. DISCUSSION: There is no statistically significant difference in novice examiner diagnostic accuracy using point-of-care echocardiograms for examination of valvular heart disease when compared with a stethoscope.

Vaccine hesitancy, state bias, and Covid-19: Evidence from a survey experiment using Phase-3 results announcement by BioNTech and Pfizer.

BACKGROUND: Past survey studies document that people strongly prefer Covid-19 vaccines developed domestically over those developed abroad. Available evidence suggests that this preference for domestic vaccines over foreign ones may stem from prejudice against foreign countries, but identifying prejudice-based vaccine preferences is difficult because people also draw inferences about the quality of vaccines based on country of origin. We exploit a unique opportunity provided by the announcement of a viable vaccine by a bi-national venture, BioNTech and Pfizer, to examine the effect of such prejudice on vaccination intentions while controlling for beliefs about the vaccine quality. METHODS: We implemented a survey experiment in Germany and the United States (n = 582, 661 respectively) a few days after the BioNTech/Pfizer announcement of a viable vaccine. We randomized the identified company (and country) responsible for the vaccine development between BioNTech (Germany) and Pfizer (U.S.) and asked respondents when they would take said vaccine. RESULTS: In either the German and U.S. samples, we find little evidence that a country of origin of the vaccine makes a difference in when respondents intend to get vaccinated. We also see no evidence that those with a general animus toward the other foreign country would be more biased against a foreign vaccine. CONCLUSION: Our findings suggest that prejudice against foreign countries may be less of a concern for vaccine hesitancy and that its effect may be highly context specific.

The Efficacy of Pectoralis Nerve Blockade in Breast Reductions: A Prospective Randomized Trial.

BACKGROUND: Pectoralis nerve (Pecs) blocks have been shown to reduce perioperative opioid consumption in patients undergoing mastectomies, but the effectiveness of these blocks in breast reductions has not been established. This trial aims to evaluate the efficacy of Pecs blocks (I and II) on perioperative pain management in patients undergoing breast reductions. METHODS: Thirty-six patients were enrolled in the randomized controlled trial divided into 2 groups. The treatment group (n = 16) received general anesthesia plus postinduction ultrasound-guided Pecs blocks. The control group (n = 20) received general anesthesia alone. The primary outcomes measured were perioperative narcotic requirements, need for postoperative antiemetics, pain scores, and length of time in the operating room (OR). We measured patient and procedural risk factors including pedicle/skin excision patterns, concurrent liposuction, weight of resection, and additional local anesthesia. Risk factors as well as outcomes were analyzed using Fischer exact and t tests. RESULTS: No statistically significant difference was shown between the group receiving the Pecs blocks and the control with regard to narcotic requirements, pain scores, and need for antiemetics. Patients undergoing Pecs blocks had a significantly higher OR time before incision (P = 0.0073). Patient and procedural risk factors were well balanced (P > 0.41). CONCLUSIONS: Pectoralis nerve blocks may be a valuable component of a multimodality pain regimen; however, when performed as a solitary adjunct, they do not seem to decrease perioperative narcotic requirements, pain scores, or the need for antiemetic medication in patients undergoing breast reductions. In addition, postinduction Pecs blocks significantly increase OR times.

Recognizing and managing upper extremity compartment syndrome.

Compartment syndrome is an acute limb-threatening condition typically treated with emergency fasciotomy. Although limbs often are saved, ischemia can cause irreversible neurologic damage to the extremity. Patients with upper extremity compartment syndrome may lose fine motor function, which can result in long-term impairment of perceived quality of life. This article reviews the anatomy, physiology, presentation, diagnosis, and treatment of upper extremity compartment syndrome, including rehabilitation, which can reduce complications that occur even in patients who were promptly and properly treated.

Persistent hypoglycemia: Glycogen storage disease type Ib.

Glycogen storage disease is a rare congenital disorder that can lead to hypoglycemic events. This article focuses on a patient in acute distress secondary to hypoglycemia that failed to respond to initial interventions. Because symptoms can be similar to severe hyperglycemia, a thorough history and physical examination are key to prompt diagnosis and appropriate management.

Heterotopic pregnancy: Simultaneous viable and nonviable pregnancies.

Heterotopic pregnancy occurs when a patient has simultaneous intrauterine and ectopic pregnancies. Rates of heterotopic pregnancy have been rising with increased availability and access to in vitro fertilization and other advanced fertility technologies. Symptoms of heterotopic pregnancy are nonspecific, such as vague abdominal pain, so transvaginal ultrasound is a crucial part of the diagnostic process. Laparoscopy is the most commonly performed treatment of the ectopic pregnancy; other options include localized injections of methotrexate and/or potassium chloride. Following definitive termination of the ectopic pregnancy, many patients will successfully deliver the intrauterine pregnancy at term. Early identification of heterotopic pregnancy can reduce maternal morbidity and mortality.

Current and emerging treatments for sickle cell disease.

Sickle cell disease (SCD) is a group of inherited blood disorders affecting the hemoglobin, shortening the lifespan of erythrocytes, and causing them to take on a distinctive sickled shape that can lead to vaso-occlusion. Current treatment aims to reduce morbidity and mortality through hydroxyurea, erythrocyte transfusion, and hematopoietic stem cell transplantation. This article reviews the disease process, typical presentations, complications, and acute and chronic treatment options.

Medulloblastoma therapy generates risk of a poorly-prognostic H3 wild-type subgroup of diffuse intrinsic pontine glioma: a report from the International DIPG Registry.

With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years). From these cases, molecular subgrouping of primary medulloblastomas with available tissue (n = 5) revealed only non-WNT, non-SHH subgroups (group 3 or 4). The estimated cumulative incidence of DIPG after post-treatment medulloblastoma ranged from 0.3-3.9%. Posterior fossa radiation exposure (including brainstem) was greater than 53.0 Gy in all cases with available details. Tumor/germline exome sequencing of three radiation-associated DIPGs revealed an H3 wild-type status and mutational signature distinct from primary DIPG with evidence of radiation-induced DNA damage. Mutations identified in the radiation-associated DIPGs had significant molecular overlap with recurrent drivers of adult glioblastoma (e.g. NRAS, EGFR, and PTEN), as opposed to epigenetic dysregulation in H3-driven primary DIPGs. Patients with radiation-associated DIPG had a significantly worse median overall survival (median 8 months; range 4-17 months) compared to patients with primary DIPG. Here, it is demonstrated that DIPG occurs as a not infrequent complication of radiation therapy in survivors of pediatric medulloblastoma and that radiation-associated DIPGs may present as a poorly-prognostic distinct molecular subgroup of H3 wild-type DIPG. Given the abysmal survival of these cases, these findings provide a compelling argument for efforts to reduce exposure of the brainstem in the treatment of medulloblastoma. Additionally, patients with radiation-associated DIPG may benefit from future therapies targeted to the molecular features of adult glioblastoma rather than primary DIPG.

Targeting matrix metalloproteinase-13 in bronchial epithelial repair.

BACKGROUND: Viral infection of the bronchial epithelium disrupts the barrier properties of the epithelium in healthy individuals and those with lung disease. Repair of the bronchial epithelium is dependent of the formation of a provisional fibrin matrix and migration of epithelial cells to cover denuded areas, followed by proliferation and differentiation. OBJECTIVE: The objective was to test the hypothesis that poly I:C, a model of viral infection, limits epithelial repair through the stimulated release of matrix metalloproteinase-13 (MMP-13). METHODS: Confluent layers of cultured normal human primary bronchial epithelial cells (NHBE) and SV-40 virus-transformed 16HBE14o- bronchial epithelial cells were mechanically wounded, and video microscopy used to measure the rate of wound closure over 2 hours, in the absence and presence of poly I:C (1-20 µg/mL). MMP-13, tissue factor and endothelin release were measured by ELISA. The effect of inhibitors of MMP-13 activity and expression and a nonspecific endothelin receptor antagonist, bosentan, on the rate of epithelial repair was investigated. RESULTS: Poly I:C limited the rate of epithelial repair, and NHBE were significantly more sensitive to poly I:C effects than 16HBE14o- cells. NHBE, but not 16HBE14o-, released MMP-13 in response to poly I:C. Inhibitors of MMP-13 activity (WAY 170523) and expression (dimethyl fumarate) significantly enhanced the rate of repair. Bosentan enhanced the rate of bronchial epithelial repair by a mechanism that was independent of MMP-13. CONCLUSIONS AND CLINICAL RELEVANCE: Bronchial epithelial repair is limited by endothelin and by MMP-13, a protease that degrades coagulation factors, such as fibrinogen, and matrix proteins essential for epithelial repair. Further studies with primary cells from patients are needed to confirm whether repurposing bosentan and inhibitors of MMP-13 expression or activity, for inhalation may be a useful therapeutic strategy in diseases where repeated cycles of epithelial injury and repair occur, such as asthma and COPD.

Wavefront-Guided Versus Wavefront-Optimized Photorefractive Keratectomy: Visual and Military Task Performance.

PURPOSE: To compare visual performance, marksmanship performance, and threshold target identification following wavefront-guided (WFG) versus wavefront-optimized (WFO) photorefractive keratectomy (PRK). METHODS: In this prospective, randomized clinical trial, active duty U.S. military Soldiers, age 21 or over, electing to undergo PRK were randomized to undergo WFG (n = 27) or WFO (n = 27) PRK for myopia or myopic astigmatism. Binocular visual performance was assessed preoperatively and 1, 3, and 6 months postoperatively: Super Vision Test high contrast, Super Vision Test contrast sensitivity (CS), and 25% contrast acuity with night vision goggle filter. CS function was generated testing at five spatial frequencies. Marksmanship performance in low light conditions was evaluated in a firing tunnel. Target detection and identification performance was tested for probability of identification of varying target sets and probability of detection of humans in cluttered environments. RESULTS: Visual performance, CS function, marksmanship, and threshold target identification demonstrated no statistically significant differences over time between the two treatments. Exploratory regression analysis of firing range tasks at 6 months showed no significant differences or correlations between procedures. Regression analysis of vehicle and handheld probability of identification showed a significant association with pretreatment performance. CONCLUSIONS: Both WFG and WFO PRK results translate to excellent and comparable visual and military performance.

Unexploded Ordnance in an Expectant Patient: A Case Report.

Retained unexploded ordnance is only one of the numerous potential threats to coalition forces while deployed in the theater of operations. Though rare, these are also very real dangers for personnel involved with patient care and movement. Principles of management include determination of device type with plain film radiography, minimizing rotational and vibratory movement, and strategic isolation of the patient from the hospital facility, hospital personnel, and other patients. Early identification of this threat, as well as early involvement of the Explosive Ordnance Disposal team is paramount to safe and successful management. We present a case of a deceased patient in the expectant triage category with a delayed identification of retained unexploded ordnance during postmortem preparation.

Abdominal aortic aneurysm: A ticking time bomb.

Abdominal aortic aneurysm (AAA) is a clinical challenge in risk assessment, recognition, treatment, and prevention. This article explores the pathogenesis, presentation, diagnosis, treatment, and prevention of AAA.

Chest discomfort in a patient with cancer.

Patients with cancer are at higher risk for venous thromboembolism than patients without cancer due to hypercoagulability associated with malignancy. This article describes a patient with metastatic renal cell carcinoma who had chest pain over several weeks caused by multiple pulmonary emboli.

Resistance and resilience responses of a range of soil eukaryote and bacterial taxa to fungicide application.

The application of plant protection products has the potential to significantly affect soil microbial community structure and function. However, the extent to which soil microbial communities from different trophic levels exhibit resistance and resilience to such compounds remains poorly understood. The resistance and resilience responses of a range of microbial communities (bacteria, fungi, archaea, pseudomonads, and nematodes) to different concentrations of the strobilurin fungicide, azoxystrobin were studied. A significant concentration-dependent decrease, and subsequent recovery in soil dehydrogenase activity was recorded, but no significant impact on total microbial biomass was observed. Impacts on specific microbial communities were studied using small subunit (SSU) rRNA terminal restriction fragment length polymorphism (T-RFLP) profiling using soil DNA and RNA. The application of azoxystrobin significantly affected fungal and nematode community structure and diversity but had no impact on other communities. Community impacts were more pronounced in the RNA-derived T-RFLP profiles than in the DNA-derived profiles. qPCR confirmed that azoxystrobin application significantly reduced fungal, but not bacterial, SSU rRNA gene copy number. Azoxystrobin application reduced the prevalence of ascomycete fungi, but increased the relative abundance of zygomycetes. Azoxystrobin amendment also reduced the relative abundance of nematodes in the order Enoplia, but stimulated a large increase in the relative abundance of nematodes from the order Araeolaimida.