Prospective analysis to determine barriers to allogeneic hematopoietic cell transplantation in patients with acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with acute leukemia. Despite this, studies have shown that only a minority of patients ultimately proceed to allo-HCT. The primary objective of this prospective, observational study was to identify the rate of allo-HCT in patients for whom it was recommended, and reasons why patients deemed appropriate and eligible for HCT did not subsequently undergo transplant. Between April 2016 and April 2021, adult patients with newly diagnosed or relapsed/refractory acute leukemia were enrolled at the time of induction/reinduction therapy. Initial transplantation workup and allo-HCT recommendations were made during the early phase of induction/reinduction. Of the 307 enrolled patients, allo-HCT was recommended to 85% (n = 259), of whom 66% (n = 170) underwent transplant. Donor sources comprised 54% human leukocyte antigen (HLA)-matched unrelated donors, 20% HLA-matched sibling donors and HLA-mismatched graft sources with 15% umbilical cord blood units, 8% HLA-mismatched unrelated donors, and 4% HLA-haploidentical donors. The most common reason for transplant disqualification in the 89 patients in whom it was initially recommended was persistent/relapsed disease (70%), followed by early patient death (10%). In this prospective study, we report a high allo-HCT rate, which may be due to early transplant referral and workup. The main allo-HCT barrier was disease control, followed by early patient death. With the increasing availability of HLA-mismatched graft sources, the lack of donor availability was not a transplant barrier. Further development of novel transplant strategies for patients not achieving remission and improvements in induction regimens could result in increased allo-HCT utilization.

CT-to-fluoroscopy registration versus scan-and-plan registration for robot-assisted insertion of lumbar pedicle screws.

OBJECTIVE: Pedicle screw insertion for stabilization after lumbar fusion surgery is commonly performed by spine surgeons. With the advent of navigation technology, the accuracy of pedicle screw insertion has increased. Robotic guidance has revolutionized the placement of pedicle screws with 2 distinct radiographic registration methods, the scan-and-plan method and CT-to-fluoroscopy method. In this study, the authors aimed to compare the accuracy and safety of these methods. METHODS: A retrospective chart review was conducted at 2 centers to obtain operative data for consecutive patients who underwent robot-assisted lumbar pedicle screw placement. The newest robotic platform (Mazor X Robotic System) was used in all cases. One center used the scan-and-plan registration method, and the other used CT-to-fluoroscopy for registration. Screw accuracy was determined by applying the Gertzbein-Robbins scale. Fluoroscopic exposure times were collected from radiology reports. RESULTS: Overall, 268 patients underwent pedicle screw insertion, 126 patients with scan-and-plan registration and 142 with CT-to-fluoroscopy registration. In the scan-and-plan cohort, 450 screws were inserted across 266 spinal levels (mean 1.7 ± 1.1 screws/level), with 446 (99.1%) screws classified as Gertzbein-Robbins grade A (within the pedicle) and 4 (0.9%) as grade B (< 2-mm deviation). In the CT-to-fluoroscopy cohort, 574 screws were inserted across 280 lumbar spinal levels (mean 2.05 ± 1.7 screws/ level), with 563 (98.1%) grade A screws and 11 (1.9%) grade B (p = 0.17). The scan-and-plan cohort had nonsignificantly less fluoroscopic exposure per screw than the CT-to-fluoroscopy cohort (12 ± 13 seconds vs 11.1 ± 7 seconds, p = 0.3). CONCLUSIONS: Both scan-and-plan registration and CT-to-fluoroscopy registration methods were safe, accurate, and had similar fluoroscopy time exposure overall.

Peripheral cannulation for extracorporeal membrane oxygenation yields superior neurologic outcomes in adult patients who experienced cardiac arrest following cardiac surgery.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest has improved mortality in post-cardiac surgery patients; however, loss of neurologic function remains one of the main and devastating complications. We reviewed our experience with ECPR and investigated the effect of cannulation strategy on neurologic outcome in adult patients who experienced cardiac arrest following cardiac surgery that was managed with ECPR. METHODS: Patients were categorized by central versus percutaneous peripheral VA-extracorporeal membrane oxygenation (ECMO) cannulation strategy. We reviewed patient records and evaluated in-hospital mortality, cause of death, and neurologic status 72 hours after cannulation. RESULTS: From January 2010 to September 2019, 44 patients underwent post-cardiac surgery ECPR for cardiac arrest. Twenty-six patients received central cannulation; 18 patients received peripheral cannulation. Mean post-operative day of the cardiac arrest was 3 and 9 days (p = 0.006), and mean time between initiation of CPR and ECMO was 40 ± 24 and 28 ± 22 minutes for central and peripheral cannulation, respectively. After 72 hours of VA-ECMO support, 30% of centrally cannulated patients versus 72% of peripherally cannulated patients attained cerebral performance status 1-2 (p = 0.01). Anoxic brain injury was the cause of death in 26.9% of centrally cannulated and 11.1% of peripherally cannulated patients. Survival to discharge was 31% and 39% for central and peripheral cannulation, respectively. CONCLUSIONS: Peripheral VA-ECMO allows for continuous CPR and systemic perfusion while obtaining vascular access. Compared to central cannulation, a peripheral cannulation strategy is associated with improved neurologic outcomes and decreased likelihood of anoxic brain death.

Intravascular Large B-Cell Lymphoma: Clinical and Histopathologic Findings.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subset of extranodal non-Hodgkin lymphoma characterized by neoplastic lymphocytes within the lumina of small to medium-sized blood vessels. IVLBCLs are B-cell tumors that can present in essentially any organ system, including the skin. Cutaneous manifestations vary greatly and can mimic other skin disease which may delay diagnosis; in the absence of skin lesions, blind skin biopsies can be utilized for diagnosis. Early studies suggested that IVLBCL is a very aggressive lymphoma with high overall mortality rate and short survival times. However, earlier diagnosis and use of new treatment modalities have shown promise in recent studies. This case series illustrates the heterogeneity of clinical and pathologic presentations of this uncommon lymphoma.

Harnessing single-cell genomics to improve the physiological fidelity of organoid-derived cell types.

BACKGROUND: Single-cell genomic methods now provide unprecedented resolution for characterizing the component cell types and states of tissues such as the epithelial subsets of the gastrointestinal tract. Nevertheless, functional studies of these subsets at scale require faithful in vitro models of identified in vivo biology. While intestinal organoids have been invaluable in providing mechanistic insights in vitro, the extent to which organoid-derived cell types recapitulate their in vivo counterparts remains formally untested, with no systematic approach for improving model fidelity. RESULTS: Here, we present a generally applicable framework that utilizes massively parallel single-cell RNA-seq to compare cell types and states found in vivo to those of in vitro models such as organoids. Furthermore, we leverage identified discrepancies to improve model fidelity. Using the Paneth cell (PC), which supports the stem cell niche and produces the largest diversity of antimicrobials in the small intestine, as an exemplar, we uncover fundamental gene expression differences in lineage-defining genes between in vivo PCs and those of the current in vitro organoid model. With this information, we nominate a molecular intervention to rationally improve the physiological fidelity of our in vitro PCs. We then perform transcriptomic, cytometric, morphologic and proteomic characterization, and demonstrate functional (antimicrobial activity, niche support) improvements in PC physiology. CONCLUSIONS: Our systematic approach provides a simple workflow for identifying the limitations of in vitro models and enhancing their physiological fidelity. Using adult stem cell-derived PCs within intestinal organoids as a model system, we successfully benchmark organoid representation, relative to that in vivo, of a specialized cell type and use this comparison to generate a functionally improved in vitro PC population. We predict that the generation of rationally improved cellular models will facilitate mechanistic exploration of specific disease-associated genes in their respective cell types.

Dermatomyositis: Histopathologic findings of parakeratosis and dermal edema revisited.

The cutaneous manifestations of dermatomyositis range from classical in the case of heliotrope rash and Gottron papules to less common papulosquamous and edematous/vesiculobullous lesions; histopathologic descriptions are dominated by interface dermatitis. We present a case of dermatomyositis with a combination of common and rare skin findings, both clinically and histologically. Increased awareness of papulosquamous and edematous lesions of dermatomyositis can help direct patient care. Although uncommon, confluent parakeratosis and dermal edema can be manifestations of dermatomyositis.

Gambling Disorder in Veterans: A Review of the Literature and Implications for Future Research.

To review the scientific literature examining gambling behavior in military veterans in order to summarize factors associated with gambling behavior in this population. Database searches were employed to identify articles specifically examining gambling behavior in military veterans. Cumulative search results identified 52 articles (1983-2017) examining gambling behavior in veteran populations. Articles generally fell into one or more of the following categories: prevalence, psychological profiles and psychiatric comorbidities, treatment evaluations, measurement, and genetic contributions to gambling disorder. Results from reviewed articles are presented and implications for future research discussed. Research to date has provided an excellent foundation to inform potential screening, intervention and research activities going forward. The authors suggest that a public health approach to future research endeavors would strengthen the evidence base regarding gambling in veteran populations and better inform strategies for screening, prevention and treatment.

Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate.

BACKGROUND: Treatment of moderate to severe atopic dermatitis (AD) is often inadequate. OBJECTIVE: We sought to evaluate the efficacy of the oral Janus kinase inhibitor tofacitinib citrate in the treatment of moderate to severe AD. METHODS: Six consecutive patients with moderate to severe AD who had failed standard treatment were treated with tofacitinib citrate. Response to treatment was assessed using the Scoring of AD index. RESULTS: Decreased body surface area involvement of dermatitis and decreased erythema, edema/papulation, lichenification, and excoriation were observed in all patients. The Scoring of AD index decreased by 66.6% from 36.5 to 12.2 (P < .05) during 8 to 29 weeks of treatment. There were no adverse events. LIMITATIONS: Small sample size, lack of placebo control group, and the possibility of bias are limitations. CONCLUSION: The oral Janus kinase inhibitor tofacitinib citrate may be beneficial in the treatment of moderate to severe AD.

Znt7-null mice are more susceptible to diet-induced glucose intolerance and insulin resistance.

The Znt7 gene encodes a ubiquitously expressed zinc transporter that is involved in transporting cytoplasmic zinc into the Golgi apparatus and a ZnT7-containing vesicular compartment. Overexpression of ZnT7 in the pancreatic ß-cell stimulates insulin synthesis and secretion through regulation of insulin gene transcription. In this study, we demonstrate that ZnT7 is expressed in the mouse skeletal muscle. The activity of the insulin signaling pathway was down-regulated in myocytes isolated from the femoral muscle of Znt7 knock-out (KO) mice. High fat diet consumption (45% kcal) induced weight gain in male Znt7 KO mice but not female Znt7 KO mice. Male Znt7 KO mice fed the high fat diet at 5 weeks of age for 10 weeks exhibited hyperglycemia in the non-fasting state. Oral glucose tolerance tests revealed that male Znt7 KO mice fed the high fat diet had severe glucose intolerance. Insulin tolerance tests showed that male Znt7 KO mice were insulin-resistant. Diet-induced insulin resistance in male Znt7 KO mice was paralleled by a reduction in mRNA expression of Insr, Irs2, and Akt1 in the primary skeletal myotubes isolated from the KO mice. Overexpression of ZnT7 in a rat skeletal muscle cell line (L6) increased Irs2 mRNA expression, Irs2 and Akt phosphorylation, and glucose uptake. We conclude that a combination of decreased insulin secretion and increased insulin resistance accounts for the glucose intolerance observed in Znt7 KO mice.

Characteristics of Distress and Support Group Participation in Caregivers of Older Allogeneic Hematopoietic Cell Transplantation Patients: A Single Institution Retrospective Review.

Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplant (allo-HCT). However, older patients often have increased comorbidities and thus may require an increased level of post-transplant care. These factors can contribute to increased caregiver distress, which has been associated with worsened health outcomes for caregivers and patients. To examine predictors of caregiver distress and support group participation in caregivers of older allo-HCT patients, we retrospectively reviewed charts of 208 patients aged 60 and older who underwent their first allo-HCT at our institution from 2014 through 2016. We systematically characterized and identified the incidence of caregiver distress and attendance in a caregiver support group from the start of conditioning through 1 year post allo-HCT. Evidence of caregiver distress and support group participation was recorded by reviewing clinical and/or social work documentation. We found that 20 caregivers (10%) endorsed stress and 44 caregivers (21%) attended our support group at least once. A patient's prior history of psychiatric diagnosis (p = .046) or the use of potentially inappropriate medications for older adults (p = .046) was found to be associated with caregiver stress. Caregivers who were spouses or partners of patients (p = .048) or caregivers of married patients were more likely to attend the support group (p = .007). While limited by retrospective design and likely underreporting, this study reveals factors associated with caregiver distress in the older allo-HCT caregiver population. This information can help providers identify caregivers at risk for distress and improve caregiver resources, which may improve both caregiver and patient outcomes.

Discrimination of benign and neoplastic mucosa with a high-resolution microendoscope (HRME) in head and neck cancer.

BACKGROUND: The efficacy of ablative surgery for head and neck squamous cell carcinoma (HNSCC) depends critically on obtaining negative margins. Although intraoperative "frozen section" analysis of margins is a valuable adjunct, it is expensive, time-consuming, and highly dependent on pathologist expertise. Optical imaging has potential to improve the accuracy of margins by identifying cancerous tissue in real time. Our goal was to determine the accuracy and inter-rater reliability of head and neck cancer specialists using high-resolution microendoscopic (HRME) images to discriminate between cancerous and benign mucosa. METHODS: Thirty-eight patients diagnosed with head and neck squamous cell carcinoma (HNSCC) were enrolled in this single-center study. HRME was used to image each specimen after application of proflavine, with concurrent standard histopathologic analysis. Images were evaluated for quality control, and a training set containing representative images of benign and neoplastic tissue was assembled. After viewing training images, seven head and neck cancer specialists with no previous HRME experience reviewed 36 test images and were asked to classify each. RESULTS: The mean accuracy of all reviewers in correctly diagnosing neoplastic mucosa was 97% (95% confidence interval (CI), 94-99%). The mean sensitivity and specificity were 98% (97-100%) and 92% (87-98%), respectively. The Fleiss kappa statistic for inter-rater reliability was 0.84 (0.77-0.91). CONCLUSIONS: Medical professionals can be quickly trained to use HRME to discriminate between benign and neoplastic mucosa in the head and neck. With further development, the HRME shows promise as a method of real-time margin determination at the point of care.

Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation.

The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia.

Screening for abuse risk in pain patients.

As opioid prescribing has dramatically expanded over the past decade, so too has the problem of prescription drug abuse. In response to these now two major public health problems - the problem of poorly treated chronic pain and the problem of opioid abuse - a new paradigm has arisen in pain management, namely risk stratification. Once a prescriber has determined that opioids will be used (a medical decision based on how intense the pain is, what has been tried and failed and, to some extent, what type of pain the patient has), he/she must then decide how opioid therapy is to be delivered. Different models of delivery of opioid therapy can be utilized, beginning the process with a risk assessment that is highly individualized to each patient. Recently, researchers have produced a wide variety of literature regarding assessment tools to be used for this purpose. And while there remains a need for larger prospective studies to examine the ability of each tool to predict aberrant drug-taking behaviors, clinicians can and should utilize one or more of these screening tools and understand their benefits and limitations. This chapter will describe the nature of current screening assessments, their potential for use in the pain population in various settings, past clinical observations and suggestions for moving forward.

Mazor X Stealth Robotic Technology: A Technical Note.

BACKGROUND: Minimally invasive techniques in spine surgery have continued to advance as robotic technology has evolved over several generations. Although traditional techniques for placing pedicle screws are still widespread in practice, newer technology has increased the reliability of accurately placing instrumentation with smaller incisions and subsequent decreased length of stay. Additionally, advancements in planning software have improved the ability to align posterior instrumentation to assist with rod placement on multilevel constructs. METHODS: This paper describes the surgical techniques and operative workflow for placing pedicle screws with the latest robotic technology. The robotic platform, registration, surgical planning, and placement of instrumentation are discussed in detail. Advantages of the Mazor X Stealth Edition compared with the previous generation robot include obviating the need for K wires and eliminating the need for a percutaneous pin, as navigation is integrated into the robot. RESULTS: Our use of this new technology has been encouraging. Using the techniques described in this paper, the first 90 pedicle screws placed with the Mazor X Stealth Edition robot yielded 100% grade A accuracy on the Gertzbein-Robbins scale confirmed on immediate postoperative CT. There were no complications experienced in any case. CONCLUSIONS: In our experience, this robotic technology has the potential to improve patient outcomes and is associated with advanced surgical planning compared with more traditional techniques.

Fixed drug eruptions, bullous drug eruptions, and lichenoid drug eruptions.

Drug reactions are among the most common reasons for inpatient dermatology consultation. These reactions are important to identify because discontinuation of the offending agent may lead to disease remission. With the rising use of immunomodulatory and targeted therapeutics in cancer care and the increased incidence in associated reactions to these drugs, the need for accurate identification and treatment of such eruptions has led to the development of the "oncodermatology" subspecialty of dermatology. Immunobullous drug reactions are a dermatologic urgency, with patients often losing a significant proportion of their epithelial barrier; early diagnosis is critical in these cases to prevent complications and worsening disease. Lichenoid drug reactions have myriad causes and can take several months to occur, often leading to difficulties identifying the offending drug. Fixed drug eruptions can often mimic other systemic eruptions, such as immunobullous disease and Stevens-Johnson syndrome, and must be differentiated from them for effective therapy to be initiated. We review the clinical features, pathogenesis, and treatment of immunobullous, fixed, and lichenoid drug reactions with attention to key clinical features and differential diagnosis.

Bacterial Baptism: Scientific, Medical, and Regulatory Issues Raised by Vaginal Seeding of C-Section-Born Babies.

Several lines of evidence suggest that children born via Cesarean section (C-section) are at greater risk for adverse health outcomes including allergies, asthma and obesity. Vaginal seeding is a medical procedure in which infants born by C-section are swabbed immediately after birth with vaginal secretions from the mother. This procedure has been proposed as a way to transfer the mother's vaginal microbiome to the child, thereby restoring the natural exposure that occurs during vaginal birth that is interrupted in the case of babies born via C-section. Preliminary evidence indicates partial restoration of microbes. However, there is insufficient evidence to determine the health benefits of the procedure. Several studies, including trial, are currently underway. At the same time, in the clinic setting, doctors are increasingly being asked to by expectant mothers to have their babies seeded. This article reports on the current research on this procedure and the issues it raises for regulators, researchers, physicians, and patients.

Transmission of resistant Gram-negative bacteria to healthcare personnel gowns and gloves during care of residents in community-based nursing facilities.

OBJECTIVE: To estimate the risk of transmission of antibiotic-resistant Gram-negative bacteria (RGNB) to gowns and gloves worn by healthcare personnel (HCP) when providing care to residents of community-based nursing facilities to identify the types of care and resident characteristics associated with transmission. DESIGN: Prospective observational study.Settings and participantsResidents and HCP from 13 community-based nursing facilities in Maryland and Michigan. METHODS: Perianal swabs were collected from residents and cultured to detect RGNB. HCP wore gowns and gloves during usual care activities, and at the end of each interaction, these were swabbed in a standardized manner. Transmission of RGNB from a colonized resident to gowns and gloves was estimated. Odds ratios (ORs) of transmission associated with type of care or resident characteristic were calculated. RESULTS: We enrolled 403 residents and their HCP in this study. Overall, 19% of enrolled residents with a perianal swab (n=399) were colonized with at least 1 RGNB. RGNB transmission to either gloves or gowns occurred during 11% of the 584 interactions. Showering the resident, hygiene or toilet assistance, and wound dressing changes were associated with a high risk of transmission. Glucose monitoring and assistance with feeding or medication were associated with a low risk of transmission. Residents with a pressure ulcer were 3 times more likely to transmit RGNB than residents without one (OR, 3.3; 95% confidence interval [CI], 1.0-11.1). CONCLUSIONS: Gown and glove use in community nursing facilities should be prioritized for certain residents and care interactions that are deemed a high risk for transmission.

Cutaneous manifestations of nontargeted and targeted chemotherapies.

Care of the oncologic patient requires an integral understanding of the adverse reactions of chemotherapy. With the advent of targeted agents and immunomodulating therapies, reactions to these newer treatments are of clinical interest. Cutaneous side effects of chemotherapeutic agents, including toxic erythema and mucositis, are common and may require cessation of treatment if associated with discomfort, superinfection, or negative impact on quality of life. This article reviews the cutaneous adverse reactions and treatment options of both conventional cytotoxic chemotherapeutic agents and newer targeted, multikinase inhibitors and immunomodulating therapies. An understanding of possible cutaneous reactions by all providers involved in the care of the oncologic patient is critical for prompt recognition, allowing for appropriate treatment and referral to dermatologists when necessary.

Somatic Mosaicism in Blaschkolinear Inflammatory Disorders.

Linear lichen planus (LP) is a rare dermatologic disease in which lichenoid lesions conform to a blaschkolinear distribution, most commonly on the extremities. Linear discoid lupus erythematosus (DLE) is a cutaneous manifestation of lupus that also conforms to Blaschko's lines. Blaschkolinear disorders have been shown to result from somatic mosaicism, most recently in nevus sebaceus, epidermal nevi, and syringocystadenoma papilliferum. In linear LP and DLE, presentation of papules along Blaschko's lines suggests that these disorders can result from keratinocytic genetic mosaicism. Their onset later in life suggests that a secondary trigger is necessary to drive inflammatory reactions to these linear lesions. To date causative mutations have not be identified. We report 2 cases of linear lichen planus and 1 case of linear discoid lupus erythematosus, all histologically confirmed. Both LP patients have experienced episodic regression and recurrence of their lesions in precisely the same distribution, with moderate symptomatic benefit from topical steroids and non-steroidal anti-inflammatories. The DLE patient showed gradual response to hydroxychloroquine over the course of 14 months. These cases highlight linear inflammatory diseases which represent localized variants of disorders for which there are few efficacious therapies. Their linear presentations suggest that they result from somatic mosaicism and genetic investigation of such disorders may reveal relevant therapeutic targets.