A core domain set for pyoderma gangrenosum trial outcomes: an international eDelphi and consensus study from the UPGRADE initiative.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerative skin condition with no current standardized outcomes or outcome measures. With a rich investigational therapeutic pipeline, standardization of outcomes and improvement of data quality and interpretability will promote the appropriate and consistent evaluation of potential new therapies. Core outcome sets (COS) are agreed, standardized sets of outcomes that represent the minimum that should be measured and reported in all clinical trials of a specific condition. OBJECTIVES: To identify and reach a consensus on which domains (what to be measured) should be included in the Understanding Pyoderma Gangrenosum: Review and Analysis of Disease Effects (UPGRADE) core domain set for clinical trials in PG. METHODS: Collaborative discussions between patients and PG experts, and a systematic review of the literature identified items and prospective domains. A three-round international eDelphi exercise was performed to prioritize the domains and refine the provisional items (consensus: ≥ 70% of participants rating a domain as 'extremely important' and < 15% of participants voting 'not important'), followed by an international meeting to reach consensus on the core domain set (consensus: < 30% disagreement). Item-generation discussions and consensus meetings were hosted via online videoconferences. The eDelphi exercise and consensus voting were performed using Qualtrics survey software. Participants were adults with PG, healthcare professionals, researchers and industry representatives. RESULTS: Collaborative discussions and systematic reviews yielded 115 items, which were distilled into 15 prospective domains. The eDelphi exercise removed the three lowest-priority domains ('laboratory tests', 'treatment costs' and 'disease impact on family') and ranked 'pain', 'quality of life' and 'physical symptoms' as the highest-priority prospective domains. Consensus was reached on the domains of 'pain', 'quality of life' and 'clinical signs'. The domain of 'disease course/disease progression' narrowly failed to reach consensus for inclusion in the core set (32% of participants voted 'no'). Refinement of this domain definition will be required and presented for consideration at future consensus meetings. CONCLUSIONS: The UPGRADE core domain set for clinical trials in PG has been agreed by international multistakeholder consensus. Future work will develop and/or select outcome measurement instruments for these domains to establish a COS.

Characterization of Legal Claims Involving Patients with Pyoderma Gangrenosum.

OBJECTIVE: To review the litigation literature related to patients with pyoderma gangrenosum (PG) to characterize the legal issues they face. DATA SOURCES: Data sources include law databases Casetext and Lexis Nexis. STUDY SELECTION: All disability and medical liability claims directly involving patients with PG were included. DATA EXTRACTION: Data extraction came directly from Casetext and Lexis Nexis. All cases extracted came from September 1965 to December 2020. This resulted in 32 cases, 18 of which were excluded because they did not mention the plaintiff having a diagnosis of PG (n = 14). DATA SYNTHESIS: The review found a total of six medical liability cases in which adverse health outcomes were reported, including prolonged suffering (2/6 cases), unnecessary treatments or procedures (2/6), exacerbation of disease (1/6 cases), and permanent scarring (1/6 cases). Despite this, two plaintiffs won their case and only one of them received any monetary award. Similarly, of the eight disability claims in the review, four were ruled in the favor of the plaintiffs and only two resulted in immediate awarding of benefits. Half of medical liability cases occurred in correctional facilities after the denial of appropriate care. CONCLUSIONS: The findings demonstrate a need for access to specialty care in incarcerated populations. Cases that occurred in a hospital setting also stress the importance of initiatives such as telemedicine to efficiently increase access to care in a cost-effective manner. Further, PG has been recognized as a severe impairment in disability claims despite patients being denied because they were deemed able to perform other work.

Correction: Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

[This corrects the article DOI: 10.1371/journal.ppat.1006753.].

Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.

Disparities in health care determine prognosis in newly diagnosed glioblastoma.

OBJECTIVE Glioblastoma (GBM) is an aggressive brain malignancy with a short overall patient survival, yet there remains significant heterogeneity in outcomes. Although access to health care has previously been linked to impact on prognosis in several malignancies, this question remains incompletely answered in GBM. METHODS This study was a retrospective analysis of 354 newly diagnosed patients with GBM who underwent first resection at the authors' institution (2007-2015). RESULTS Of the 354 patients (median age 61 years, and 37.6% were females), 32 (9.0%) had no insurance, whereas 322 (91.0%) had insurance, of whom 131 (40.7%) had Medicare, 45 (14%) had Medicaid, and 146 (45.3%) had private insurance. On average, insured patients survived almost 2-fold longer (p < 0.0001) than those who were uninsured, whereas differences between specific insurance types did not influence survival. The adjusted hazard ratio (HR) for death was higher in uninsured patients (HR 2.27 [95% CI 1.49-3.33], p = 0.0003). Age, mean household income, tumor size at diagnosis, and extent of resection did not differ between insured and uninsured patients, but there was a disparity in primary care physician (PCP) status-none of the uninsured patients had PCPs, whereas 72% of insured patients had PCPs. Postoperative adjuvant treatment rates with temozolomide (TMZ) and radiation therapy (XRT) were significantly less in uninsured (TMZ in 56.3%, XRT in 56.3%) than in insured (TMZ in 75.2%, XRT in 79.2%; p = 0.02 and p = 0.003) patients. Insured patients receiving both agents had better prognosis than uninsured patients receiving the same treatment (9.1 vs 16.34 months; p = 0.025), suggesting that the survival effect in insured patients could only partly be explained by higher treatment rates. Moreover, having a PCP increased survival among the insured cohort (10.7 vs 16.1 months, HR 1.65 [95% CI 1.27-2.15]; p = 0.0001), which could be explained by significant differences in tumor diameter at initial diagnosis between patients with and without PCPs (4.3 vs 4.8 cm, p = 0.003), and a higher rate of clinical trial enrollment, suggesting a critical role of PCPs for a timelier diagnosis of GBM and proactive cancer care management. CONCLUSIONS Access to health care is a strong determinant of prognosis in newly diagnosed patients with GBM. Any type of insurance coverage and having a PCP improved prognosis in this patient cohort. Higher rates of treatment with TMZ plus XRT, clinical trial enrollment, fewer comorbidities, and early diagnosis may explain survival disparities. Lack of health insurance or a PCP are major challenges within the health care system, which, if improved upon, could favorably impact the prognosis of patients with GBM.

DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury.

Traumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.

Patients cured of acromegaly do not experience improvement of their skull deformities.

PURPOSE: Acromegaly is a rare disease that is associated with many co-morbidities. This condition also causes progressive deformity of the skull which includes frontal bossing and cranial thickening. Surgical and/or medical management can cure this condition in many patients, but it is not understood if patients cured of acromegaly experience regression of their skull deformities. METHODS: We performed a retrospective analysis on patients treated at our dedicated pituitary center from 2009 to 2014. We looked at all MRI images taken during the treatment of these patients and recorded measurements on eight skull dimensions. We then analyzed these measurements for changes over time. RESULTS: 29 patients underwent curative treatment for acromegaly within our timeframe. The mean age for this population was 45.0 years old (range 19-70) and 55.2 % (n = 16) were female. All of these patients were treated with a transsphenoidal resection for a somatotropic pituitary adenoma. 9 (31.1%) of these patients required further medical therapy to be cured. We found statically significant variation in the coronal width of the sella turcica after therapy, which is likely attributable to changes from transsphenoidal surgery. None of the other dimensions had significant variation over time after cure. CONCLUSION: Patients cured of acromegaly should not expect natural regression of their skull deformities. Our study suggests that both frontal bossing and cranial thickening do not return to normal after cure.

Update on critical care for acute spinal cord injury in the setting of polytrauma.

Traumatic spinal cord injury (SCI) often occurs in patients with concurrent traumatic injuries in other body systems. These patients with polytrauma pose unique challenges to clinicians. The current review evaluates existing guidelines and updates the evidence for prehospital transport, immobilization, initial resuscitation, critical care, hemodynamic stability, diagnostic imaging, surgical techniques, and timing appropriate for the patient with SCI who has multisystem trauma. Initial management should be systematic, with focus on spinal immobilization, timely transport, and optimizing perfusion to the spinal cord. There is general evidence for the maintenance of mean arterial pressure of > 85 mm Hg during immediate and acute care to optimize neurological outcome; however, the selection of vasopressor type and duration should be judicious, with considerations for level of injury and risks of increased cardiogenic complications in the elderly. Level II recommendations exist for early decompression, and additional time points of neurological assessment within the first 24 hours and during acute care are warranted to determine the temporality of benefits attributable to early surgery. Venous thromboembolism prophylaxis using low-molecular-weight heparin is recommended by current guidelines for SCI. For these patients, titration of tidal volumes is important to balance the association of earlier weaning off the ventilator, with its risk of atelectasis, against the risk for lung damage from mechanical overinflation that can occur with prolonged ventilation. Careful evaluation of infection risk is a priority following multisystem trauma for patients with relative immunosuppression or compromise. Although patients with polytrauma may experience longer rehabilitation courses, long-term neurological recovery is generally comparable to that in patients with isolated SCI after controlling for demographics. Bowel and bladder disorders are common following SCI, significantly reduce quality of life, and constitute a focus of targeted therapies. Emerging biomarkers including glial fibrillary acidic protein, S100ß, and microRNAs for traumatic SCIs are presented. Systematic management approaches to minimize sources of secondary injury are discussed, and areas requiring further research, implementation, and validation are identified.

Temporal profile of care following mild traumatic brain injury: predictors of hospital admission, follow-up referral and six-month outcome.

OBJECTIVE: To investigate the clinical management and medical follow-up of patients with mild traumatic brain injury (mTBI) presenting to emergency departments (EDs). METHODS: Overall, 168 adult patients with mTBI from the prospective, multicentre Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study with Glasgow Coma Scale (GCS) 13-15, no polytrauma and alive at six months were included. Predictors for hospital admission, three-month follow-up referral and six-month functional disability (Glasgow Outcome Scale-Extended (GOSE) ≤ 6) were analysed using multivariable regression. RESULTS: Overall, 48% were admitted to hospital, 22% received three-month referral and 27% reported six-month functional disability. Intracranial pathology on ED head computed tomography (multivariable odds ratio (OR) = 81.08, 95% confidence interval (CI) [10.28-639.36]) and amnesia (>30-minutes: OR = 5.27 [1.75-15.87]; unknown duration: OR = 4.43 [1.26-15.62]) predicted hospital admission. Older age (per-year OR = 1.03 [1.01-1.05]) predicted three-month referral, while part-time/unemployment predicted lack of referral (OR = 0.17 [0.06-0.50]). GCS < 15 (OR = 2.46 [1.05-5.78]) and prior history of seizures (OR = 3.62 [1.21-10.89]) predicted six-month functional disability, while increased education (per-year OR = 0.86 [0.76-0.97]) was protective. CONCLUSIONS: Clinical factors modulate triage to admission, while demographic/socioeconomic elements modulate follow-up care acquisition; six-month functional disability associates with both clinical and demographic/socioeconomic variables. Improving triage to acute and outpatient care requires further investigation to optimize resource allocation and outcome after mTBI. ClinicalTrials.gov registration: NCT01565551.

Atopic Dermatitis: A Guide to Transitioning to Janus Kinase Inhibitors.

Janus kinase inhibitors (JAKis) are promising medications that the Food and Drug Administration recently approved for treatment of atopic dermatitis in January 2022. These medications offer a novel therapeutic mechanism and may be an additional treatment avenue for patients who are currently reliant on conventional immunosuppressants, such as cyclosporine A, methotrexate, or mycophenolate mofetil, or newer medications, such as dupilumab. However, redundant treatment puts patients at risk for excessive toxicity and polypharmacy, whereas abrupt tapering of a preexisting regimen may cause flares of the disease. Thus, transitioning to JAKis should be implemented strategically to retain the therapeutic benefit and minimize the risk of flares. Herein, we outline gradual transition schemas for patients needing to transition to JAKis from conventional immunosuppressants or dupilumab. There is no evidence-based guideline to instruct this transition to JAKis, and our recommendations are based on expert experience and the review of efficacy data from pivotal trials.

COVID-19 Infection in Hidradenitis Suppurativa Patients: A Retrospective Study.

Introduction: Hidradenitis suppurativa (HS) is associated with comorbidities that are risk factors for severe COVID-19 infection. We evaluated demographics and COVID-19 outcomes in HS patients. Methods: HS patients with COVID-19 (HS+/COVID+) and a randomized age-, race-, and sex-matched control population of patients without HS with COVID-19 (HS-/COVID+) were selected through a retrospective chart review. Data were collected on demographics, medications, comorbidities, vaccination status, and COVID-19 treatment/outcomes. Fisher's exact test was used to analyze the relationship between risk factors and COVID-19 outcomes. A p value of <0.05 was considered statistically significant. Results: There were 58 HS+/COVID+ patients, primarily African American (83%, n = 48) and female (88%, n = 51). Compared to HS+/COVID+ patients, HS-/COVID+ patients were significantly more likely to have cardiovascular disease (51% vs. 24%; p = 0.0029) and be pregnant (23% vs. 4%; p = 0.0093). HS+/COVID+ and HS-/COVID+ patients did not vary significantly in vaccination rate at time of COVID-19 diagnosis (6% vs. 5%; p = 0.78). HS-/COVID+ patients were significantly more likely to have COVID-19 complications (35% vs. 7%; p = 0.001) and receive COVID-19 treatment (37% vs. 7%; p = 0.0001) when compared to HS+/COVID+ patients. Conclusion: Our findings support the growing evidence that having HS itself may not be a risk factor for severe COVID-19 outcomes.

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects.

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

Discordant Timing of Hypoglycemic Agent Screening Causing Delayed Diagnosis of Sulfonylurea-Induced Hypoglycemia.

Background: Oral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used. Case Report: A 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (<18.8 pmol/L), and insulin level was 164 mU/L (<17 mU/L). An initial hypoglycemic agent screening, performed 24 hours after admission, yielded a negative result, leading to prolonged and recurrent hospitalizations for workup and localization of insulinoma. A hypoglycemic agent screening at a subsequent presentation, concordant with hypoglycemia, yielded a positive result for glipizide, which was at a level of 320 ng/mL (reporting limit, 40 ng/mL). An examination of the patient's home medications revealed a container, labeled as benztropine, containing glipizide tablets. After the diagnosis of glipizide-induced hypoglycemia, the patient had no further episodes of hypoglycemia. Discussion: The failure to detect glipizide using the initial hypoglycemia agent assay was likely because of a combination of a delay in the initial screening and low sensitivity of the assay for glipizide compared with that of other available assays. Here, we discuss important considerations for the interpretation of hypoglycemic agent screening in the diagnosis of hypoglycemia, including the timing of collection and reporting, pharmacokinetics of culprit agents, and sensitivity of the hypoglycemic agent panel used. Conclusion: Screening tests for hypoglycemic agents are necessary for the evaluation of hypoglycemia because their biochemical evaluation may be indistinguishable from that of insulinoma.

Allergen Composition, Marketing Claims, and Affordability of Pediatric Sunscreens.

BACKGROUND: Childhood sun exposure is associated with development of future skin cancers. Sunscreens are an important tool to prevent harmful ultraviolet rays. OBJECTIVES: The aims of the study are to evaluate sunscreens targeted to children and to analyze cost, marketing claims, ingredients, and allergens to help consumers select products. METHODS: The top 50 pediatric sunscreens across retailers were analyzed for their cost, marketing claims, ingredients, vehicles, and containers. Ingredients were compared with the American Contact Dermatology Society 2020 Core Allergen List. RESULTS: The mean price was $6.20 per ounce (range, $0.25-$39.98). The mean sun protection factor was 48.5 (range, 30-100; SD, 48.5). There was a mean of 17.5 ingredients and a mean of 1.1 allergens in products. On average, products marketed as "sensitive skin" were not only significantly more expensive ($8.90 vs $3.50 per ounce, P = 0.01) but also were significantly more likely to not contain any allergens (36.0%, n = 18 vs 12%, n = 6; P = 0.05). Products with mineral-only UV blockers were significantly less likely to have any allergen when compared with products that had chemical UV blockers (5.6%, n = 1 vs 94.4%, n = 17; P = 0.02). CONCLUSIONS: The current market of pediatric sunscreens varies significantly in price, marketing claims, and active ingredients. Products marked as suitable for sensitive skin had significantly fewer allergens, but a majority of these products still had at least one allergen. Many sunscreens contain contact allergens, which is an important selection consideration.

Relationship Disturbances in Hidradenitis Suppurativa: A Patient Perspective.

Introduction: Hidradenitis suppurativa (HS) can significantly impact patients' relationships. Methods: Using an anonymous electronic survey, we aimed to determine what aspects of sexual relationships are affected by HS discomfort and patients' reluctance to discuss HS with their partner. Results: Among the 873 participants, 60.9% reported that some aspect of their relationship was affected by HS discomfort, with the greatest being their sexual encounters with spouse (49.1%). Furthermore, 43.0% (320) of participants reported feeling reluctant to discuss HS with their spouse/significant other, with the more common reason being fear of partner seeing boils and scars (84.7%). Multiple aspects of relationships can be affected by HS such as sexual encounters, overall relationship, and finding a relationship. Additionally, several communication barriers are present, such as fear of partner seeing boils and scars, partner thinking they had an infection such as a sexually transmitted disease, and fear of bloody or malodorous drainage, among others. The presence of anogenital pain, Hurley stage, gender, and age significantly affect these findings. Conclusion: Addressing HS-related relationship disturbances should be included in HS management.