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Background Non-physician practitioners (NPPS), including nurse practitioners (NPs) and physician assistants (PAs) are expanding their scope of practice outside of primary care and performing more procedures in dermatology. Objective To understand the scope and geographic pattern of practice by NPs and PAs in dermatology in the US. Methods Cross-sectional retrospective cohort analysis of dermatology practices in the 2014 Medicare Physician/Supplier Procedure Summary Master File, which reflects Part B carrier and durable medical equipment fee-for-service claims in the US. Results Over 4 million procedures were billed independently by NPs and PAs, which accounts for 11.51% of all. Injection, simple repair, and biopsy were the most commonly billed by non-physician practitioners, but complex procedures were also increasingly billed independently by NPs and PAs. Proportions of their claims are higher in the East Coast, Midwest, and Mountain states. Limitations Data is at the state level, limited to Medicare beneficiaries, and doesn’t include billing incident-to physicians. Conclusions This study demonstrated the increasing scope of practice of NPs and PAs in dermatology, despite limited training and lack of uniform regulations. To ensure quality and safety of care, it is prudent to set benchmarks for proper supervision and utilization of procedures in dermatology.

Background Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. Objective To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared to the gold standard histopathology. Methods Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically-defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue and histopathology was correlated with RCM results. Results Seventy-two patients were included. Mean age was 66.8 years (SD 11.1; 38 – 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 – 5 cm). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p Limitations No RCM imaging beyond initial planned margins was performed. Conclusion RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

Lymphedema is a frequent debilitating condition among cancer patients. Daily supportive treatment may be necessary without long-term improvement. We describe two cases with chronic refractory lymphedema treated with fractional 10,600 nm CO2 laser. A 61-year-old female with locally advanced cervical cancer presented with postsurgical edematous swelling of the vulva and mons pubis and recurring cellulitis due to chronic lymphangiectasia. After six treatments of fractional CO2 laser, she noticed an 80% reduction of lymphorrea, swelling, and frequency of cellulitis. A 32-year old melanoma patient presented with refractory right lower leg lymphedema post right inguinal lymph node dissection and radiation. After fractional CO2 laser, she noted increased softness of her inguinal scar and a decrease of the lower leg edema. Fractional CO2 laser may be useful in addressing chronic refractory lymphedema. Further research should confirm our findings to consider fractional laser as a standard method in the treatment of chronic lymphedema.

Conventional tissue sampling can lead to misdiagnoses and repeated biopsies. Additionally, tissue processed for histopathology suffers from poor nucleic acid quality and/or quantity for downstream molecular profiling. Targeted micro-sampling of tissue can ensure accurate diagnosis and molecular profiling in the presence of spatial heterogeneity, especially in tumors, and facilitate acquisition of fresh tissue for molecular analysis. In this study, we explored the feasibility of performing 1–2 mm precision biopsies guided by high-resolution reflectance confocal microscopy (RCM) and optical coherence tomography (OCT), and reflective metallic grids for accurate spatial targeting. Accurate sampling was confirmed with either histopathology or molecular profiling through next generation sequencing (NGS) in 9 skin cancers in 7 patients. Imaging-guided 1–2 mm biopsies enabled spatial targeting for in vivo diagnosis, feature correlation and depth assessment, which were confirmed with histopathology. In vivo 1-mm targeted biopsies achieved adequate quantity and high quality of DNA for next-generation sequencing. Subsequent mutational profiling was confirmed on 1 melanoma in situ and 2 invasive melanomas, using a 505-gene mutational panel called Memorial Sloan Kettering-Integrated mutational profiling of actionable cancer targets (MSK-IMPACT). Differential mutational landscapes, in terms of number and types of mutations, were found between invasive and in situ melanomas in a single patient. Our findings demonstrate feasibility of accurate sampling of regions of interest for downstream histopathological diagnoses and molecular pathology in both in vivo and ex vivo settings with broad diagnostic, therapeutic and research potential in cutaneous diseases accessible by RCM-OCT imaging.

Introduction Frontal plane knee control is essential to athletic knee injury prevention. Aim To evaluate knee valgus frontal plane projection angle (FPPA), knee safety, and sports movement capability confidence during single leg triple hop for distance (SLTHD) under knee sleeve, distal thigh compression garment (DTCG), and no device (control) conditions. Methods A single-session, experimental study was performed using a within-subject design, and randomized device order. Two-dimensional FPPA measurements were collected during the final SLTHD landing of 18 healthy female college athletes for each condition. Sports movement capability and knee safety confidence were measured using 10-cm visual analog scale questions. One-way ANOVA assessed group differences, and Pearson correlations delineated FPPA, knee safety and sports movement capability confidence relationships (p Results The DTCG group had less valgus FPPA than the control group. The knee sleeve group had greater knee safety confidence than the control group. The DTCG (r = 0.48) had a moderate positive relationship between mean SLTHD and knee safety confidence. The DTCG group also had a moderate relationship between maximum SLTHD and knee safety confidence (r = 0.52). The DTCG and knee sleeve groups displayed moderate direct, and moderate inverse relationships between FPPA and sports movement capability confidence (r = 0.48 and r = −0.44, respectively). Conclusion Reduced FPPA and relationships between maximum SLTHD magnitude and knee safety confidence, and between FPPA magnitude and sports movement capability confidence suggests that the DTCG may enhance pelvic deltoid kinesthetic acuity and dynamic knee stability through iliotibial tract compression. Clinical relevance The DTCG was superior to the standard knee sleeve or control conditions for displaying characteristics that might better prevent knee injury, while still enabling effective sports movement capability.

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel–related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 106 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel.

Prone positioning, a postural adjuvant therapy for improving ventilation, has been widely used to treat COVID-19 pneumonia complicated by acute respiratory distress syndrome that can reduce mortality when used for at least 12 hours a day.1 The extensive time needed for prone positioning to be effective may result in prolonged pressure points on the face leading to facial ulcers. Before the COVID-19 pandemic, facial pressure ulcers due to prone positioning in the setting of acute respiratory distress syndrome had already been described.1 These facial ulcers frequently occur at the level of the bony structures, including the forehead, cheekbone, and chin.1 It has been hypothesized that in the context of severe COVID-19 pneumonia, hypoxemia, microvascular injury, and thrombosis may increase the risk of pressure ulcers.1 Once healed, these wounds can have a lasting impact on the patient as they may lead to scarring, dyspigmentation, and atrophy. Patients find hypopigmented scars to be more bothersome than hyperpigmented scars.2 These scars are particularly stigmatizing distressing when in the cervicofacial region and in patients of color who represent more than 60% of the world's population.2, 3, 4 Hypopigmented scars are difficult for dermatologists to treat because there are limited effective and practical treatment options available that yield long-lasting results. Treatment options implicated in the management of hypopigmented scars include cosmetic camouflage, microneedling, dermabrasion, chemical peels, skin excision, and laser therapy. Herein, we report our success in achieving repigmentation in the setting of atrophic, depigmented, and hypopigmented scars using CO2 laser drug delivery of bimatoprost and microneedling.

International audience; BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p

The COVID-19 pandemic has demonstrated the need for real-time, open-access epidemiological information to inform public health decision-making and outbreak control efforts. In Canada, authority for healthcare delivery primarily lies at the provincial and territorial level; however, at the outset of the pandemic no definitive pan-Canadian COVID-19 datasets were available. The COVID-19 Canada Open Data Working Group was created to fill this crucial data gap. As a team of volunteer contributors, we collect daily COVID-19 data from a variety of governmental and non-governmental sources and curate a line-list of cases and mortality for all provinces and territories of Canada, including information on location, age, sex, travel history, and exposure, where available. We also curate time series of COVID-19 recoveries, testing, and vaccine doses administered and distributed. Data are recorded systematically at a fine sub-national scale, which can be used to support robust understanding of COVID-19 hotspots. We continue to maintain this dataset, and an accompanying online dashboard, to provide a reliable pan-Canadian COVID-19 resource to researchers, journalists, and the general public., Measurement(s) COVID-19 Cases • COVID-19 Mortalities • COVID-19 vaccination Technology Type(s) digital curation Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location Canada Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.14331311

ObjectiveWhile the contribution of B-cells to SLE is well established, its role in chronic cutaneous lupus erythematosus (CCLE) remains unclear. Here, we compare B-cell and serum auto-antibody profiles between patients with systemic lupus erythematosus (SLE), CCLE, and overlap conditions.MethodsB-cells were compared by flow cytometry amongst healthy controls, CCLE without systemic lupus (CCLE+/SLE−) and SLE patients with (SLE+/CCLE+) or without CCLE (SLE+/CCLE−). Serum was analyed for autoreactive 9G4+, anti-double-stranded DNA, anti-chromatin and anti-RNA antibodies by ELISA and for anti-RNA binding proteins (RBP) by luciferase immunoprecipitation.ResultsPatients with CCLE+/SLE− share B-cell abnormalities with SLE including decreased unswitched memory and increased effector B-cells albeit at a lower level than SLE patients. Similarly, both SLE and CCLE+/SLE- patients have elevated 9G4+ IgG autoantibodies despite lower levels of anti-nucleic acid and anti-RBP antibodies in CCLE+/SLE−. CCLE+/SLE− patients could be stratified into those with SLE-like B-cell profiles and a separate group with normal B-cell profiles. The former group was more serologically active and more likely to have disseminated skin lesions.ConclusionCCLE displays perturbations in B-cell homeostasis and partial B-cell tolerance breakdown. Our study demonstrates that this entity is immunologically heterogeneous and includes a disease segment whose B-cell compartment resembles SLE and is clinically associated with enhanced serological activity and more extensive skin disease. This picture suggests that SLE-like B-cell changes in primary CCLE may help identify patients at risk for subsequent development of SLE. B-cell profiling in CCLE might also indentify candidates who would benefit from B-cell targeted therapies.

The only difference between fractured and non-fractured postmenopausal women with PHPT of same sex, age, and BMI was a significantly mean higher serum k-periostin level. K-periostin value was associated with fracture at any site (odds ratio 1.044, 95% CI 1.005–1.091, p = 0.03). To assess serum k-periostin fragment levels in patients with primary hyperparathyroidism (PHPT), fractured and non-fractured matched for sex, age, and body mass index. Twenty-five Caucasian fractured postmenopausal women with PHPT (group Fx) and 25 PHPT non-fractured (group NFx) were enrolled. Each patient underwent DXA scan at lumbar, hip, and forearm, spine X-ray, and biochemical evaluation of calcium metabolism. For k-periostin analyses, we utilized a specific ELISA test that detects CatK-generated fragment levels in the bloodstream. We found no difference in mean BMD and bone turnover marker values between Fx and NFx groups. Prevalence of osteoporosis was not significantly different in Fx vs NFx (72% vs 60%, p = 0.55). Among Fx, 16% reported multiple fractures, 28% morphometric vertebral fractures, 4% femoral fractures, 28% non-vertebral non-femoral fractures, and 8% wrist fractures. The only detectable difference between Fx and NFx group was a significantly mean higher k-periostin serum level (46.2 ± 21.4 vs 34.7 ± 13.5 ng/ml, p = 0.02). K-periostin was associated with fracture at any site (odds ratio 1.044, 95% CI 1.005–1.091, p = 0.03). No difference in mean k-periostin values was found between patients with vertebral fracture vs those with non-vertebral fracture, and between those with multiple fractures vs those with single fracture. Serum k-periostin is significantly associated with fracture in PHPT. If confirmed by further studies, k-periostin could be considered a new marker of bone fragility in PHPT, independently of BMD.

Background There are no well-defined clinical factors to predict the risk of occult invasion in melanoma of the lentigo maligna type (LM) before complete histopathologic analysis. Objective To evaluate whether clinical size was a predictor of invasion in LM and subclinical extension. Methods Consecutive cases of LM were recorded in a prospectively maintained database from 2006 to 2019. Patient and tumor data were recorded during initial evaluation. The LM clinical area was calculated in square millimeters (length × width). All patients were treated with staged excision. Results We included 600 patients. The mean age was 65.9 years (standard deviation, 12.3; range, 27-95 years); 62.8% (n = 377) were men. The mean LM clinical area was 128.32 mm2 for in situ lesions versus 200.14 mm for invasive lesions (P = .1). Based on quantile regression, the median margin required for complete removal increased with LM clinical area. Limitations The study was performed in a tertiary cancer center with possible referral bias and more complex cases. Conclusions LM can present with variable clinical size, which may correlate with subclinical extension; however, the presence of invasion is not well estimated by LM clinical area.

To avoid excessive usage of antibiotics and antimicrobial agents, smart wound dressings permitting controlled drug release for treatment of bacterial infections are highly desired. In search of a sensitive stimulus to activate drug release under physiological conditions, we found that the glass transition temperature (

The second article in this continuing medical education series reviews the evidence regarding the intraoperative and postoperative risks for patients and health care workers. We share the most up-to-date recommendations for risk management and postoperative complication management to ensure optimal surgical efficacy and patient safety.

To quantify the frequency of serious maternal complications associated with cerclage use during pregnancy.We performed a retrospective population-based cohort study of all live births in Ohio from 2006 to 2015. Maternal sociodemographic, medical, and obstetric characteristics were compared for births in which cerclage was utilized during the pregnancy versus those without cerclage. The primary outcome for the study was a composite of adverse outcome including maternal intensive care unit (ICU) admission, blood product transfusion, uterine rupture and unplanned hysterectomy in all births. Secondary outcomes included each of the individual adverse outcomes as well as maternal hospital transfer to a tertiary facility, unplanned operation after delivery and chorioamnionitis. Each outcome was also analyzed separately in singleton and twin births. Generalized linear modeling was used to estimate the relative risk of adverse maternal outcomes associated with cerclage placement after adjustment for coexisting risk factors.Of the 1,428,655 singleton and twin live births in Ohio from 2006 to 2015, 4595 [0.3%] were recorded on the birth certificate as having cerclage during pregnancy. Of those, 11.7% experienced a serious adverse maternal outcome, compared to 3.7% without cerclage, adjRR 2.7 [95% CI 2.5, 3.0]. The rate of the composite maternal adverse outcome was significantly increased for pregnancies with cerclage versus those without overall, and in singleton and twin pregnancies when measured individually [allOver 1 in 10 women with cerclage experience an adverse maternal outcome. Even after adjusting for gestational age at delivery and other risk factors, maternal risk for serious adverse event remains over twofold increased for pregnancies with cerclage. This information may be helpful in counseling women regarding potential maternal risk when considering neonatal benefit of cerclage in pregnancies at high risk of preterm birth.

Metastatic primary cutaneous extramammary Paget disease (EMPD) is a rare clinical entity with a 5-year survival

While telemedicine has been utilized with more frequency over the past two decades, there remained significant barriers to its broad implementation. The COVID-19 global pandemic served as a stimulus for rapid expansion and implementation of telemedicine services across medical institutions worldwide in order to maximize patient care delivery, minimize exposure risk among healthcare providers and patients alike, and avoid overcrowding of patient care facilities. In this experience report, we highlight the teledermatology initiatives executed by the Dermatology Service at Memorial Sloan Kettering Cancer Center in New York City, with particular emphasis on image ingestion and potential for future automation and improvement.

BACKGROUND Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool. OBJECTIVE To evaluate the treatment of EMPD patients and the role of RCM. METHODS Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded. RESULTS Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01). LIMITATIONS Relatively small sample size. CONCLUSION Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD.

Purpose To (1) determine the diagnostic efficacy of artificial intelligence (AI) methods for detecting anterior cruciate ligament (ACL) and meniscus tears and to (2) compare the efficacy to human clinical experts. Methods PubMed, OVID/Medline, and Cochrane libraries were queried in November 2019 for research articles pertaining to AI use for detection of ACL and meniscus tears. Information regarding AI model, prediction accuracy/area under the curve (AUC), sample sizes of testing/training sets, and imaging modalities were recorded. Results A total of 11 AI studies were identified: 5 investigated ACL tears, 5 investigated meniscal tears, and 1 investigated both. The AUC of AI models for detecting ACL tears ranged from 0.895 to 0.980, and the prediction accuracy ranged from 86.7% to 100%. Of these studies, 3 compared AI models to clinical experts. Two found no significant differences in diagnostic capability, whereas one found that radiologists had a significantly greater sensitivity for detecting ACL tears (P = .002) and statistically similar specificity and accuracy. Of the 5 studies investigating the meniscus, the AUC for AI models ranged from 0.847 to 0.910 and prediction accuracy ranged from 75.0% to 90.0%. Of these studies, 2 compared AI models with clinical experts. One found no significant differences in diagnostic accuracy, whereas one found that the AI model had a significantly lower specificity (P = .003) and accuracy (P = .015) than radiologists. Two studies reported that the addition of AI models significantly increased the diagnostic performance of clinicians compared to their efforts without these models. Conclusions AI prediction capabilities were excellent and may enhance the diagnosis of ACL and meniscal pathology; however, AI did not outperform clinical experts. Clinical Relevance AI models promise to improve diagnosing certain pathologies as well as or better than human experts, are excellent for detecting ACL and meniscus tears, and may enhance the diagnostic capabilities of human experts; however, when compared with these experts, they may not offer any significant advantage.

ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.

d-myo-Inositol 1,4,5-trisphosphate receptors (IP3Rs) are Ca2+ channels activated by the intracellular messenger inositol 1,4,5-trisphosphate (IP3, 1). The glyconucleotide adenophostin A (AdA, 2) is a potent agonist of IP3Rs. A recent synthesis of d-chiro-inositol adenophostin (InsAdA, 5) employed suitably protected chiral building blocks and replaced the d-glucose core by d-chiro-inositol. An alternative approach to fully chiral material is now reported using intrinsic sugar chirality to avoid early isomer resolution, involving the coupling of a protected and activated racemic myo-inositol derivative to a d-ribose derivative. Diastereoisomer separation was achieved after trans-isopropylidene group removal and the absolute ribose-inositol conjugate stereochemistry assigned with reference to the earlier synthesis. Optimization of stannylene-mediated regiospecific benzylation was explored using the model 1,2-O-isopropylidene-3,6-di-O-benzyl-myo-inositol and conditions successfully transferred to one conjugate diastereoisomer with 3:1 selectivity. However, only roughly 1:1 regiospecificity was achieved on the required diastereoisomer. The conjugate regioisomers of benzyl derivatives 39 and 40 were successfully separated and 39 was transformed subsequently to InsAdA after amination, pan-phosphorylation, and deprotection. InsAdA from this synthetic route bound with greater affinity than AdA to IP3R1 and was more potent in releasing Ca2+ from intracellular stores through IP3Rs. It is the most potent full agonist of IP3R1 known and .equipotent with material from the fully chiral synthetic route.

BACKGROUND: Squamous cell carcinoma in situ (SCCIS) of the nail unit is a complex malignancy; with little understanding of rate of upstaging or occult invasion in these patients. OBJECTIVES: We sought to evaluate the rate of upstaging in nail unit SCCIS after Mohs micrographic surgery (MMS). METHODS: Retrospective review of 346 patients who referred for and underwent MMS for biopsy proven SCCIS on the hands and feet between January 1, 2000 and December 30, 2019. Only cases in the nail unit were included. Clinical, surgical details, histopathological features, HPV status and rate of upstaging were recorded. RESULTS: Thirty-one cases met the inclusion criteria and were analyzed. Twenty-four patients were male (77.4%). Mean age was 55 years (SD 17.26, range 27–84). Mean clinical size was 9.9 mm; 19 cases tested for HPV, 15/19 were positive (78.9%) and 8/19 (42.1%) were associated with high-risk HPV. Three patients (9.7%) were upstaged to invasive on either MMS margins or tumor-debulking. Limitations included a relatively small sample size and retrospective in nature. CONCLUSION: Rate of upstaging of SCCIS in the nail unit is not frequent, and when upstaging occurred it was focal, superficial, and with no PNI or bone invasion.

INTRODUCTION: The aim of this study was the evaluation of two different techniques on post-operative analgesia and motor recovery after hallux valgus correction in one-day surgery patients. MATERIALS AND METHODS: We enrolled 26 patients scheduled for hallux valgus surgery and treated with the same surgical technique (SCARF osteotomy). After subgluteal sciatic nerve block with a short acting local anaesthetic (Mepivacaine 1.5%, 15ml), each patient received an ultrasound-guided Posterior Tibialis Nerve Block (PTNB) with Levobupivacaine 0.5% (7-8ml). We measured the postoperative intensity of pain using a Visual Analogue Scale (VAS), the consumption of oxycodone after operative treatment and the motor recovery. VAS was detected at baseline (time 0, before the surgery) and at 3, 6, 12 and 24 hours after the operative procedure (T1, T2, T3, T4 respectively). Control group of 26 patients were treated with another post-operative analgesia technique: local infiltration (Local Infiltration Anaesthesia, LIA) with Levobupivacaine 0.5% (15ml) performed by the surgeon. RESULTS: PTNB group showed a significant reduction of VAS score from the sixth hour after surgery compared to LIA group (p

Neelapu and colleagues report a post hoc subgroup analysis from the ZUMA-1 trial of chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B cell lymphoma. In comparison with younger patients, those ≥65 years old have similar rates of complete response and durable response at 2 years, but higher rates of neurological toxicity.

Background Minimally invasive intratumoural administration of thermoresponsive hydrogels, that transition from liquid to gel in response to temperature, has been proposed as a potential treatment modality for solid tumours. The aim of this study was to assess the inherent cytotoxicity of a poloxamer-based thermoresponsive hydrogel in a murine xenograft model of lung cancer. Methods In vitro viability assessment was carried out in a lung cancer (A549) and non-cancerous (Balb/c 3T3 clone A31) cell line. Following intratumoural administration of saline or the thermoresponsive hydrogel to an A549 xenograft model in female Athymic Nude-Foxn1nu mice (n = 6/group), localisation was confirmed using IVIS imaging. Tumour volume was assessed using callipers measurements over 14 days. Blood serum was analysed for liver and kidney damage and ex vivo tissue samples were histologically assessed. Results The thermoresponsive hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. Tumour volume increase was statistically significantly lower than saline treated control at day 14 (n = 6, p = 0.0001), with no associated damage of hepatic or renal tissue observed. Conclusions Presented is a poloxamer-based thermoresponsive hydrogel, suitable for intratumoural administration and retention, which has demonstrated preliminary evidence of local tumour control, with minimal off-site toxicity.

Background Tremor is the most common movement disorder with the highest prevalence in the upper limbs. The mechanical suppression of involuntary movements is an alternative and additional treatment to medication or surgery. Here we present a new, soft, lightweight, task asjustable and passive orthosis for tremor suppression. Methods A new concept of a manual, textile-based, passive orthosis was designed with an integrated, task adjustable, air-filled structure, which can easily be inflated or deflated on-demand for a certain daily activity. The air-filled structure is placed on the dorsal side of the wrist and gets bent and compressed by movements when inflated. In a constant volume air-filled structure, air pressure increases while it is inflating, creating a counterforce to the compression caused by bending. We characterised the air-filled structure stiffness by measuring the reaction torque as a function of the angle of deflection on a test bench. Furthermore, we evaluated the efficacy of the developed passive soft orthosis by analysing the suppression of involuntary movements in the wrist of a tremor-affected patient during different activities of daily living (i.e. by calculating the power spectral densities of acceleration). Results By putting special emphasis on the comfort and wearability of the orthosis, we achieved a lightweight design (33 g). The measurements of the angular deflection and resulting reaction torques show non-linear, hysteretic, behaviour, as well as linear behaviour with a coefficient of determination (R2) between 0.95 and 0.99. Furthermore, we demonstrated that the soft orthosis significantly reduces tremor power for daily living activities, such as drinking from a cup, pouring water and drawing a spiral, by 74 to 82% (p = 0.03); confirmed by subjective tremor-reducing perception by the patient. Conclusion The orthosis we developed is a lightweight and unobtrusive assistive technology, which suppresses involuntary movements and shows high wearability properties, with the potential to be comfortable. This air-structure technology could also be applied to other movement disorders, like spasticity, or even be integrated into future exoskeletons and exosuits for the implementation of variable stiffness in the systems., Journal of NeuroEngineering and Rehabilitation, 17 (1), ISSN:1743-0003

INTRODUCTION: Recently, a combined reflectance confocal microscopy (RCM)-optical coherence tomography (OCT) has been tested for the diagnosis of basal cell carcinoma (BCC). Evaluating the role of RCM-OCT in management of complex BCCs has not been studied. The objective of the study was to investigate the utility of a new combined RCM-OCT device in the evaluation and management of complex BCCs in a descriptive study. METHODS: Prospective study of consecutive cases (July 2018- June 2019) of biopsy proven ‘complex’ BCC defined as BCC in the head and neck area with multiple high risk criteria such as large size in the mask area, multiple recurrences, and infiltrative subtype. All cases were evaluated with a combined RCM-OCT device that provided simultaneous image viewing on a screen. Lesions were evaluated bedside with RCM-OCT according to previously described criteria. RESULTS: Ten patients with complex head and neck BCCs had mean age of 73.1±13.0 years. Six (60%) patients were males. Mean BCC clinical size was 1.9±1.2 cm (range 0.6–4.0 cm). RCM detected residual BCC in 8 out of 10 cases (80%) and OCT detected residual BCC in all 10 cases (100%). Six BCCs (60%) had a depth estimate of >1000 μm under OCT. In 5 cases, (50%) RCM-OCT imaging results led to a change/modification in BCC management. CONCLUSION: The use of a combined RCM-OCT device may help in the evaluation of complex head and neck BCCs by guiding treatment selection and defining the extent of surgery.

BACKGROUND Men represent a growing segment of the facial aesthetic market. OBJECTIVE To evaluate investigator-assessed efficacy, patient-reported outcomes, and safety after onabotulinumtoxinA treatment of forehead lines (FHL) in men. METHODS Subjects with moderate to severe FHL received onabotulinumtoxinA (frontalis: 20 U; glabellar complex: 20 U, with/without 24 U in crow's feet regions) or placebo in 6-month, double-blind periods of 2 pivotal trials. Results for men were pooled. RESULTS Men comprised 12% (140/1,178) of subjects. Day 30 male responder rates for achieving at least 1-grade Facial Wrinkle Scale (FWS) improvement at maximum eyebrow elevation and at rest were 98.2% and 93.3%, respectively; a significant difference in responder rates was maintained versus placebo (p < .05) through Day 150. Despite men having proportionately more severe FHL at baseline, 81.8% and 79.8% achieved Day 30 FWS ratings of none or mild at maximum eyebrow elevation and at rest, respectively (p < .05); significance versus placebo was maintained through Day 120. Men reported high satisfaction rates and improved psychological impacts. No new safety signals were detected. CONCLUSION Standard dosing and administration of onabotulinumtoxinA significantly improved static and dynamic FHL appearance, despite men having proportionately more severe FHL at baseline. Men reported high satisfaction and appearance-related psychological impact improvements.

Analogues of the Ca2+-releasing intracellular messenger d-myo-inositol 1,4,5-trisphosphate [1, Ins(1,4,5)P3] are important synthetic targets. Replacement of the α-glucopyranosyl motif in the natural product mimic adenophostin 2 by d-chiro-inositol in d-chiro-inositol adenophostin 4 increased the potency. Similar modification of the non-nucleotide Ins(1,4,5)P3 mimic ribophostin 6 may increase the activity. d-chiro-Inositol ribophostin 10 was synthesized by coupling as building blocks suitably protected ribose 12 with l-(+)-3-O-trifluoromethylsulfonyl-6-O-p-methoxybenzyl-1,2:4,5-di-O-isopropylidene-myo-inositol 11. Separable diastereoisomeric 3-O-camphanate esters of (±)-6-O-p-methoxy-benzyl-1,2:4,5-di-O-isopropylidene-myo-inositol allowed the preparation of 11. Selective trans-isopropylidene deprotection in coupled 13, then monobenzylation gave separable regioisomers 15 and 16. p-Methoxybenzyl group deprotection of 16, phosphitylation/oxidation, then deprotection afforded 10, which was a full agonist in Ca2+-release assays; its potency and binding affinity for Ins(1,4,5)P3R were similar to those of adenophostin. Both 4 and 10 elicited a store-operated Ca2+ current ICRAC in patch-clamped cells, unlike Ins(1,4,5)P3 consistent with resistance to metabolism. d-chiro-Inositol ribophostin is the most potent small-molecule Ins(1,4,5)P3 receptor agonist without a nucleobase yet synthesized.

Objective To quantify the reported prevalence and trend of maternal hepatitis C virus (HCV) infection in the United States (2009-2017) and identify maternal characteristics and obstetric outcomes associated with HCV infection during pregnancy. Methods We conducted a population-based retrospective cohort study of all live births in the United States for the period 2009 through 2017 using National Center for Health Statistics birth records. We estimated reported prevalence and trends over this time period for the United States. We also evaluated demographic factors and pregnancy outcomes associated with maternal HCV infection for a contemporary U.S. cohort (2014-2017). Results During the 9-year study period, there were 94,824 reported cases of maternal HCV infection among 31,207,898 (0.30%) live births in the United States. The rate of maternal HCV infection increased from 1.8 cases per 1,000 live births to 4.7 cases per 1,000 live births (relative risk [RR] 2.7, 95% CI 2.6-2.8) in the United States. After adjusting for various confounders in the contemporary U.S. cohort (2014-2017), demographic characteristics associated with HCV infection included non-Hispanic white race (adjusted RR 2.8, 95% CI 2.7-2.8), Medicaid insurance (adjusted RR 3.3, CI 3.2-3.3), and cigarette smoking (adjusted RR 11.1, CI 10.9-11.3). Co-infection during pregnancy with hepatitis B (adjusted RR 19.2, CI 18.1-20.3), gonorrhea, chlamydia, or syphilis were also associated with maternal HCV infection. Obstetric and neonatal outcomes associated with maternal HCV infection included cesarean delivery, preterm birth, maternal intensive care unit admission, blood transfusion, having small-for-gestational-age neonates (less than the 10th percentile) birth weight, neonatal intensive care unit admission, need for assisted neonatal ventilation, and neonatal death. Conclusion The reported prevalence of maternal HCV infection has increased 161% from 2009 to 2017.

Background Short leukocyte telomere length (TL) is associated with atherosclerotic cardiovascular disease. Endothelial repair plays a key role in the development of atherosclerosis. The objective was to examine associations between TL and proliferative dynamics of endothelial colony‐forming cells (ECFCs), which behave as progenitor cells displaying endothelial repair activity. Methods and Results To isolate ECFCs, we performed a clonogenic assay on blood samples from 116 participants (aged 24–94 years) in the TELARTA (Telomere in Arterial Aging) cohort study. We detected no ECFC clones in 29 (group 1), clones with no replating capacity in other 29 (group 2), and clones with replating capacity in the additional 58 (group 3). Leukocyte TL was measured by Southern blotting and ECFCs (ECFC‐TL). Age‐ and sex‐adjusted leukocyte TL (mean±SEM) was the shortest in group 1 (6.51±0.13 kb), longer in group 2 (6.69±0.13 kb), and the longest in group 3 (6.78±0.09 kb) ( P P P r =0.82; P Conclusions Individuals with longer telomeres display a higher number of self‐renewing ECFCs. Our results also indicate that leukocyte TL, as a proxy of TL dynamics in ECFCs, could be used as a surrogate marker of endothelial repair capacity in clinical and laboratory practice because of easy accessibility of leukocytes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02176941.

Summary Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that link extracellular stimuli to Ca2+ signals. Ca2+ release from intracellular stores is “quantal”: low IP3 concentrations rapidly release a fraction of the stores. Ca2+ release then slows or terminates without compromising responses to further IP3 additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP3Rs and use it to demonstrate that quantal responses do not require heterogenous Ca2+ stores. IP3Rs respond incrementally to IP3 and close after the initial response to low IP3 concentrations. Comparing functional responses with IP3 binding shows that only a tiny fraction of a cell’s IP3Rs mediate incremental Ca2+ release; inactivation does not therefore affect most IP3Rs. We conclude, and test by simulations, that Ca2+ signals evoked by IP3 pulses arise from rapid activation and then inactivation of very few IP3Rs. This allows IP3Rs to behave as increment detectors mediating graded Ca2+ release., Graphical abstract, Highlights • IP3 evokes quantal Ca2+ release from the endoplasmic reticulum • IP3 receptors rapidly activate and then inactivate • Submaximal responses to IP3 require activation of very few IP3 receptors • Rapid activation and inactivation of very few IP3Rs allow incremental responses to IP3, Rossi et al. define mechanisms for IP3-evoked quantal Ca2+ release that reconcile response termination with undiminished sensitivity to further IP3 additions. They show that responses require very few IP3 receptors that rapidly open and then inactivate, allowing graded responses despite the ability of IP3 receptors to propagate regenerative Ca2+ signals.

Objective In 2014, the leading obstetric societies published an executive summary of a joint workshop to establish obstetric interventions to be considered for periviable births. Antenatal corticosteroid administration between 220/7 and 226/7 weeks was not recommended given existing evidence. We sought to evaluate whether antenatal steroid exposure was associated with improved survival among resuscitated newborns delivered between 22 and 23 weeks of gestation. Study design We conducted a population-based cohort study of all resuscitated livebirths delivered between 220/7 and 236/7 weeks of gestation in the United States during 2009 to 2014 utilizing National Center for Health Statistics data. The primary outcome was rate of survival to 1 year of life (YOL) between infant cohorts based on antenatal steroid exposure. Multivariable logistic regression estimated the association of antenatal steroid exposure on survival outcomes. Results In the United States between 2009 and 2014, there were 2,635 and 7,992 infants who received postnatal resuscitation after delivery between 220/7 to 226/7 and 230/7 to 236/7 weeks of gestation, respectively. Few infants born at 22 (15.9%) and 23 (26.0%) weeks of gestation received antenatal corticosteroids (ANCS). Among resuscitated neonates, survival to 1 YOL was 45.2 versus 27.8% (adjusted relative risk [aRR]: 1.6, 95% confidence interval [CI]: 1.2-2.1) and 57.9 versus 47.7% (aRR: 1.3, 95% CI: 1.1-1.5) for infants exposed to ANCS compared with those not exposed at 22 and 23 weeks of gestation, respectively. When stratified by 100 g birth weight category, ANCS were associated with survival among neonates weighing 500 to 599 g (aRR: 1.9, 95% CI: 1.3-2.9) and 600 to 699 g (aRR: 1.7, 95% CI: 1.1-2.6) at 22 weeks. Conclusion Exposure to ANCS was associated with higher survival rates to 1 YOL among resuscitated infants born at 22 and 23 weeks. National guidelines recommending against ANCS utilization at 22 weeks should be re-evaluated given emerging evidence of benefit. Key points · Exposure to antenatal steroids was associated with higher survival rates at 22 and 23 weeks of gestation.. · Women exposed to antenatal steroids were more likely to have an adverse outcome.. · The association between steroids and survival was observed among infants with birth weights > 500 g..

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor-β (TGF-β). Previously, αV integrins were found to be critical for the onset of TGF-β-mediated PCO in vivo; however, the functional heterodimer was unknown. Here, β8 integrin-conditional knockout (β8ITG-cKO) lens epithelial cells (LCs) attenuated their fibrotic responses, while both β5 and β6 integrin-null LCs underwent fibrotic changes similar to WT at 5 days post cataract surgery (PCS). RNA-Seq revealed that β8ITG-cKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGF-β-induced signaling, at 24 hours PCS. Treatment of β8ITG-cKO eyes with active TGF-β1 at the time of surgery rescued the fibrotic response. Treatment of WT mice with an anti-αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGF-β signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses were established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGF-β activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.

SummaryIntratumoral (IT) delivery of immune-activating viruses can serve as an important strategy to turn “cold” tumors into “hot” tumors, resulting in overcoming resistance to immune checkpoint blockade (ICB). Modified vaccinia virus Ankara (MVA) is a highly attenuated, non-replicative vaccinia virus that has a long history of human use. Here we report that IT recombinant MVA (rMVA), lacking E5R encoding an inhibitor of the DNA sensor cyclic GMP-AMP synthase (cGAS), expressing a dendritic cell growth factor, Fms-like tyrosine kinase 3 ligand (Flt3L), and a T cell co-stimulator, OX40L, generates strong antitumor immunity, which is dependent on CD8+ T cells, the cGAS/STING-mediated cytosolic DNA-sensing pathway, and STAT1/STAT2-mediated type I IFN signaling. Remarkably, IT rMVA depletes OX40hi regulatory T cells via OX40L/OX40 interaction and IFNAR signaling. Taken together, our study provides a proof-of-concept for improving MVA-based cancer immunotherapy, through modulation of both innate and adaptive immunity.One Sentence SummaryIntratumoral delivery of recombinant MVA for cancer immunotherapy

SummaryIntegration of Human Papillomaviruses (HPV) is an important mechanism of carcinogenesis but is absent in a significant fraction of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors. In two HPV16+ cell lines, we identified large tandem arrays of full-length and truncated viral genomes integrated into multiple locations indicating formation as extrachromosomal DNA (HPV superspreading). An HPV16+ cell line with episomal DNA has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). WGS of HPV16+ cervical tumors revealed that 11/20 with only episomal HPV (EP) have intact monomer episomes. The remaining nine EP tumors have multimer and rearranged HPV genomes. Most HPV rearrangements disrupt the E1 and E2 genes, and EP tumors overexpress the E6 and E7 viral oncogenes. Tumors with both episomal and integrated HPV16 display multimer episomes and concatemers of human and viral sequences. One tumor has a recurrent deletion of an inhibitory site regulating E6 and E7 expression, and another has a recurrent duplication consistent with HPV superspreading. Therefore, HPV16 can cause cancer without integration through aberrant episomal replication, forming rearranged and multimer episomes.

Low-energy fission of and radioactive beams, provided by the Fragment Separator (FRS) of the GSI Helmholtzzentrum fur Schwerionenforschung facility (GSI), has been studied using the Reactions with Relativistic Radioactive Beams / Studies on Fission with Aladin (R3B/SOFIA) setup. The latter allows us, on an event-by-event basis, to simultaneously identify, in terms of their mass and atomic numbers, the fissioning nucleus in coincidence with both fission fragments after prompt-neutron emission. This article reports new results on elemental, isotonic, isobaric, and isotopic yields. Moreover, the high accuracy of our data allowed us to study in detail proton even-odd staggering, from elemental yields; neutron excess, from isotopic yields; and total prompt-neutron multiplicity, from the difference of masses of the fissioning nucleus and fission fragments. These results are then compared to previous experimental data in order to probe how these fission observables change as function of the excitation energy and atomic and neutron numbers of the compound nucleus.

Thermal ablation has attracted attention as a minimally invasive tissue ablation treatment. Steam flow was recently introduced as a novel ablation procedure. This work aimed to assess the applicability of pulsated steam flow for tumor ablation. Ex vivo ablation was performed using liver, muscle, and fat tissues of sheep. Three experimental protocols of pulse number were administered to these tissues, while computational simulation was conducted according to the ex vivo tests for each tissue. Real-time measurements of temperature revealed heat propagation during and subsequent to ablation. The peak temperature was achieved after ablation. The time to reach the peak (highest temperature) increased with the distance from the thermal sensor to the steam needle according to thermal conductivity, except for steam leakage along to gap between the tissue and blood vessel. A cross-section of the ablated specimen clearly revealed the boundaries of cell defects. The ablated area was droplet shaped up to the steam needle. Computational simulations revealed that the ablated area was consistent with the area with the highest temperature. Though several limitations still remain such as no blood circulation, pulsated steam flow can ablate diverse animal tissues.

Point-of-care diagnostics of platelet and coagulation function present demanding challenges. Current clinical diagnostics often use centrifuged plasmas or platelets and frozen plasma standards, recombinant protein standards, or even venoms. Almost all commercialized tests of blood do not recreate the in vivo hemodynamics where platelets accumulate to high densities and thrombin is generated from a procoagulant surface. Despite numerous drugs that target platelets, insufficient coagulation, or excess coagulation, POC blood testing is essentially limited to viscoelastic methods that provide a clotting time, clot strength, and clot lysis, while used mostly in trauma centers with specialized capabilities. Microfluidics now allows small volumes of whole blood (

Antibodies targeting the spike (S) and nucleocapsid (N) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential tools. In addition to important roles in the treatment and diagnosis of infection, the availability of high-quality specific antibodies for the S and N proteins is essential to facilitate basic research of virus replication and in the characterization of mutations responsible for variants of concern. We have developed panels of mouse and rabbit monoclonal antibodies (mAbs) to the SARS-CoV-2 spike receptor-binding domain (S-RBD) and N protein for functional and antigenic analyses. The mAbs to the S-RBD were tested for neutralization of native SARS-CoV-2, with several exhibiting neutralizing activity. The panels of mAbs to the N protein were assessed for cross-reactivity with the SARS-CoV and Middle East respiratory syndrome (MERS)-CoV N proteins and could be subdivided into sets that showed unique specificity for SARS-CoV-2 N protein, cross-reactivity between SARS-CoV-2 and SARS-CoV N proteins only, or cross-reactivity to all three coronavirus N proteins tested. Partial mapping of N-reactive mAbs were conducted using truncated fragments of the SARS-CoV-2 N protein and revealed near complete coverage of the N protein. Collectively, these sets of mouse and rabbit monoclonal antibodies can be used to examine structure/function studies for N proteins and to define the surface location of virus neutralizing epitopes on the RBD of the S protein.