Intermountain St. George Regional Hospital

OBJECTIVE: To assess the safety/tolerability and perform a preliminary efficacy evaluation of a multiple-dosing regimen of recombinant human vascular endothelial growth factor (VEGF165 or rhVEGF; telbermin) applied topically to chronic diabetic neuropathic foot ulcers. METHOD: Subjects with type 1 or 2 diabetes mellitus were randomised to receive either topical applied telbermin (72 microg/cm2) (n=29) or placebo (n=26) treatment to the foot ulcer surface in conjunction with standard ulcer care. Subjects received treatment every 48 hours (maximum three doses per week) for up to six weeks. Weekly 35mm photography, quantitative planimetry and physical examinations documented the ulcer appearance, surface area and stage. Safety endpoints included incidence of clinically significant hypotension, adverse events and ulcer infection. Exploratory efficacy endpoints included percentage reduction in total ulcer surface area, incidence of complete ulcer healing and time to complete ulcer healing. RESULTS: Incidence of adverse events was comparable in the two treatment groups. None of the adverse events were attributed to study drug, and no hypotension was observed as a result of telbermin treatment. Occurrence of infected study ulcers appeared to be balanced between the treatment groups. Positive trends suggestive of potential signals of biological activity were observed for incidence of complete ulcer healing (41.4% telbermin versus 26.9% placebo at day 43 [P=0.39]) and time to complete ulcer healing (25th percentile of 32.5 days telbermin versus 43.0 days placebo [log-rank P=0.13]). CONCLUSION: The topical application of telbermin 72 microg/cm2 three times a week for up to six weeks appeared to be well tolerated. Further studies are required to characterise the safety/efficacy of telbermin more completely.

BACKGROUND: We previously reported that in the year 2006, approximately 35% of the transfusions administered in the Intermountain Healthcare neonatal intensive care units (NICU) were noncompliant with our transfusion guidelines. In January 2009 we instituted an electronic NICU transfusion ordering and monitoring system as part of a new program to improve compliance with transfusion guidelines. STUDY DESIGN AND METHODS: In the four largest NICUs of Intermountain Healthcare, we performed a pre-post analysis of compliance with transfusion guidelines and transfusion usage. RESULTS: After beginning the new transfusion compliance program all four NICUs had an increase in compliance from 65% to 90%. Accompanying the improved compliance, all four NICUs had a reduction in transfusions administered. Specifically, compared with 2007 and 2008, there were 984 fewer NICU transfusions given in 2009. This included 554 fewer red blood cell (RBC) transfusions, 174 fewer platelet transfusions, and 256 fewer frozen plasma infusions. We calculate that in 2009, a total of 200 NICU patients who in previous years would have received one or more transfusions instead received none. Applying specific Intermountain Healthcare billing data to the observed transfusion reductions, this new program resulted in an annual decrease of $780,074 in blood bank charges (blood administration charges were not included). During the 3-year period, January 2007 through December 2009, we detected no change in NICU demographics, major morbidities, length of hospital stay, or mortality rate. CONCLUSION: Implementing a systemwide NICU program to improve compliance with already-established transfusion guidelines increased compliance from 65% to 90%. Improved compliance with transfusion guidelines was accompanied by a significant reduction in transfusions given, with no increase in NICU length of stay or mortality rate.

BACKGROUND: There are limited options for patients who present with antiarrhythmic-drug (AAD)-refractory ventricular tachycardia (VT) with recurrent implantable cardioverter defibrillator (ICD) shocks. Ranolazine is a drug that exerts antianginal and antiischemic effects and also acts as an antiarrhythmic in isolation and in combination with other class III medications. Ranolazine may be an option for recurrent AAD-refractory ICD shocks secondary to VT, but its efficacy, outcomes, and tolerance are unknown. METHODS AND RESULTS: Twelve patients (age 65 ± 9.7 years) were treated with ranolazine. Eleven (92%) were male, and 10 (83%) had ischemic heart disease with an average ejection fraction of 0.34 ± 0.13. All patients were on a class III AAD (11 amiodarone, one sotalol), with six (50%) receiving mexilitene or lidocaine. Five patients had a prior ablation and two were referred for a VT ablation at the index presentation. The QRS increased nonsignificantly from 128 ± 31 ms to 133 ± 31 ms, and the QTc increased nonsignificantly from 486 ± 32 ms to 495 ± 31 ms after ranolazine initiation. Over a follow-up of 6 ± 6 months, 11 (92%) patients had a significant reduction in VT and no ICD shocks were observed. VT ablation was not required in those referred. In two patients, gastrointestinal side effects limited long-term use. Of these two patients, one died due to progressive heart failure. In one patient, severe hypoglycemia limited dosing to 500 mg daily, but this was sufficient for VT control. CONCLUSION: Ranolazine proved effective in reducing VT burden and ICD shocks in patients with AAD-refractory VT. Ranolazine should be further tested for this indication and considered for clinical application when other options have proven ineffective.

BACKGROUND: Procedural success and clinical outcomes after transcatheter aortic valve replacement (TAVR) have improved, but residual aortic regurgitation (AR) and new permanent pacemaker implantation (PPI) rates remain variable because of a lack of uniform periprocedural management and implantation. OBJECTIVES: The Optimize PRO study evaluates valve performance and procedural outcomes using an "optimized" TAVR care pathway and the cusp overlap technique (COT) in patients receiving the Evolut PRO/PRO+ (Medtronic) self-expanding valves. METHODS: Optimize PRO, a nonrandomized, prospective, postmarket study conducted in the United States, Canada, Europe, Middle East, and Australia, is enrolling patients with severe symptomatic aortic stenosis and no pre-existing pacemaker. Sites follow a standardized TAVR care pathway, including early discharge and a conduction disturbance management algorithm, and transfemoral deployment using the COT. RESULTS: A total of 400 attempted implants from the United States and Canada comprised the main cohort of this second interim analysis. The mean age was 78.7 ± 6.6 years, and the mean Society of Thoracic Surgeons predictive risk of mortality was 3.0 ± 2.4. The median length of stay was 1 day. There were no instances of moderate or severe AR at discharge. At 30 days, all-cause mortality or stroke was 3.8%, all-cause mortality was 0.8%, disabling stroke was 0.7%, hospital readmission was 10.1%, and cardiovascular rehospitalization was 6.1%. The new PPI rate was 9.8%, 5.8% with 4-step COT compliance. In the multivariable model, right bundle branch block and the depth of the implant increased the risk of PPI, whereas using the 4-step COT lowered 30-day PPI. CONCLUSIONS: The use of the TAVR care pathway and COT resulted in favorable clinical outcomes with no moderate or severe AR and low PPI rates at 30 days while facilitating early discharge and reproducible outcomes across various sites and operators. (Optimize PRO; NCT04091048).

Fatal hemolytic anemia developed in a 52-year-old woman who was treated with a cephalosporin, ceftriaxone. The patient's red cells (RBCs) were coated with C3, but no RBC-bound IgG, IgA, or IgM was detected. Her serum contained an antibody that did not react with cephalosporin-coated RBCs but reacted strongly with RBCs in vitro when her serum was added to drug and RBCs. This is the first case of immune hemolytic anemia associated with ceftriaxone, the first case of fatal cephalosporin-induced hemolytic anemia, and the second case in which a cephalosporin antibody showed in vitro and in vivo characteristics usually thought to be associated with the so-called immune complex mechanism.

Clinicians who rarely perform neonatal resuscitation exhibit skill deterioration. Telehealth addresses this challenge by facilitating video connections between neonatologists at tertiary care centers and providers at smaller hospitals. However, there is little empirical evidence about the benefits of telehealth programs for neonatal resuscitation. Thus, we conducted a multiple-baseline study to evaluate the effect of video-assisted resuscitation on the transfer of newborns from eight community hospitals that implemented neonatal telehealth in the period November 2014-December 2015 to level 3 newborn intensive care units. The intervention was associated with a reduction of 0.70 transfers per facility-month and a 29.4 percent reduction in a newborn's odds of being transferred. Annually, this corresponds to 67.2 fewer transfers and an estimated savings of $1,220,352 per year. Avoiding transfers keeps families closer to home, increases community hospital revenue, and eliminates transfer-associated risk. Yet lack of reimbursement for telehealth limits its adoption. Policy changes are necessary to align payment incentives and promote the use of telehealth services.

AML1 is a transcriptional activator that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. We recently identified 3 patients in whom pancytopenia developed almost 50 years after high-level radiation exposure from nuclear explosions during or after World War II. In all 3 patients, acute myeloid leukemia (AML) eventually developed that had similar characteristics and clinical courses. Cytogenetics from the 3 patients revealed a t(1;21)(p36;q22), a t(18;21)(q21;q22), and a t(19;21)(q13.4;q22). By fluorescent in situ hybridization (FISH), all 3 translocations disrupted the AML1 gene. Two of these AML1 translocations, the t(18;21) and the t(19;21), have not been reported previously. It is possible that the AML1 gene is a target for radiation-induced AML. (Blood. 2000;95:4011-4013)

Correlation between plasma cholinesterase activity and duration of neuromuscular blockade following succinylcholine (SCh) was studied in 30 healthy women undergoing laparoscopic tubal coagulation and 20 pregnany women indergoing elective repeat cesarean section. All patients received N2O-thiopental anesthesia. Cholinesterase activity in nonpregnant patients was significantly greater than in pregnant patients. Time to 90 percent recovery of control twitch height following 40 or 80 mg/m2 BSA of SCh was not significantly different in pregnant versus nonpregnant patients. There also was no correlation between plasma cholinesterase activity and duration of paralysis from SCh. The authors conclude that pregnant patients have lower cholinesterase activity, but prolonged neuromuscular blockade from SCh should not occur unless the patient is grossly overdosed with SCh. Routine use of a peripheral nerve stimulator is recommended to avoid such overdosage.

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

We tabulated the incidence of necrotizing enterocolitis (NEC) during a recent 4-year period among three neonatal intensive care units (NICUs) within a single health-care system. We then sought associations to explain differences in NEC incidence between the centers. Between January 1, 2002, and December 31, 2005, 6787 neonates were admitted to the three NICUs. The incidence of NEC (Bell's stage II or higher) among these patients was correlated with birthweight, gestational age, maternal and neonatal demographics, and various events and practices. These events and practices included feeding practices, the management of patent ductus arteriosus, rates of systemic bacterial and fungal infection, transfers to the regional children's hospital for surgical treatment, and mortality rate. Bell's stage II or higher NEC was documented in 131 of 6787 NICU patients. The incidence was 7.4% among those with birthweights <750 g (16 of 217), 6.9% among those of birthweights 750 to 1250 g (36 of 519), and 1.3% (79 of 6051) among those with birthweights >1250 g. Center A had an incidence of NEC significantly higher than the other two, accounting for 72% of the total cases (94 of 131). Among patients <1250 g, Center A had a rate of NEC of 14.5%; Centers B (2.3%) and C (2.3%) had lower rates ( P<0.0001). After controlling for gestational age, birthweight, small for gestational age status, and Apgar scores, the overall odds ratio of developing NEC in Center A, compared with the other two, was 21.6 (95% confidence interval, 14.7 to 31.6). This difference could not be accounted for by differences in maternal or neonatal demographic characteristics, bed occupancy rates, or a higher incidence of culture-proven nosocomial bacterial or fungal infections. Although the incidence of NEC was significantly higher at Center A, the percentage of patients with NEC transferred to the children's hospital for surgical evaluation and treatment was similar. The mortality rate of patients who developed NEC was similar among the three hospitals. Centers B and C utilize standardized feeding guidelines. During each of the 4-year study periods, one of three NICUs within the same health-care system had a higher incidence of NEC than the other two. Once NEC developed, the outcome was similar in all three NICUs. The higher incidence in Center A could not be explained by differences in demographics, socioeconomics, or systemic nosocomial infections. Similarities in feeding practices between Centers B and C suggest to us that these may be responsible, at least in part, for the differences in the incidence of NEC. Changing the feeding practices at Center A to those at Centers B and C is planned to test this theory.

Abstract Rationale Care of emergency department (ED) patients with pneumonia can be challenging. Clinical decision support may decrease unnecessary variation and improve care. Objectives To report patient outcomes and processes of care after deployment of electronic pneumonia clinical decision support (ePNa): a comprehensive, open loop, real-time clinical decision support embedded within the electronic health record. Methods We conducted a pragmatic, stepped-wedge, cluster-controlled trial with deployment at 2-month intervals in 16 community hospitals. ePNa extracts real-time and historical data to guide diagnosis, risk stratification, microbiological studies, site of care, and antibiotic therapy. We included all adult ED patients with pneumonia over the course of 3 years identified by International Classification of Diseases, 10th Revision discharge coding confirmed by chest imaging. Measurements and Main Results The median age of the 6,848 patients was 67 years (interquartile range, 50–79), and 48% were female; 64.8% were hospital admitted. Unadjusted mortality was 8.6% before and 4.8% after deployment. A mixed effects logistic regression model adjusting for severity of illness with hospital cluster as the random effect showed an adjusted odds ratio of 0.62 (0.49–0.79; P &amp;lt; 0.001) for 30-day all-cause mortality after deployment. Lower mortality was consistent across hospital clusters. ePNa-concordant antibiotic prescribing increased from 83.5% to 90.2% (P &amp;lt; 0.001). The mean time from ED admission to first antibiotic was 159.4 (156.9–161.9) minutes at baseline and 150.9 (144.1–157.8) minutes after deployment (P &amp;lt; 0.001). Outpatient disposition from the ED increased from 29.2% to 46.9%, whereas 7-day secondary hospital admission was unchanged (5.2% vs. 6.1%). ePNa was used by ED clinicians in 67% of eligible patients. Conclusions ePNa deployment was associated with improved processes of care and lower mortality. Clinical trial registered with www.clinicaltrials.gov (NCT03358342).

Impulsive behavior has been conceptualized from several vantage points including biological, sociological and psychological phenomenon. A comprehensive review of the empirical literature revealed that there is a paucity of research examining the association between working memory, executive functioning and impulsivity. A total sample of 170 aggressive outpatient participants was recruited for the study. Participants were administered a comprehensive neuropsychological battery. Principal components analysis of the 19 CVLT indices revealed five factors, accounting for 68% of the total variance. Results from the canonical correlation revealed one significant canonical variate with loadings from three CVLT factors (General Verbal Learning, Response Discrimination, and Proactive Interference), two executive functioning measures (Trail Making Test and Controlled Oral Word Association Test), and one impulsivity subscale (Attentional Impulsiveness). The findings of this study underscore the importance of memory functioning in determining impulsive aggressive behavior.

This article examines the effectiveness of Integrative Restoration (iRest) Yoga Nidra meditation on mindfulness, sleep, and pain in health care workers. As health care workers provide emotional support to patients, it is not uncommon for workers to experience both physical and mental exhaustion. One holistic approach to support employees is mindfulness training. iRest Yoga Nidra is a complementary and integrative health therapy that increases mindfulness. A pre-/postinterveniton descriptive survey design was used. Before and after experiencing iRest meditation, participants completed a 51-item questionnaire consisting of demographics plus 3 validated instruments: the Five-Facet Mindfulness Questionnaire (FFMQ), the Epworth Sleepiness Scale (ESS), and Department of Defense/Veterans Administration (DoD/VA) Pain Supplemental Questions (PSQ). A total of 15 participants completed both questionnaires. Postintervention FFMQ scores were significantly higher than preintervention (z = -3.294, P = .001). The highest subscale scores were "acting with awareness" and "nonjudging of inner experience." There was a not a significant difference in the mean ESS scores at baseline and follow-up. However, there was a strong negative correlation between the mean ESS improvement score and the number of weeks attended (rs = -0.705, P = .003). There was a not a significant difference in the mean pain baseline and follow-up scores. This study showed significant improvement in mindfulness of health care workers following a guided 8-week iRest Yoga Nidra program. The results of this study may provide some insight into helping health care workers deal with the demands of their profession in a positive manner, thus leading to an improved workplace environment.

Canyoning is a recreational activity that has increased in popularity in the last decade in Europe and North America, resulting in up to 40% of the total search and rescue costs in some geographic locations. The International Commission for Mountain Emergency Medicine convened an expert panel to develop recommendations for on-site management and transport of patients in canyoning incidents. The goal of the current review is to provide guidance to healthcare providers and canyoning rescue professionals about best practices for rescue and medical treatment through the evaluation of the existing best evidence, focusing on the unique combination of remoteness, water exposure, limited on-site patient management options, and technically challenging terrain. Recommendations are graded on the basis of quality of supporting evidence according to the classification scheme of the American College of Chest Physicians.

Clostridium taeniosporum spores have about 12 large, flat, ribbon-like appendages attached through a common trunk at one spore pole to a previously unknown surface layer outside the coat that is proposed to be called the 'encasement'. Appendages are about 4.5 microm long, 0.5 microm wide and 30 nm thick and taper at the attachment end into a semicircle that is twisted relative to the flat ribbon. Individual fibrils, about 45 nm in length with spherical heads and long thin tails, form a hair-like nap, visible along the appendage edge. Four appendage proteins have been detected: a paralogous pair of 29 kDa (designated P29a and P29b), a glycoprotein of about 37 kDa (designated GP85) and an orthologue of the Bacillus spore morphogenetic protein SpoVM. The P29 proteins consist of duplicated regions and each region includes a domain of unknown function 11. The GP85 glycoprotein contains a collagen-like region. The genes for P29a and b, GP85 and possibly related proteins are closely linked on two small chromosome fragments. Putative sigma(K)-dependent promoters upstream of the P29a and b genes indicate that they likely are expressed late in the mother cell, consistent with their deposition into the layer external to the coat.

AIMS: Cutaneous malignant melanoma is among the deadliest human cancers, broadly resistant to most clinical therapies. A majority of patients with BRAFV600E melanomas respond well to inhibitors such as vemurafenib, but all ultimately relapse. Moreover, there are no viable treatment options available for other non-BRAF melanoma subtypes in the clinic. A key to improving treatment options lies in a better understanding of mechanisms underlying melanoma progression, which are complex and heterogeneous. METHODS: In this study we integrated gene and microRNA (miRNA) expression data from genetically engineered mouse models of highly and poorly malignant melanocytic tumors, as well as available human melanoma databases, and discovered an important role for a pathway centered on a tumor suppressor miRNA, miR-32. RESULTS: Malignant tumors frequently exhibited poor expression of miR-32, whose targets include NRAS, PI3K and notably, MCL-1. Accordingly, MCL-1 was often highly expressed in melanomas, and when knocked down diminished oncogenic potential. Forced MCL-1 overexpression transformed immortalized primary mouse melanocytes, but only when also expressing activating mutations in BRAF, CRAF or PI3K. Importantly, both miR-32 replacement therapy and the MCL-1-specific antagonist sabutoclax demonstrated single-agent efficacy, and acted synergistically in combination with vemurafenib in preclinical melanoma models. CONCLUSIONS: We here identify miR-32/MCL-1 pathway members as key early genetic events driving melanoma progression, and suggest that their inhibition may be an effective anti-melanoma strategy irrespective of NRAS, BRAF, and PTEN status.

CONTEXT: It is not clear if antagonizing the GIP (glucose-dependent insulinotropic polypeptide) receptor (GIPR) for treatment of obesity is likely to increase the risk of fractures, or to lower bone mineral density (BMD) beyond what is expected with rapid weight loss. OBJECTIVE: The objective of this study was to investigate the risk of fracture and BMD of sequence variants in GIPR that reduce the activity of the GIP receptor and have been associated with reduced body mass index (BMI). METHODS: We analyzed the association of 3 missense variants in GIPR, a common variant, rs1800437 (p.Glu354Gln), and 2 rare variants, rs139215588 (p.Arg190Gln) and rs143430880 (p.Glu288Gly), as well as a burden of predicted loss-of-function (LoF) variants with risk of fracture and with BMD in a large meta-analysis of up to 1.2 million participants. We analyzed associations with fractures at different skeletal sites in the general population: any fractures, hip fractures, vertebral fractures and forearm fractures, and specifically nonvertebral and osteoporotic fractures in postmenopausal women. We also evaluated associations with BMD at the lumbar spine, femoral neck, and total body measured with dual-energy x-ray absorptiometry (DXA), and with BMD estimated from heel ultrasound (eBMD). RESULTS: None of the 3 missense variants in GIPR was significantly associated with increased risk of fractures or with lower BMD. Burden of LoF variants in GIPR was not associated with fractures or with BMD measured with clinically validated DXA, but was associated with eBMD. CONCLUSION: Missense variants in GIPR, or burden of LoF variants in the gene, are not associated with risk of fractures or with lower BMD.

BACKGROUND: Previous studies have reported the use of cord blood for admission laboratory complete blood counts (CBCs). However, no studies have investigated its stability for the first 30 min after delivery. OBJECTIVES: We quantified blood cells drawn from the umbilical vein to determine the effect of (1) the time after placental delivery, and (2) the site of blood sampling (umbilical vein on an isolated cord segment vs. umbilical vein on the placental surface). METHODS: Timed phlebotomies were drawn at 2, 10, and 30 min from (1) the umbilical vein on an isolated, double-clamped cord segment, and (2) the umbilical vein near or on the placental surface. Leukocyte count, hemoglobin, platelet count, and fibrinogen were measured on each phlebotomy sample. RESULTS: Blood drawn from the isolated umbilical cord segments had leukocyte count, hemoglobin, platelet count, and fibrinogen that remained unchanged between the phlebotomies at 2, 10, and 30 min after delivery. However, blood drawn from the umbilical vein on the placental surface had, at 30 min, a leukocyte count (p = 0.002), hemoglobin (p = 0.01), and platelet count (p = 0.001) that were statistically different from the values at 2 and 10 min after delivery. There was no difference in fibrinogen at 2, 10, or 30 min. CONCLUSIONS: If cord blood is used for a neonate's initial CBC, the blood should be drawn within 10 min of the placental delivery when it is taken from the umbilical vein on or near the placenta. If an umbilical cord segment is obtained, the phlebotomy can be delayed for up to 30 min.

Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the 'o' position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease-causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly-shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.

Background: Skin cancers are the most common malignancies diagnosed worldwide. While the early detection and treatment of pre-cancerous and cancerous skin lesions can dramatically improve outcomes, factors such as a global shortage of pathologists, increased workloads, and high rates of diagnostic discordance underscore the need for techniques that improve pathology workflows. Although AI models are now being used to classify lesions from whole slide images (WSIs), diagnostic performance rarely surpasses that of expert pathologists. Objectives: The objective of the present study was to create an AI model to detect and classify skin lesions with a higher degree of sensitivity than previously demonstrated, with potential to match and eventually surpass expert pathologists to improve clinical workflows. Methods: We combined supervised learning (SL) with semi-supervised learning (SSL) to produce an end-to-end multi-level skin detection system that not only detects 5 main types of skin lesions with high sensitivity and specificity, but also subtypes, localizes, and provides margin status to evaluate the proximity of the lesion to non-epidermal margins. The Supervised Training Subset consisted of 2188 random WSIs collected by the PathologyWatch (PW) laboratory between 2013 and 2018, while the Weakly Supervised Subset consisted of 5161 WSIs from daily case specimens. The Validation Set consisted of 250 curated daily case WSIs obtained from the PW tissue archives and included 50 "mimickers". The Testing Set (3821 WSIs) was composed of non-curated daily case specimens collected from July 20, 2021 to August 20, 2021 from PW laboratories. Results: The performance characteristics of our AI model (i.e., Mihm) were assessed retrospectively by running the Testing Set through the Mihm Evaluation Pipeline. Our results show that the sensitivity of Mihm in classifying melanocytic lesions, basal cell carcinoma, and atypical squamous lesions, verruca vulgaris, and seborrheic keratosis was 98.91% (95% CI: 98.27%, 99.55%), 97.24% (95% CI: 96.15%, 98.33%), 95.26% (95% CI: 93.79%, 96.73%), 93.50% (95% CI: 89.14%, 97.86%), and 86.91% (95% CI: 82.13%, 91.69%), respectively. Additionally, our multi-level (i.e., patch-level, ROI-level, and WSI-level) detection algorithm includes a qualitative feature that subtypes lesions, an AI overlay in the front-end digital display that localizes diagnostic ROIs, and reports on margin status by detecting overlap between lesions and non-epidermal tissue margins. Conclusions: Our AI model, developed in collaboration with dermatopathologists, detects 5 skin lesion types with higher sensitivity than previously published AI models, and provides end users with information such as subtyping, localization, and margin status in a front-end digital display. Our end-to-end system has the potential to improve pathology workflows by increasing diagnostic accuracy, expediting the course of patient care, and ultimately improving patient outcomes.