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Wound care accounts for more than $6 billion of health expenditure in the United States annually. In addition, Medicare reimbursement per relative value unit has remained flat with respect to inflation over the past 20 years. Yet, physicians face increasing operating costs. The economic effects of declining inflation-adjusted Medicare physician reimbursement on the use of wound debridement procedures have yet to be elucidated. This study describes trends in Medicare reimbursement, utilization, and total Medicare expenditure for wound debridement procedures. Using Medicare claims data, we aggregated the volume of services and average Medicare reimbursement for wound debridement procedures over the calendar years 2012 to 2017. For each billing code, we estimated inflation-adjusted total Medicare expenditure by multiplying the average inflation-adjusted Medicare reimbursement by the aggregate volume of services. The average inflation-adjusted payment for wound debridement procedures decreased by 6% from 2012 to 2017. Over this time period, the utilization of wound care procedures increased 32%. Total inflation-adjusted annual Medicare expenditure on wound care increased 24% from 2012 to 2017. Therefore, despite declining physician reimbursement rates, total Medicare expenditure on wound debridement increased from 2012 to 2017. This increase in total Medicare expenditure was driven by higher utilization of wound debridement procedures.

Recent advances in chimeric antigen receptor (CAR) T-cell therapy have demonstrated promising results for diseases ranging from acute lymphoblastic leukemia (ALL) to glioblastoma.1,2 Leukemia cutis is a rare manifestation of leukemia, in which leukemic cells infiltrate the skin; as such, there is a paucity of literature describing the effects of CAR T-cell therapy in the context of leukemia cutis. Here we present a case of B-cell lymphoblastic leukemia cutis flaring and spontaneously resolving following CAR T-cell therapy.

OPINION STATEMENT Choice of therapy in mycosis fungoides is based on both patient- and lymphoma-specific factors, such as disease characteristics, comorbidities, symptoms and effect on quality of life, potential associated toxicities of therapy, response and tolerance to prior lines of therapy, and convenience and practicality. Generally, we sequence therapies from least toxic, targeted, nonimmunosuppressive to more toxic, immunosuppressive and from single agent to multiple agents, as necessary. If more toxic, immunosuppressive agents are required to alleviate disease burden or symptoms, we generally use them just long enough to control the disease, then transition to a maintenance regimen with less toxic, less immunosuppressive agents.

Background The factors influencing medical student clinical specialty choice have important implications for the future composition of the US physician workforce. The objective of this study was to determine the career net present values (NPVs) of US medical students’ clinical specialty choices and identify any relationships between a specialty’s NPV and competitiveness of admissions as measured by the US Medical Licensing Examination (USMLE) Step 1 scores. Methodology NPVs were calculated using the results of the 2019 Doximity Physician Compensation report, a survey of 90,000 physicians. Mean USMLE Step 1 scores for matched US allopathic seniors in the 2018 National Resident Matching Program were used as a measure of clinical specialties’ competitiveness of admissions. We calculated a composite measure of NPV and annual work-hours by dividing each specialty’s NPV by the reported average number of hours worked per year. Results In our analysis, orthopedic surgery had the highest NPV ($10,308,868), whereas family medicine had the lowest NPV ($5,274,546). Dermatology and plastic surgery had the highest mean USMLE Step 1 scores (249 for both), whereas family medicine had the lowest (220). Clinical specialties’ NPVs were positively associated with mean USMLE Step 1 scores (Pearson’s r = 0.82; p < 0.001). Conclusions In this study, we describe associations suggesting that medical students respond to financial incentives in choosing clinical specialties and that these decisions are mediated by USMLE Step 1 scores. This underscores the importance of titrating and aligning incentives to improve the allocation of medical students into clinical specialties.

This cohort study describes recent trends in use and payment rates and in overall expenditure for skin cancer procedures in the Medicare Part B population in the United States.

Monoclonal antibodies (mABs) are of great biopharmaceutical importance for the diagnosis and treatment of diseases. However, their production in mammalian expression hosts usually requires extensive production times and is expensive. Escherichia coli has become a new platform for production of functional small antibody fragment variants. In this study, we have used a rhamnose-inducible expression system that allows precise control of protein expression levels. The system was first evaluated for the cytoplasmic production of super folder green fluorescence protein (sfGFP) in various production platforms and then for the periplasmic production of the anti-HIV single-chain variable antibody fragment (scFv) of PGT135. Anti-HIV broadly neutralizing antibodies, like PGT135, have potential for clinical use to prevent HIV transmission, to promote immune responses and to eradicate infected cells. Different concentrations of L-rhamnose resulted in the controlled production of both sfGFP and scFv PGT135 antibody. In addition, by optimizing the culture conditions, the amount of scFv PGT135 antibody that was expressed soluble or as inclusions bodies could be modulated. The proteins were produced in batch bioreactors, with yields of 4.9 g/L for sfGFP and 0.8 g/L for scFv. The functionality of the purified antibodies was demonstrated by their ability to neutralize a panel of different HIV variants in vitro. We expect that this expression system will prove very useful for the development of a more cost-effective production process for proteins and antibody fragments in microbial cells. Electronic supplementary material The online version of this article (10.1007/s00253-019-10145-1) contains supplementary material, which is available to authorized users.

The COVID-19 pandemic has spurred healthcare systems across the world to rapidly redesign their models of care delivery. As such, this pandemic has accelerated the adoption of teledermatology in the United States. However, it remains unknown whether this momentum will be maintained after the pandemic. The future of teledermatology in the United States will be significantly influenced by a complex set of policy, legal, and regulatory frameworks. An understanding of these frameworks will help dermatologists more effectively adopt and implement teledermatology platforms. In this article, we review the current state of teledermatology in the United States, including policy dimensions, the regulatory landscape, market characteristics, and future directions.

ImportanceThe Affordable Care Act expanded Medicaid eligibility in participating states to individuals with incomes up to 138% of the federal poverty line. The effects of this policy on the diagnosis and treatment of melanoma in low-income populations has yet to be described.ObjectiveTo evaluate the effect of Medicaid expansion on changes in insurance status and clinical characteristics of low-income patients with newly diagnosed melanoma.Design, Setting, and ParticipantsThis cross-sectional study included patients younger than 65 with a new diagnosis of malignant melanoma from January 1, 2011 to December 31, 2016, in the US National Cancer Institute’s Surveillance Epidemiology and End Results database.ExposuresResidence in a state that expanded Medicaid on January 1, 2014.Main Outcomes and MeasuresThe primary outcomes were insurance status, melanoma staging, and overall survival.ResultsIn Medicaid expansion states, there were 1,719 low-income patients with newly diagnosed melanoma during the pre-expansion time period and 1,984 (15% increase) during the post-expansion time period. In nonexpansion states, there were 326 low-income patients with newly diagnosed melanoma during the pre-expansion time period, and 288 during the post-expansion time period (12% decrease). Compared with nonexpansion states, expansion states had a significantly greater reduction in percentage of uninsured patients following Medicaid expansion (adjusted odds ratio, 6.27 [95% CI, 4.83 to 8.14]). Overall survival was not statistically different between expansion and nonexpansion states (HR, 0.89 [95% CI, 0.74 to 1.06]). There were no statistically significant differences in melanoma staging at diagnosis between the expansion and nonexpansion groups (p = 0.05).Conclusions and RelevanceMedicaid expansion was associated with increased melanoma diagnoses in low-income patients and a decreased proportion of uninsured patients. However, our study did not identify differences in clinical outcomes associated with Medicaid expansion.Key PointsQuestionWas Medicaid expansion associated with changes in insurance status and clinical characteristics of low-income melanoma patients?FindingsMedicaid expansion was associated with increased diagnoses of melanoma in low-income populations and reductions in the proportion of uninsured melanoma patients. However, there were no statistically significant changes in staging at diagnosis or overall survival associated with Medicaid expansion.MeaningIncreased health insurance coverage associated with Medicaid expansion could potentially improve timely detection and treatment of melanoma for low-income populations.

The treatment of skin cancers represents a growing share of healthcare expenditures. At the same time, Medicare reimbursement rates for physician services have declined with respect to inflation. The objective of this study was to describe the economic effects of declining Medicare reimbursement for skin cancer procedures. In this ecological study, we used the Medicare Physician Supplier and Other Provider Public Use File (POSPUF) to analyze trends in Medicare reimbursement rates, use rates, and overall Medicare expenditures for skin cancer procedures from 2012 to 2017. We adjusted reimbursement rates for inflation by converting payment amounts into units of 2017 dollars. From 2012 to 2017, overall inflation-adjusted Medicare expenditure on skin cancer procedures increased 9%. Over this time period, inflation-adjusted Medicare reimbursement rates declined for each procedure class, with the exception of shave excision. Concurrently, the use rate of Mohs micrographic surgery increased 23%, while the use rate for all other skin cancer procedure classes declined. In summary, this study describes trends suggesting declining Medicare reimbursement rates have been associated with increasing use rates for higher cost skin cancer procedures. Clinicians and policy makers should collaborate to develop value-based payment models that incentivize patient outcomes rather than procedural volumes.

Due to a convergence of the availability of large datasets, graphics-specific computer hardware, and important theoretical advancements, artificial intelligence (AI) has recently contributed to dramatic progress in medicine. One type of artificial intelligence known as deep learning (DL) has been particularly impactful for medical image analysis. Deep learning applications have shown promising results in dermatology and other specialties including radiology, cardiology and ophthalmology. The modern clinician will benefit from an understanding of the basic features of deep learning in order to effectively use new applications as well as to better gauge their utility and limitations. In this second article of a two part series, we review the existing and emerging clinical applications of deep learning in dermatology and discuss future opportunities and limitations. Part 1 of this series offered an introduction to the basic concepts of deep learning to facilitate effective communication between clinicians and technical experts.

10016 Background: The impact of race and socioeconomic status (SES) on cancer mortality has been elucidated in adult patients, but is not well described in pediatric oncology. We hypothesize that racial and socioeconomic disparities exist in pediatric cancer patients, resulting in higher rates of hospitalization and mortality. Methods: We analyzed the Kids’ Inpatient Database (KID) which shows national estimates of inpatient stays for pediatric patients. Inclusion criteria included patients who were ≤20 with a cancer diagnosis identified through the Clinical Classifications Software (CCS). Variables analyzed were discharge status, patient demographics, hospital characteristics, expected payment source, total visit charge, and length of stay. Initial comparisons between cancer and non-cancer related discharges were performed using a chi-square test. To estimate disparities by race, clinical comparisons were performed across five racial groups: White, Black, Hispanic, Asian/Pacific Islander, and Native American/Other. A multivariable logistic regression model was used to examine predictors of hospitalization and mortality. Results: From 2006-2012, there were 9,488,477 non-cancer related pediatric inpatient stays and 242,489 cancer related stays. Patients with cancer related visits were more likely to be white, male (54.9% vs 46.1%, p < 0.0001), older at admission, have private insurance (52.5% vs 41.7%), and were from a higher income quartile (76th-100th percentile, 25.2% vs 19.9%, p < 0.001). These patients also had a higher rate of death during admission (1.2% vs 0.5%, p < 0.0001), higher cost of visit charge ($25,097 vs $8,267, p < 0.001), longer length of stay (4 vs 2 days), and were less likely to be discharged (85.5% vs 92.0%, p < 0.0001).The four most frequent cancer diagnoses associated with hospital admission were leukemia (n = 75,807), Other and Unspecified Primary (n = 50,076), bone/connective tissue tumor (n = 42,477), and central nervous system tumor (n = 27,958). Patients who were non-white were more likely to die during their inpatient stay (1.5% Non-white versus 0.9% White, p < 0.001). On multivariate logistic regression, Black (OR: 1.61, 95% CI: 1.57-1.66, p < 0.0001) and Native American (OR: 1.39, 95% CI: 1.34-1.44, p < 0.0001) race, as well as lower income quartile (OR: 1.24, 95% CI: 1.19-1.28, p < 0.001) were associated with increased odds of death during admission. Conclusions: This is the largest observational study to date to identify the impact of race and SES on pediatric cancer hospitalization and mortality in the United States. Non-white race and lower SES was associated with significantly increased odds of death during admission. Given the significant difference in mortality by race, healthcare policy makers and insurance companies should investigate the specific drivers of increased admission and mortality and develop strategies to address inequity in cancer care.

Protein investment costs are considered a major driver for the choice of alternative metabolic strategies. We tested this premise in Lactococcus lactis, a bacterium that exhibits a distinct, anaerobic version of the bacterial Crabtree/Warburg effect; with increasing growth rates it shifts from a high yield metabolic mode [mixed-acid fermentation; 3 adenosine triphosphate (ATP) per glucose] to a low yield metabolic mode (homolactic fermentation; 2 ATP per glucose). We studied growth rate-dependent relative transcription and protein ratios, enzyme activities, and fluxes of L. lactis in glucose-limited chemostats, providing a high-quality and comprehensive data set. A three- to fourfold higher growth rate rerouted metabolism from acetate to lactate as the main fermentation product. However, we observed hardly any changes in transcription, protein levels and enzyme activities. Even levels of ribosomal proteins, constituting a major investment in cellular machinery, changed only slightly. Thus, contrary to the original hypothesis, central metabolism in this organism appears to be hardly regulated at the level of gene expression, but rather at the metabolic level. We conclude that L. lactis is either poorly adapted to growth at low and constant glucose concentrations, or that protein costs play a less important role in fitness than hitherto assumed.

Transfer RNAs (tRNAs) through their abundance and modification pattern significantly influence protein translation. Here, we present a systematic analysis of the tRNAome of Lactococcus lactis. Using the next-generation sequencing approach, we identified 40 tRNAs which carry 16 different post-transcriptional modifications as revealed by mass spectrometry analysis. While small modifications are located in the tRNA body, hypermodified nucleotides are mainly present in the anticodon loop, which through wobbling expand the decoding potential of the tRNAs. Using tRNA-based microarrays, we also determined the dynamics in tRNA abundance upon changes in the growth rate and heterologous protein overexpression stress. With a fourfold increase in the growth rate, the relative abundance of tRNAs cognate to low abundance codons decrease, while the tRNAs cognate to major codons remain mostly unchanged. Significant changes in the tRNA abundances are observed upon protein overexpression stress, which does not correlate with the codon usage of the overexpressed gene but rather reflects the altered expression of housekeeping genes.

Summary Dimerization and inactivation of ribosomes in Escherichia coli is a two-step process that involves the binding of ribosome modulation factor (RMF) and hibernation promotion factor (HPF). Lactococcus lactis MG1363 expresses a protein, YfiALl, which associates with ribosomes in the stationary phase of growth and is responsible for dimerization of ribosomes. We show that full-length YfiALl is necessary and sufficient for ribosome dimerization in L. lactis but also functions heterologously in vitro with E. coli ribosomes. Deletion of the yfiA gene has no effect on the growth rate but diminishes the survival of L. lactis under energy-starving conditions. The N-terminal domain of YfiALl is homologous to HPF from E. coli, whereas the C-terminal domain has no counterpart in E. coli. By assembling ribosome dimers in vitro, we could dissect the roles of the N- and C-terminal domains of YfiALl. It is concluded that the dimerization and inactivation of ribosomes in L. lactis and E. coli differ in several cellular and molecular aspects. In addition, two-dimensional maps of dimeric ribosomes from L. lactis obtained by single particle electron microscopy show a marked structural difference in monomer association in comparison to the ribosome dimers in E. coli.

Appropriate use criteria (AUC) for coronary revascularization have been developed to provide a practical standard to assess the quality of patient selection for percutaneous coronary interventions (PCI). However, the economic impact of AUC implementation has yet to be quantified. A peer-reviewed AUC process was implemented at UnityPoint Trinity in February 2012. Volumes of PCI cases were measured in 12-month intervals for 2 years after AUC implementation and compared with volumes from the corresponding 12-month intervals in the 2 years preceding implementation of AUC. Hospital reimbursement was averaged based on each year's payer mix and reimbursement contracts. In the 2 years preceding AUC implementation, PCI volumes were similar (1,414 in 2010 and 1,411 in 2011). After AUC implementation, volumes of PCI decreased by 17% in both 2012 and 2013. From 2012 to 2013, the relative ratio of elective to acute interventions decreased from 1.36 to 1.02. In the same time frame, the proportion of appropriate PCI significantly increased from 76% to 84% (p

Protein investment costs are considered a major driver for the choice of alternative metabolic strategies. We tested this premise in Lactococcus lactis, a bacterium that exhibits a distinct, anaerobic version of the bacterial Crabtree/Warburg effect; with increasing growth rates it shifts from a high yield metabolic mode [mixed-acid fermentation; 3 adenosine triphosphate (ATP) per glucose] to a low yield metabolic mode (homolactic fermentation; 2 ATP per glucose). We studied growth rate-dependent relative transcription and protein ratios, enzyme activities, and fluxes of L. lactis in glucose-limited chemostats, providing a high-quality and comprehensive data set. A three- to fourfold higher growth rate rerouted metabolism from acetate to lactate as the main fermentation product. However, we observed hardly any changes in transcription, protein levels and enzyme activities. Even levels of ribosomal proteins, constituting a major investment in cellular machinery, changed only slightly. Thus, contrary to the original hypothesis, central metabolism in this organism appears to be hardly regulated at the level of gene expression, but rather at the metabolic level. We conclude that L. lactis is either poorly adapted to growth at low and constant glucose concentrations, or that protein costs play a less important role in fitness than hitherto assumed.

Acetate kinase (ACK) converts acetyl phosphate to acetate along with the generation of ATP in the pathway for mixed-acid fermentation in Lactococcus lactis . The reverse reaction yields acetyl phosphate for assimilation purposes. Remarkably, L. lactis has two ACK isozymes, and the corresponding genes are present in an operon. We purified both enzymes (AckA1 and AckA2) from L. lactis MG1363 and determined their oligomeric state, specific activities, and allosteric regulation. Both proteins form homodimeric complexes, as shown by size exclusion chromatography and static light-scattering measurements. The turnover number of AckA1 is about an order of magnitude higher than that of AckA2 for the reaction in either direction. The K m values for acetyl phosphate, ATP, and ADP are similar for both enzymes. However, AckA2 has a higher affinity for acetate than does AckA1, suggesting an important role under acetate-limiting conditions despite the lower activity. Fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, and phospho- enol -pyruvate inhibit the activities of AckA1 and AckA2 to different extents. The allosteric regulation of AckA1 and AckA2 and the pool sizes of the glycolytic intermediates are consistent with a switch from homolactic to mixed-acid fermentation upon slowing of the growth rate.

Dimerization and inactivation of ribosomes in Escherichia coli is a two-step process that involves the binding of ribosome modulation factor (RMF) and hibernation promotion factor (HPF). Lactococcus lactis MG1363 expresses a protein, YfiA(L) (l) , which associates with ribosomes in the stationary phase of growth and is responsible for dimerization of ribosomes. We show that full-length YfiA(L) (l) is necessary and sufficient for ribosome dimerization in L. lactis but also functions heterologously in vitro with E. coli ribosomes. Deletion of the yfiA gene has no effect on the growth rate but diminishes the survival of L. lactis under energy-starving conditions. The N-terminal domain of YfiA(L) (l) is homologous to HPF from E. coli, whereas the C-terminal domain has no counterpart in E. coli. By assembling ribosome dimers in vitro, we could dissect the roles of the N- and C-terminal domains of YfiA(L) (l) . It is concluded that the dimerization and inactivation of ribosomes in L. lactis and E. coli differ in several cellular and molecular aspects. In addition, two-dimensional maps of dimeric ribosomes from L. lactis obtained by single particle electron microscopy show a marked structural difference in monomer association in comparison to the ribosome dimers in E. coli.

Nationally, more than $10 billion is spent annually on Percutaneous Coronary Interventions (PCI). The ACC developed an Appropriate Use Criteria (AUC) for coronary revascularization in an attempt to curb rising healthcare costs and to assist both clinicians and patients in choosing the best procedure

Energy coupling factor (ECF) proteins are ATP-binding cassette transporters involved in the import of micronutrients in prokaryotes. They consist of two nucleotide-binding subunits and the integral membrane subunit EcfT, which together form the ECF module and a second integral membrane subunit that captures the substrate (the S component). Different S components, unrelated in sequence and specific for different ligands, can interact with the same ECF module. Here, we present a high-resolution crystal structure at 2.1 Å of the biotin-specific S component BioY from Lactococcus lactis . BioY shares only 16% sequence identity with the thiamin-specific S component ThiT from the same organism, of which we recently solved a crystal structure. Consistent with the lack of sequence similarity, BioY and ThiT display large structural differences (rmsd = 5.1 Å ), but the divergence is not equally distributed over the molecules: The S components contain a structurally conserved N-terminal domain that is involved in the interaction with the ECF module and a highly divergent C-terminal domain that binds the substrate. The domain structure explains how the S components with large overall structural differences can interact with the same ECF module while at the same time specifically bind very different substrates with subnanomolar affinity. Solitary BioY (in the absence of the ECF module) is monomeric in detergent solution and binds D-biotin with a high affinity but does not transport the substrate across the membrane.

The identification of proteins in proteomics experiments is usually based on mass information derived from tandem mass spectrometry data. To improve the performance of the identification algorithms, additional information available in the fragment peak intensity patterns has been shown to be useful. In this study, we consider the effect of iTRAQ labeling on the fragment peak intensity patterns of singly charged peptides from MALDI tandem MS data. The presence of an iTRAQmodified basic group on the N-terminus leads to a more pronounced set of b-ion peaks and distinct changes in the abundance of specific peptide types. We performed a simple intensity prediction by using a decision-tree machine learning approach and were able to show that the relative ion abundance in a spectrum can be correctly predicted and distinguished from closely related sequences. This information will be useful for the development of improved method-specific intensity-based protein identification algorithms.

Background The control of antibiotic production in Streptomyces coelicolor A3(2) involves complicated regulatory networks with multiple regulators controlling the expression of antibiotic biosynthetic pathways. One such regulatory network is that of the γ-butyrolactones, the so-called S. coelicolor butanolide (SCB) system. The γ-butyrolactones in this system serve as signalling molecules and bind to the receptor protein ScbR, releasing the repression of its target genes. The resulting expression changes affect the production of the two pigmented antibiotics Act and Red, as well as the transcription of the cpk antibiotic biosynthesis gene cluster and the synthesis of the γ-butyrolactones themselves. Results We identified a natural variant of ScbR in S. coelicolor (ScbRM600) that differs from ScbR in the genome-sequenced strain M145 (ScbRM145) by a single amino acid change, R120S. ScbRM600 is impaired in its DNA binding ability and alters the expression of the pathway-specific regulatory genes of the red and cpk antibiotic biosynthesis gene clusters. Also, expression of the γ-butyrolactone biosynthesis gene scbA and production of the signalling molecules is slightly reduced. Conclusions The γ-butyrolactone receptor, ScbR, plays a key role in the SCB regulatory cascade and in determining the onset of the expression of the antibiotic regulatory genes.