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The proinflammatory state associated with diabetes mellitus (DM) remains poorly understood. We found patients with DM have 3- to 14-fold elevations of blood-borne microparticles (MPs) that bind phalloidin (Ph; Ph positive [+] MPs), indicating the presence of F-actin on their surface. We hypothesized that F-actin–coated MPs were an unrecognized cause for DM-associated proinflammatory status. Ph+MPs, but not Ph-negative MPs, activate human and murine (Mus musculus) neutrophils through biophysical attributes of F-actin and membrane expression of phosphatidylserine (PS). Neutrophils respond to Ph+MPs via a linked membrane array, including the receptor for advanced glycation end products and CD36, PS-binding membrane receptors. These proteins in conjunction with TLR4 are coupled to NO synthase 1 adaptor protein (NOS1AP). Neutrophil activation occurs because of Ph+MPs causing elevations of NF-κB and Src kinase (SrcK) via a concurrent increased association of NO synthase 2 and SrcK with NOS1AP, resulting in SrcK S-nitrosylation. We conclude that NOS1AP links PS-binding receptors with intracellular regulatory proteins. Ph+MPs are alarmins present in normal human plasma and are increased in those with DM and especially those with DM and a lower-extremity ulcer.

Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in “remission” (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 ∼ 2DS4*001:01 ∼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.

The burnout literature is replete with burnout score results from quantitative surveys. There is a paucity of qualitative research that seeks to understand the impact of physician stressors on work-life balance and burnout. This study aimed to identify factors that support and disrupt work-life balance, drivers of burnout, and potential solutions among academic dermatologists. The objective was to better understand factors that promote wellness and ameliorate burnout. Concurrent explanatory mixed methods consisted of scores on the Abbreviated Maslach Burnout Inventory and open-ended semi-structured telephone interviews. The results were that positive factors, such as supportive home life and satisfaction derived from academic endeavors, compete with ongoing feelings of exhaustion, frustration, and apathy. Negative stressors include the electronic medical record, insufficient staffing, administrative and clinical task burden, and perceived lack of interest from mid-level and senior health system leadership in addressing clinicians' needs. This was a single-center academic study. As with all qualitative studies, these results may not be generalizable to all dermatologists. In addition, some participants were concerned about their anonymity. Modifiable root causes of burnout require institutional commitment to sustain the pace required by academic dermatologists.

ImportanceKeratinocyte carcinomas are the most common cancers in the US. However, keratinocyte carcinomas are not included in US national cancer registries, and information on the anatomic locations of keratinocyte carcinomas is lacking.ObjectiveTo investigate the anatomic location of keratinocyte carcinomas in the US using a large claims data set.Design, Setting, and ParticipantsWe performed a cohort study using a deidentified, random sample of 4 999 999 fee-for-service Medicare beneficiaries aged 65 years or older (2009-2018).Main Outcomes and MeasuresProportion of procedurally treated keratinocyte carcinomas at each anatomic location, identified by linking diagnosis and treatment codes.ResultsA total of 2 415 514 keratinocyte carcinomas were identified in 792 393 beneficiaries. The mean (SD) age was 76.6 (8.1) years, 410 364 (51.8%) were women, and 96.7% were White. Of the 2 415 514 keratinocyte carcinomas, 796 542 could be subtyped into basal cell carcinoma (33.0%), 927 984 into squamous cell carcinoma (38.4%), and 690 988 (28.6%) could not be subtyped. The most common location of squamous cell carcinomas was the head and/or neck (44.3%) followed by upper limbs (26.7%). The most common location of basal cell carcinomas was head and/or neck (63.8%), followed by trunk (14.9%). In women, keratinocyte carcinomas were most common on the head and/or neck (47.3%) followed by upper and lower limb (18.5% and 16.6%, respectively). In men, keratinocyte carcinomas were most common on the head and/or neck (58.7%) followed by upper limb and trunk (17.3% and 11.4%, respectively).Conclusions and RelevanceThe results of this large Medicare cohort study highlight the anatomic locations of keratinocyte carcinomas over recent years and show the predominance of lesions occurring at head and/or neck anatomic location. This foundational information on keratinocyte carcinoma anatomic locations in the US is valuable for improved keratinocyte risk factor differentiation and skin cancer surveillance.

Central centrifugal cicatricial alopecia (CCCA) is a common cause of hair loss among patients of African and/or Caribbean descent, and there is little data exploring the quality of life of patients with this condition. This pilot demonstrates that CCCA has a significant impact on overall quality of life, and patients may benefit from resources to address psychosocial aspects of this diagnosis.

Mitochondrial defects are a hallmark of early pathophysiology in Alzheimer’s disease, with pathologically phosphorylated tau reported to induce mitochondrial toxicity. Mitophagy constitutes a key pathway in mitochondrial quality control by which damaged mitochondria are targeted for autophagy. However, few details are known regarding the intersection of mitophagy and pathologies in tauopathy. Here, by applying biochemical and cell biological approaches including time-lapse confocal imaging in live tauopathy neurons, combined with gene rescue experiments via stereotactic injections of adeno-associated virus particles into tauopathy mouse brains, electrophysiological recordings and behavioural tests, we demonstrate for the first time that mitochondrial distribution deficits at presynaptic terminals are an early pathological feature in tauopathy brains. Furthermore, Parkin-mediated mitophagy is extensively activated in tauopathy neurons, which accelerates mitochondrial Rho GTPase 1 (Miro1) turnover and consequently halts Miro1-mediated mitochondrial anterograde movement towards synaptic terminals. As a result, mitochondrial supply at tauopathy synapses is disrupted, impairing synaptic function. Strikingly, increasing Miro1 levels restores the synaptic mitochondrial population by enhancing mitochondrial anterograde movement and thus reverses tauopathy-associated synaptic failure. In tauopathy mouse brains, overexpression of Miro1 markedly elevates synaptic distribution of mitochondria and protects against synaptic damage and neurodegeneration, thereby counteracting impairments in learning and memory as well as synaptic plasticity. Taken together, our study reveals that activation of the Parkin pathway triggers an unexpected effect—depletion of mitochondria from synaptic terminals, a characteristic feature of early tauopathy. We further provide new mechanistic insights into how parkin activation-enhanced Miro1 degradation and impaired mitochondrial anterograde transport drive tauopathy-linked synaptic pathogenesis and establish a foundation for future investigations into new therapeutic strategies to prevent synaptic deterioration in Alzheimer’s disease and other tauopathies.

The anterior dorsolateral striatum (DLS) is heavily innervated by convergent excitatory projections from the primary motor (M1) and sensory cortex (S1) and is considered an important site of sensorimotor integration. M1 and S1 corticostriatal synapses have functional differences in the strength of their connections with striatal spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in the DLS, and as a result exert an opposing influence on sensory-guided behaviors. In the present study, we tested whether M1 and S1 inputs exhibit differences in the subcellular anatomical distribution onto striatal neurons. We injected adeno-associated viral vectors encoding spaghetti monster fluorescent proteins (sm.FPs) into M1 and S1, and used confocal microscopy to generate 3D reconstructions of corticostriatal inputs to single identified SPNs and FSIs obtained through ex-vivo patch-clamp electrophysiology. We found that SPNs are less innervated by S1 compared to M1, but FSIs receive a similar number of inputs from both M1 and S1. In addition, M1 and S1 inputs were distributed similarly across the proximal, medial, and distal regions of SPNs and FSIs. Notably, clusters of inputs were prevalent in SPNs but not FSIs. Our results suggest that SPNs have stronger functional connectivity to M1 compared to S1 due to a higher density of synaptic inputs. The clustering of M1 and S1 inputs onto SPNs but not FSIs suggest that cortical inputs are integrated through cell-type specific mechanisms and more generally have implications for how sensorimotor integration is performed in the striatum.Significance StatementThe dorsolateral striatum (DLS) is a key brain area involved in sensorimotor integration due to its dense innervation by the primary motor (M1) and sensory cortex (S1). However, the quantity and anatomical distribution of these inputs to the striatal cell population has not been well characterized. In this study we demonstrate that corticostriatal projections from M1 and S1 differentially innervate spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in the DLS. S1 inputs innervate SPNs less than M1 and are likely to form synaptic clusters in SPNs but not in FSIs. These findings suggest that sensorimotor integration is partly achieved by differences in the synaptic organization of corticostriatal inputs to local striatal microcircuits.

BackgroundThe inappropriate use of antibiotics is understood to contribute to antimicrobial resistance. Oral antibiotics are regularly used to treat moderate-to-severe acne vulgaris. In practice, we do not know the typical length of oral antibiotic treatment courses for acne in routine primary care and what proportion of people receive more than one course of treatment following a new acne diagnosis.ObjectivesTo describe how oral antibiotics are prescribed for acne over time in UK primary care.MethodsWe conducted a descriptive longitudinal drug utilization study using routinely collected primary care data from the Clinical Practice Research Datalink GOLD (2004–2019). We included individuals (8–50 years) with a new acne diagnosis recorded between 1 January 2004 and 31 July 2019.ResultsWe identified 217 410 people with a new acne diagnosis. The median age was 17 years [interquartile range (IQR) 15–25] and median follow-up was 4.3 years (IQR 1.9–7.6). Among people with a new acne diagnosis, 96 703 (44.5%) received 248 560 prescriptions for long-term oral antibiotics during a median follow-up of 5.3 years (IQR 2.8–8.5). The median number of continuous courses of antibiotic therapy (≥ 28 days) per person was four (IQR 2–6). The majority (n = 59 010, 61.0%) of first oral antibiotic prescriptions in those with a recorded acne diagnosis were between the ages of 12 and 18. Most (n = 71 544, 74.0%) first courses for oral antibiotics were for between 28 and 90 days. The median duration of the first course of treatment was 56 days (IQR 50–93 days) and 18 127 (18.7%) of prescriptions of ≥ 28 days were for < 6 weeks. Among people who received a first course of oral antibiotic for ≥ 28 days, 56 261 (58.2%) received a second course after a treatment gap of ≥ 28 days. The median time between first and second courses was 135 days (IQR 67–302). The cumulative duration of exposure to oral antibiotics during follow-up was 255 days (8.5 months).ConclusionsFurther work is needed to understand the consequences of using antibiotics for shorter periods than recommended. Suboptimal treatment duration may result in reduced clinical effectiveness or repeated exposures, potentially contributing to antimicrobial resistance.

DPA1*01:03:01:57 and DPA1*02:01:01:29 differ by a single nucleotide from their closest references, DPA1*01:03:01:02 and DPA1*02:01:01:06.

OBJECTIVE: The goal of this study was to evaluate whether circulating endothelial precursor cells (CEPCs) and neutrophil microparticles (MP) can predict diabetic foot ulcer healing. RESEARCH DESIGN AND METHODS: A multicenter study was designed to evaluate circulating cellular markers, CEPCs and MPs, as prognostic factors associated with the healing of DFU by the 16(th) week of care. Flow cytometry analysis of CEPCS and MPs were obtained at the first visit and compared to wound healed status. RESULTS: 207 subjects were enrolled at four sites. 40.0% (28.4,41.5) of the subjects healed by the 16(th) week of care. Several CEPCs measured were associated with healing after adjustment for wound area and wound duration. Typical of this analysis was CD34(+)CD45(dim), the univariate OR was 1.19(0.88,1.61) and after adjustment for wound area and wound duration the OR was 1.67(1.16,2.42) p=0.006). A prognostic model with CEPCs CD34(+) CD45(dim), wound area, and wound duration had an area under the curve (AUC) of 0.75(0.67, 0.82) and, simpler, CD34(+) CD45(dim) per initial wound area, as a solitary predictor, has an AUC of 0.72 (0.64, 0.79). MPs were not associated with a healed wound. CONCLUSIONS: Previous studies have indicated that CEPCs measured at the first office visit are associated with a healed DFU. In this multi-centered prospective study, we confirm this finding, show the importance of adjusting CEPCs measurements by wound are, and show that a single number based on CEPCs per wound area is highly predictive of a healed DFU by 16(th) week of care.

Atopic dermatitis (AD) is a chronic, inflammatory skin condition with a multifactorial pathophysiology. The filaggrin gene (FLG) has particularly been implicated given loss of function (LoF) mutations in this gene lead to skin barrier dysfunction and such mutations can increase a patient's likelihood of developing AD. FLG has intragenic copy number variation (CNV) which impacts the total amount of filaggrin produced. Previous research reported a dose-dependent effect such that as amount of FLG increases, risk of AD decreases. To gain a better understanding, we evaluated FLG CNV in a large case-control study of Whites and Blacks with and without AD. The goal of our study was to determine if FLG CNV has a dose-dependence effect on the risk of developing AD as well as to determine if FLG CNV varies by race. The frequencies as well as odd ratios comparing a given CNV by race or race within those with AD did not significantly vary. It had been thought that FLG CNV might vary by race and represent an important association with AD in Black AD subjects. However, our work suggests that while there are racial differences with respect to CNV, these differences do not appear to explain AD risk.

Atopic Dermatitis (AD) is a chronic, inflammatory skin condition that imposes an enormous personal and economic burden in the United States. Due to the ubiquity of the use of electronic medical records (EMR) in the United States, utilizing such data is critically important to studying common dermatologic diseases, such as AD. Our goal was to create a simple-to-use algorithm applied to EMR data to accurately identify AD patients thereby making it possible to efficiently use EMR data to ascertain and then study individuals with AD. Our results suggest that the algorithm that is most likely to accurately identify AD patients from the EMR based on PPV utilizes ICD-10 code for L20.89, L20.9, or L20.84 in conjunction with a diagnosis code for asthma or allergic rhinitis, treatment code, and dermatology consult code. This approach yields a PPV of 95.00% in our training cohort and 100.00% in our validation cohort. Therefore, future studies can use this algorithm to better assure that a subject has AD for studies of the pathogenesis and/or potential treatment targets of AD.

Atopic dermatitis (AD) is a disease of immune dysregulation and skin barrier dysfunction with a relapsing, remitting course and has been associated with several different genetic risk variants. HLA represent a highly variable set of genes that code for cell surface protein molecules involved in the Ag-specific immune response, including the regulation or functioning of T cells, NK cells, and APCs. The purpose of this study was to evaluate associations between HLA class I polymorphisms and the progression of AD over time. We evaluated the associations of AD symptoms and HLA class I polymorphisms based on high-resolution two-field typing in a longitudinal cohort of children with AD (up to 10 y of follow-up). Seven hundred and ninety-two children were evaluated every 6 mo, resulting in 12,752 AD evaluations. Using generalized estimating equations and corrected p values, B*44:02 was found to be associated with AD remission (1.83 [1.35, 2.47]; p = 0.0015). The HLA-B residues at position 116 (d-aspartate) and 80 (T-threonine) were associated with remission (1.42 [1.13, 1.76], p = 0.003; corrected p = 0.028) and (1.45 [1.17, 1.80], p = 0.0008; corrected p = 0.0024), respectively. B80T is a killer-cell Ig-like receptor (KIR) site. Our findings reveal that two axes of immune response (T cell and NK cell) may influence disease progression. Identifying binding pocket changes in addition to other factors (e.g., allergens) that increase the risk or severity of AD can improve our understanding of the immunologic mechanisms associated with AD and may lead to personalized therapies for improving patient care.

Objective. Early diagnosis of mild traumatic brain injury (mTBI) is challenging, yet crucial for providing patients with timely treatments and minimizing the risks of developing injury-related disorders. To tackle this problem, this paper presents a framework based on measures of frequency-specified brain functional networks identifying mTBI. Approach. Cortical activity of 15 control and 15 injury Thy1-GCaMP6s mice are recorded, using widefield calcium imaging, prior to and 20 minutes after inducing injury. Power spectral distribution (PSD) of the recorded cortical activities is examined, and the frequency bands with significant difference in PSD between the injury and control groups are identified. Frequency-specified functional networks are then constructed. Employing graph theoretical analysis, various network measures from the constructed frequency-specified functional networks are extracted and used as features. Several classifiers are utilized to evaluate the performance of the computed network measures, either individually or collectively as features, to classify mTBI from control. Main results. Spectral analysis reveals the presence of two dominant frequency bands (low: < 1 Hz) and high: [1–8] Hz) in the cortical activities recorded via calcium imaging. Comparison of the brain networks of control and injury groups shows significant reduction (p Significance. Results signifies the importance of considering frequency-specific analysis in functional networks for mTBI identification, and demonstrate the possibility of using network measures for early mTBI diagnosis.

Diabetic foot ulcers (DFU) are a critical problem for those with diabetes mellitus. Predicting the healing likelihood of a DFU is important to implementing appropriate care, allocating resources, having access to advanced therapies, having successful clinical trials, calibrating clinical trial results, and providing information to administrative entities on patient and provider outcomes. Prognostic modeling can also be important when attempting to compare results across trials or care centers. In a prospective cohort study, we demonstrate and replicate that simple wound characteristics like wound area and wound duration can be used to predict wound healing by the 16(th) week of care. The models were based on previous literature and replicated using a machine learning algorithm. The use of wound duration and wound area in a prognostic model continues to be important when comparing study results, center-based outcomes, as well as designing clinical trials.

Background Skin diseases, such as psoriasis, hidradenitis suppurativa, acne, and alopecia areata, have increasingly been linked to systemic and mental health comorbidities, such as depression. Although identification and management of these comorbidities is typically a part of primary care, some patients might not have an established relationship with a primary care provider and may only be seeing their dermatologist. Objective To examine the frequency with which dermatologists are the main contact within a health care system for patients with these chronic skin conditions. Methods We performed a retrospective cohort study using Optum's deidentified Clinformatics Data Mart Database. The primary outcome was the proportion of patients who established care with a dermatologist and had no encounters with a primary care provider during the subsequent year after this dermatology encounter. Results Across each of the skin diseases evaluated, 21.6%-31.2% of men and 16.9%-26.2% of women had no primary care visits in the subsequent year after establishing care with their dermatologist. Conclusion and Relevance For many patients with chronic skin diseases, their dermatologist might be their only source of contact with the health care system. There may be an opportunity for dermatologists to improve the quality of care for our patients by screening for associated comorbidities.

PURPOSE OF REVIEW: Mutations in the Filaggrin gene can cause absent or reduced filaggrin protein, leading to impaired keratinization and skin barrier defect, which produce characteristic phenotypes. In this short review, we report current evidence on the topic with special reference to atopic dermatitis, suggest future directions, and discuss therapeutic implications. RECENT FINDINGS: Numerous candidate gene association studies, genome-wide association studies, studies on copy number variations and most recently, sequencing studies, have confirmed the robust association of mutations in the Filaggrin gene with atopic dermatitis, and have also linked these mutations with several other disorders. SUMMARY: Filaggrin gene defects remain the strongest identified genetic risk factors for atopic dermatitis. Taken in conjunction with other genes found to be associated with this condition, genetic screening and identification of individuals at risk for atopic dermatitis could lead to personalized therapy. Manipulation of genetic regulatory elements to increase the amount of filaggrin protein in deficient individuals is an attractive treatment option for the future.

OBJECTIVE: To evaluate the association of different contraceptive methods on the incidence and severity of acne. METHODS: Using a de-identified commercial claims database, we performed a retrospective cohort study evaluating the incidence of clinical encounters for acne in the first year after initiation of contraception among female patients aged 12–40 years who were new contraceptive users. To evaluate the association of contraception class with acne severity, a subgroup analysis was performed among a cohort of patients with a history of acne examining the incidence of treatment escalation from topical acne medications to an oral tetracycline-class antibiotic in the year after initiation of contraception. RESULTS: Among new contraceptive users with no history of acne (n=336,738), compared to combined oral contraceptives, the copper intrauterine device (HR 1.14; 95% CI 1.01–1.29) and levonorgestrel intrauterine devices (HR 1.09; 95% CI 1.03–1.16) were associated with increased risk of clinical encounters with for acne. Among those with a history of acne (n=21,178), compared to combined oral contraceptives, the copper intrauterine device (HR 1.44; 95% CI 1.00–2.06) and levonorgestrel intrauterine devices (HR 1.34; 95% CI 1.10–1.64) were associated with increased risk of treatment escalation from topical acne medications to an oral tetracycline class antibiotic. CONCLUSION: Combined oral contraceptives appear to be associated with a modest (or small) protective effect with respect to incident acne and treatment escalation compared to other contraceptive methods. However, absolute differences between contraceptive methods were small.

Data collected from standardized clinical practices can be valuable in evaluating the real-world therapeutic benefit of skin substitutes in the treatment of venous leg ulcers (VLU). Utilizing such a dataset, this study aimed to validate the effectiveness of a bioactive human split-thickness skin allograft for the treatment of VLU in the real-world setting and to understand how certain variables impacted healing rates. From a pool of 1474 VLU treated with allograft, 862 ulcers in 742 patients were selected from a large wound EMR database and analyzed. All patients received standard wound care prior to allograft application. Impact of ulcer duration, number of applications, ulcer size, and time to application were analyzed. The VLU, on average, were of 189 days duration with a mean ulcer size of 19.3 cm2 . During treatment, 70.7% of wounds healed, with an average time to closure of 15 weeks (SD = 14.1 weeks). The percentage of VLU less than one-year duration that healed was significantly higher (72.3%) than the percentage of VLU with duration of greater than 1 years (51.5%) ( χ2 = 18.17; P < .001). Ulcers less than 10 cm2 in size were more likely to heal (73.9%) than those larger than 10 cm2 (67.9%) ( χ2 = 8.65, P = .03). VLU receiving allograft within 90 days of initial presentation are 1.4 times more likely to heal vs those receiving their first BSA application after 90 days of standard of care (95% CI: [1.05, 1.86], P = .02). Allograft used in wound clinics healed a majority of refractory VLU, even in large ulcers of long duration, which are more difficult to heal. Smaller wound, size, and shorter wound duration were associated with greater likelihood of healing. VLUs treated earlier with allograft had better healing outcomes. Clinicians may consider more aggressive and timely treatment with allograft for refractory VLU.

Atopic dermatitis (AD) is a skin disease that results from a combination of skin barrier dysfunction and immune dysregulation. The immune dysregulation is often associated with IgE sensitivity. There is also evidence that autoallergens Hom s 1, 2, 3, and 4 play a role in AD; it is possible that patients with specific HLA subtypes are predisposed to autoreactivity due to increased presentation of autoallergen peptides. The goal of our study was to use in silico epitope prediction platforms as an approach to identify HLA subtypes that may preferentially bind autoallergen peptides and are thus candidates for further study. Considering the previously described association of DRB1 alleles with AD and progression of disease, emphasis was placed on DRB1. Certain DRB1 alleles (08:04, 11:01, and 11:04) were identified by both algorithms to bind a significant percent of the generated autoallergen peptides. Conversely, autoallergen core peptide sequences FRQLSHRFH and IRAKLRLQA (Hom s 1), IRKSKNILF (Hom s 2), FKWVPVTDS and MAAIEKVRK (Hom s 3), and FRYFATLKV (Hom s 4) were predicted to bind many DRB1 alleles and, thus, may play a role in the pathogenesis of AD. Our findings provide candidate DRB1 alleles and autoallergen epitopes that will guide future studies exploring the relationship between DRB1 subtype and autoreactivity in AD. A similar approach can be used for any antigen that has been associated with an IgE response and AD.

Fundamental aspects of brain function, including development, plasticity, learning, and memory, can take place over time scales of days to years. Chronic in vivo imaging of neural activity with cellular resolution is a powerful method for tracking the long-term activity of neural circuits. We review recent advances in our understanding of neural circuit function from diverse brain regions that have been enabled by chronic in vivo cellular imaging. Insight into the neural basis of learning and decision-making, in particular, benefit from the ability to acquire longitudinal data from genetically identified neuronal populations, deep brain areas, and subcellular structures. We propose that combining chronic imaging with further experimental and computational innovations will advance our understanding of the neural circuit mechanisms of brain function.

Background As a result of concerns about hypertriglyceridemia, liver enzyme abnormalities, and leukopenia during isotretinoin therapy for acne, patients are often monitored closely with routine laboratory assessments, although the value of this practice has been questioned. Methods We conducted a cohort study of patients receiving isotretinoin for acne between January 1, 2008, and June 30, 2017, using the OptumInsights Electronic Health Record Database (Optum, Eden Prairie, MN) to evaluate the frequency of laboratory abnormalities. Poisson regression was used to evaluate for changes to the frequency of routine laboratory monitoring over time. Results Among 1863 patients treated with isotretinoin, grade 3 or greater triglyceride and liver function testing abnormalities were noted in fewer than 1% and 0.5% of patients screened, respectively. No grade 3 or greater cholesterol or complete blood count abnormalities were observed. There were no meaningful changes in the frequency of laboratory monitoring over time. Limitations Limitations include that we are unable to evaluate the clinical notes to understand the exact clinical decision making when clinicians encountered abnormal laboratory values. Conclusion Although laboratory abnormalities are rare and often do not influence management, frequent laboratory monitoring remains a common practice. There are opportunities to improve the quality of care among patients being treated with isotretinoin for acne by reducing the frequency of lipid and liver function monitoring and by eliminating complete blood count monitoring.

Immediate-early gene (IEG) expression has been used to identify small neural ensembles linked to a particular experience, based on the principle that a selective subset of activated neurons will encode specific memories or behavioral responses. The majority of these studies have focused on “engrams” in higher-order brain areas where more abstract or convergent sensory information is represented, such as the hippocampus, prefrontal cortex, or amygdala. In primary sensory cortex, IEG expression can label neurons that are responsive to specific sensory stimuli, but experience-dependent shaping of neural ensembles marked by IEG expression has not been demonstrated. Here, we use a fosGFP transgenic mouse to longitudinally monitor in vivo expression of the activity-dependent gene c-fos in superficial layers (L2/3) of primary somatosensory cortex (S1) during a whisker-dependent learning task. We find that sensory association training does not detectably alter fosGFP expression in L2/3 neurons. Although training broadly enhances thalamocortical synaptic strength in pyramidal neurons, we find that synapses onto fosGFP+ neurons are not selectively increased by training; rather, synaptic strengthening is concentrated in fosGFP− neurons. Taken together, these data indicate that expression of the IEG reporter fosGFP does not facilitate identification of a learning-specific engram in L2/3 in barrel cortex during whisker-dependent sensory association learning.