Surface NMR using quantum sensors in diamond.

NMR is a noninvasive, molecular-level spectroscopic technique widely used for chemical characterization. However, it lacks the sensitivity to probe the small number of spins at surfaces and interfaces. Here, we use nitrogen vacancy (NV) centers in diamond as quantum sensors to optically detect NMR signals from chemically modified thin films. To demonstrate the method's capabilities, aluminum oxide layers, common supports in catalysis and materials science, are prepared by atomic layer deposition and are subsequently functionalized by phosphonate chemistry to form self-assembled monolayers. The surface NV-NMR technique detects spatially resolved NMR signals from the monolayer, indicates chemical binding, and quantifies molecular coverage. In addition, it can monitor in real time the formation kinetics at the solid-liquid interface. With our approach, we show that NV quantum sensors are a surface-sensitive NMR tool with femtomole sensitivity for in situ analysis in catalysis, materials, and biological research.

Using Metal-Organic Frameworks to Confine Liquid Samples for Nanoscale NV-NMR.

Atomic-scale magnetic field sensors based on nitrogen vacancy (NV) defects in diamonds are an exciting platform for nanoscale nuclear magnetic resonance (NMR) spectroscopy. The detection of NMR signals from a few zeptoliters to single molecules or even single nuclear spins has been demonstrated using NV centers close to the diamond surface. However, fast molecular diffusion of sample molecules in and out of the nanoscale detection volumes impedes their detection and limits current experiments to solid-state or highly viscous samples. Here, we show that restricting diffusion by confinement enables nanoscale NMR spectroscopy of liquid samples. Our approach uses metal-organic frameworks (MOF) with angstrom-sized pores on a diamond chip to trap sample molecules near the NV centers. This enables the detection of NMR signals from a liquid sample, which would not be detectable without confinement. These results set the route for nanoscale liquid-phase NMR with high spectral resolution.

Dynamics of frequency-swept nuclear spin optical pumping in powdered diamond at low magnetic fields.

A broad effort is underway to improve the sensitivity of NMR through the use of dynamic nuclear polarization. Nitrogen vacancy (NV) centers in diamond offer an appealing platform because these paramagnetic defects can be optically polarized efficiently at room temperature. However, work thus far has been mainly limited to single crystals, because most polarization transfer protocols are sensitive to misalignment between the NV and magnetic field axes. Here we study the spin dynamics of NV-13C pairs in the simultaneous presence of optical excitation and microwave frequency sweeps at low magnetic fields. We show that a subtle interplay between illumination intensity, frequency sweep rate, and hyperfine coupling strength leads to efficient, sweep-direction-dependent 13C spin polarization over a broad range of orientations of the magnetic field. In particular, our results strongly suggest that finely tuned, moderately coupled nuclear spins are key to the hyperpolarization process, which makes this mechanism distinct from other known dynamic polarization channels. These findings pave the route to applications where powders are intrinsically advantageous, including the hyperpolarization of target fluids in contact with the diamond surface or the use of hyperpolarized particles as contrast agents for in vivo imaging.

Use of teledermatology by dermatology hospitalists is effective in the diagnosis and management of inpatient disease.

BACKGROUND: Patient outcomes are improved when dermatologists provide inpatient consultations. Inpatient access to dermatologists is limited, illustrating an opportunity to use teledermatology. Little is known about the ability of dermatologists to accurately diagnose disease and manage inpatients with teledermatology, particularly when using nondermatologist-generated clinical data. METHODS: This prospective study assessed the ability of teledermatology to diagnose disease and manage 41 dermatology consultations from a large urban tertiary care center, using internal medicine referral documentation and photographs. Twenty-seven dermatology hospitalists were surveyed. Interrater agreement was assessed by the κ statistic. RESULTS: There was substantial agreement between in-person and teledermatology assessment of the diagnosis with differential diagnosis (median κ = 0.83), substantial agreement in laboratory evaluation decisions (median κ = 0.67), almost perfect agreement in imaging decisions (median κ = 1.0), and moderate agreement in biopsy decisions (median κ = 0.43). There was almost perfect agreement in treatment (median κ = 1.0), but no agreement in follow-up planning (median κ = 0.0). There was no association between raw photograph quality and the primary plus differential diagnosis or primary diagnosis alone. LIMITATIONS: Selection bias and single-center nature. CONCLUSIONS: Teledermatology may be effective in the inpatient setting, with concordant diagnosis, evaluation, and management decisions.

Brigham Eyebrow Tool for Alopecia: A Reliable Assessment of Eyebrow Alopecia Areata.

There are no tools to evaluate eyebrow involvement in patients with alopecia areata. We developed and assessed the reliability of the Brigham Eyebrow Tool for Alopecia (BETA) as a quantitative evaluation of eyebrow alopecia areata. BETA uses facial landmarks of eyebrow anatomy and is calculated using surface area and density. A total of 50 eyebrow images with varying levels of hair loss were distributed to six board-certified dermatologists at three academic medical centers with standardized instructions and examples. Interrater and intrarater reliability were calculated using intraclass correlation coefficients (ICCs). BETA demonstrated high interrater (ICC = 0.88, confidence interval = 0.83-0.92 right eyebrow scores and ICC = 0.90, confidence interval = 0.85-0.94 left eyebrow scores) and intrarater (ICC = 0.90, confidence interval = 0.85-0.93 right eyebrow scores and ICC = 0.91, confidence interval = 0.87-0.94 left eyebrow scores) reliability. When measured in the same patient with varying degrees of hair loss over time, BETA demonstrated sensitivity to change. BETA is a simple and reliable objective assessment of eyebrow alopecia areata. BETA is easy-to-use and quick to calculate, making it feasible for a variety of clinical and research settings. Although developed for alopecia areata, we hope that BETA will be investigated in other etiologies of eyebrow alopecia to serve as a universal tool for monitoring disease progression, improvement, and response to treatment.

A video-based, flipped classroom, simulation curriculum for dermatologic surgery: A prospective, multi-institution study.

BACKGROUND: Medical education is evolving to emphasize trainee engagement. The impact of a flipped classroom curriculum and surgical simulation on dermatology resident education has not been evaluated. OBJECTIVE: To assess the impact of video education and surgical simulation on dermatology resident procedural skills. METHODS: We created a curriculum on foundational surgical skills for 31 first- and second-year dermatology residents at 3 institutions. The flipped classroom approach replaces traditional in-person lectures with at-home viewing of instructional videos. After this self-directed learning, trainees had 3 hands-on sessions using simulated skin models. The Objective Structured Assessment of Technical Skills (OSATS) instrument was used to assess residents performing a simulated elliptical excision with intermediate repair before and after the curriculum. Residents completed precurriculum and postcurriculum surveys evaluating operative confidence and perceived value of the curriculum. RESULTS: Residents' total OSATS score increased from a median of 27 (interquartile range, 22-38.5) before the curriculum to 46 (interquartile range, 39.5-51.5) after the curriculum (P < .001). Self-reported confidence in surgical performance significantly improved, and residents were highly satisfied. LIMITATIONS: Limitations include the small sample size and potential influence from concurrent learning on surgical rotations. CONCLUSIONS: Video education and simulation are effective for improving dermatology residents' procedural skills. We hope to serve as a template for other institutions and nondermatology trainees hoping to improve procedural skills.

Risk of developing pyoderma gangrenosum after procedures in patients with a known history of pyoderma gangrenosum-A retrospective analysis.

BACKGROUND: The risk of postoperative pyoderma gangrenosum (PG) in patients with a known history of PG is unknown. OBJECTIVE: To quantify risk and identify patient- and/or procedure-related risk factors for postsurgical recurrence or exacerbation of PG in patients with a known history of PG. METHODS: We retrospectively evaluated the likelihood of postsurgical recurrence or exacerbation of PG for all patients with a confirmed diagnosis of PG at Brigham and Women's Hospital and Massachusetts General Hospital from 2000 to 2015. RESULTS: In all, 5.5% of procedures (n = 33) led to recurrence of PG in 15.1% of patients (n = 25). Compared with skin biopsy, small open surgical procedures had an adjusted odds ratio (aOR) of 8.65 (95% confidence interval [CI], 1.55-48.33) for PG recurrence or exacerbation; large open surgical procedures had an aOR of 5.97 (95% CI, 1.70-21.00); and Mohs micrographic surgery/skin excision had an aOR of 6.47 (95% CI, 1.77-23.61). PG chronically present at the time of the procedure had an aOR of 4.58 (95% CI, 1.72-12.22). Immunosuppression, time elapsed since the original PG diagnosis, and procedure location did not significantly influence risk. LIMITATIONS: Our study is limited by its retrospective nature and relatively small sample size. CONCLUSION: There is a small but clinically meaningful risk for postsurgical recurrence or exacerbation of PG in patients with a known history of PG; higher risks occur with more invasive procedures and chronically present PG.

Successful Use of Cyclosporin A for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Three Children.

BACKGROUND/OBJECTIVES: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are medical emergencies. Mainstays of treatment include removal of the offending agent, supportive care, and wound care. The use of immunosuppressive agents such as corticosteroids and intravenous immunoglobulin (IVIg) is controversial. Some case reports and small studies report the successful use of cyclosporin A (CsA) for SJS/TEN in halting disease progression, fostering reepithelialization, and reducing mortality. OBJECTIVE: To report on the efficacy of cyclosporine A in the treatment of SJS/TEN in three pediatric patients. METHODS: We describe three pediatric patients seen at a tertiary care hospital in Boston, Massachusetts, diagnosed with SJS/TEN confirmed by skin biopsy who were successfully treated with CsA with improvements seen in time to cessation of disease progression or new lesion formation, reepithelialization, and duration of hospital stay. RESULTS: The average time cessation of disease progression or new lesion formation after CsA administration was 2.2 days (range 1.5-3 days) and average time to remission or reepithelialization was 13 days (range 10-15 days). The average length of hospital stay was 11.7 days (range 4-19 days). CONCLUSIONS: We describe three pediatric patients treated successfully with CsA and provide evidence for the use of cyclosporine in children with SJS/TEN. These results further support previous observations that CsA use for SJS/TEN produces consistently favorable outcomes. The results in this case series are limited by their observational nature. Additional trials are needed to evaluate the safety and efficacy of CsA use in children.

Cutaneous T-cell lymphoma (CTCL): Current practices in blood assessment and the utility of T-cell receptor (TCR)-Vß chain restriction.

BACKGROUND: Accurate quantification of malignant cells in the peripheral blood of patients with cutaneous T-cell lymphoma is important for early detection, prognosis, and monitoring disease burden. OBJECTIVE: We sought to determine the spectrum of current clinical practices; critically evaluate elements of current International Society for Cutaneous Lymphomas (ISCL) B1 and B2 staging criteria; and assess the potential role of T-cell receptor-Vß analysis by flow cytometry. METHODS: We assessed current clinical practices by survey, and performed a retrospective analysis of 161 patients evaluated at Yale (2011-2014) to compare the sensitivity, specificity, positive predictive value, and negative predictive value of parameters for ISCL B2 staging. RESULTS: There was heterogeneity in clinical practices among institutions. ISCL B1 criteria did not capture 5 Yale cohort cases with immunophenotypic abnormalities that later progressed. T-cell receptor-Vß testing was more specific than polymerase chain reaction and aided diagnosis in detecting clonality, but was of limited benefit in quantification of tumor burden. LIMITATIONS: Because of limited follow-up involving a single center, further investigation will be necessary to conclude whether our proposed diagnostic algorithm is of general clinical benefit. CONCLUSION: We propose further study of modified B1 criteria: CD4/CD8 ratio 5 or greater, %CD4(+) CD26(-) 20% or greater, or %CD4(+) CD7(-) 20% or greater, with evidence of clonality. T-cell receptor-Vß testing should be considered in future diagnostic and staging algorithms.

Midchildhood acne associated with inhaled corticosteroids: report of two cases and review of the literature.

Midchildhood acne has been attributed to a number of causes in the literature, including adrenocortical tumor, hyperandrogenemia due to hypothalamic dysfunction, and contact with greasy topical skin care products. There are only a few case reports of inhaled steroids causing acneiform eruptions, all of which occurred in adults and with symptoms suggesting that the acne resulted from systemic absorption. We present two cases of comedonal and inflammatory midchildhood acne temporally associated with the use of inhaled corticosteroids administered through face masks, implicating a causative relationship between topical steroid exposure and midchildhood acne that does not necessitate systemic absorption.

Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol.

BACKGROUND: Cholesterol cholelithiasis is a multifactorial disease influenced by a complex interaction of genetic and environmental factors and represents a failure of biliary cholesterol homoeostasis in which the physical-chemical balance of cholesterol solubility in bile is disturbed. DESIGN: The primary pathophysiologic event is persistent hepatic hypersecretion of biliary cholesterol, which has both hepatic and small intestinal components. The majority of the environmental factors are probably related to Western-type dietary habits, including excess cholesterol consumption. RESULTS: Laparoscopic cholecystectomy, one of the most commonly performed surgical procedures in the United States, is nowadays a major treatment for gallstones. However, it is invasive and can cause surgical complications, and not all patients with symptomatic gallstones are candidates for surgery. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been employed as first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol gallstones. Long-term administration of UDCA can promote the dissolution of cholesterol gallstones. However, the optimal use of UDCA is not always achieved in clinical practice because of failure to titrate the dose adequately. CONCLUSIONS: Therefore, the development of novel, effective and noninvasive therapies is crucial for reducing the costs of health care associated with gallstones. In this review, we summarize recent progress in investigating the inhibitory effects of ezetimibe and statins on intestinal absorption and hepatic biosynthesis of cholesterol, respectively, for the treatment of gallstones, as well as in elucidating their molecular mechanisms by which combination therapy could prevent this very common liver disease worldwide.

Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection.

BACKGROUND: Hand-foot-and-mouth disease (HFMD) is an acute viral illness commonly caused by coxsackievirus (CV)-A16 and enterovirus 71 infections. Recently, atypical HFMD has been reported in association with CV-A6, an uncommon enterovirus strain. OBJECTIVE: We sought to describe the clinical features of atypical HFMD associated with CV-A6 infection and its diagnostic laboratory evaluation. METHODS: Patients presenting to our institution with history and examination suggestive of atypical HFMD from January 2012 to July 2012 were identified. Morphology and distribution of mucocutaneous lesions were recorded. Enterovirus infection was assessed by reverse transcriptase polymerase chain reaction of biologic specimens. Enterovirus type was determined by viral capsid protein 1 gene sequencing. RESULTS: Two adults and 3 children with atypical HFMD were identified. Four of 5 patients exhibited widespread cutaneous lesions. In 2 patients with a history of atopic dermatitis, accentuation in areas of dermatitis was noted. Associated systemic symptoms prompted 4 of 5 patients to seek emergency care, and both adults were hospitalized for diagnostic evaluation. Infection with CV-A6 was confirmed in all patients. LIMITATIONS: This study is a case series from a single institution. CONCLUSION: Consideration of the expanded range of cutaneous findings in atypical HFMD caused by CV-A6 infection may assist clinicians in diagnosis and management.

Experimental model of trigger finger through A1 pulley constriction in a human cadaveric hand: a pilot study.

PURPOSE: Although it can be reasonably assumed that trigger digits occur as the result of a size mismatch in the pulley-tendon system, it is unclear whether locking, histological changes, and nodule formation occur owing to an intrinsically too small pulley or an enlarged digital flexor tendon. Our purposes in this feasibility study were to (1) create a model of trigger digit by pulley constriction in nonpreserved human tissue, (2) measure the change in work of flexion as the force of pulley constriction increased, (3) compare the work of flexion between nontriggering and triggering conditions, and (4) determine whether triggering can occur at the A2, A3, and A4 pulleys under similar conditions. METHODS: Using a tensiometer, we studied the work of flexion in 4 fingers (thumb, index, middle, and ring) in a human cadaveric hand. The load of flexion was measured as the A1 to A4 pulleys were incrementally constricted in order to induce triggering. Work of flexion was analyzed for differences among trial conditions. RESULTS: Triggering was successfully induced in all 4 digits through constriction of the A1 pulley. No triggering occurred in any of the A2, A3, or A4 pulley systems in this model. CONCLUSIONS: We successfully created a trigger model in a human cadaveric hand. Our results demonstrate that the A1 pulley can cause triggering from manual constriction of the pulley alone. CLINICAL RELEVANCE: A trigger model such as this may allow investigations of pathophysiology, and this may result in novel treatment strategies and modalities.

Evaluation of Point-of-Care Decision Support for Adult Acne Treatment by Primary Care Clinicians.

Importance: Acne is a common reason for referral to dermatologists from primary care clinicians. We previously modeled the impact of algorithm-based acne care in reducing dermatology referrals, missed appointments, and treatment delays. Objective: To prospectively evaluate the downstream outcomes following a real-time, algorithm-based electronic decision-support tool on the treatment of patients referred for acne. Design, Setting, and Participants: This prospective cohort study included 260 treatment-naive patients referred to a dermatologist for the chief concern of acne, as well as the referring primary care clinicians, at 33 primary care sites affiliated with Brigham and Women's Hospital from March 2017 to March 2018. Interventions: We developed and implemented a decision-support tool into the electronic medical record system at an academic medical center. The algorithm identified patients referred to a dermatologist who had not previously been treated for acne and offered guideline-based recommendations for treatment via a real-time notification. Main Outcomes and Measures: Treatment modification by referring clinicians. Results: Of 260 patients referred for acne, 209 (80.4%) were women, 146 (56.1%) were non-Hispanic white, and 236 (90.8%) listed English as the preferred language. Patients had a median (quartile 1-quartile 3) age of 28.8 years (24.4-35.1 years) and 185 of 260 had private insurance (71.1%). In total, the algorithm was associated with cancellation of the initial referral in 35 of 260 (13.5%) instances and treatment initiation by the referring clinician in 51 of 260 (19.6%) instances. Conclusions and Relevance: This decision-support algorithm was associated with a modest reduction in rates of acne-related referrals to dermatologists, and an increased likelihood of treatment initiation by the referring clinician.

Hyperpolarized in vivo pH imaging reveals grade-dependent acidification in prostate cancer.

There is an unmet clinical need for new and robust imaging biomarkers to distinguish indolent from aggressive prostate cancer. Hallmarks of aggressive tumors such as a decrease in extracellular pH (pHe) can potentially be used to identify aggressive phenotypes. In this study, we employ an optimized, high signal-to-noise ratio hyperpolarized (HP) 13C pHe imaging method to discriminate between indolent and aggressive disease in a murine model of prostate cancer. Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice underwent a multiparametric MR imaging exam, including HP [13C] bicarbonate MRI for pHe, with 1H apparent diffusion coefficient (ADC) mapping and HP [1-13C] pyruvate MRI to study lactate metabolism. Tumor tissue was excised for histological staining and qRT-PCR to quantify mRNA expression for relevant glycolytic enzymes and transporters. We observed good separation in pHe between low- and high-grade tumor regions, with high-grade tumors demonstrating a lower pHe. The pHe also correlated strongly with monocarboxylate transporter Mct4 gene expression across all tumors, suggesting that lactate export via MCT4 is associated with acidification in this model. Our results implicate extracellular acidification as an indicator of indolent-to-aggressive transition in prostate cancer and suggest feasibility of HP pHe imaging to detect high-grade, clinically significant disease in men as part of a multiparametric MRI examination.

Orientation-independent room temperature optical 13C hyperpolarization in powdered diamond.

Dynamic nuclear polarization via contact with electronic spins has emerged as an attractive route to enhance the sensitivity of nuclear magnetic resonance beyond the traditional limits imposed by magnetic field strength and temperature. Among the various alternative implementations, the use of nitrogen vacancy (NV) centers in diamond-a paramagnetic point defect whose spin can be optically polarized at room temperature-has attracted widespread attention, but applications have been hampered by the need to align the NV axis with the external magnetic field. We overcome this hurdle through the combined use of continuous optical illumination and a microwave sweep over a broad frequency range. As a proof of principle, we demonstrate our approach using powdered diamond with which we attain bulk 13C spin polarization in excess of 0.25% under ambient conditions. Remarkably, our technique acts efficiently on diamond crystals of all orientations and polarizes nuclear spins with a sign that depends exclusively on the direction of the microwave sweep. Our work paves the way toward the use of hyperpolarized diamond particles as imaging contrast agents for biosensing and, ultimately, for the hyperpolarization of nuclear spins in arbitrary liquids brought in contact with their surface.