Role of human Kallistatin in glucose and energy homeostasis in mice.

OBJECTIVE: Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with pleiotropic properties. Clinical studies in humans revealed reduced KST levels in obesity. The exact role of KST in glucose and energy homeostasis in the setting of insulin resistance and type 2 diabetes is currently unknown. METHODS: Kallistatin mRNA expression in human subcutaneous white adipose tissue (sWAT) of 47 people with overweight to obesity of the clinical trial "Comparison of Low Fat and Low Carbohydrate Diets With Respect to Weight Loss and Metabolic Effects (B-SMART)" was measured. Moreover, we studied transgenic mice systemically overexpressing human KST (hKST-TG) and wild type littermate control mice (WT) under normal chow (NCD) and high-fat diet (HFD) conditions. RESULTS: In sWAT of people with overweight to obesity, KST mRNA increased after diet-induced weight loss. On NCD, we did not observe differences between hKST-TG and WT mice. Under HFD conditions, body weight, body fat and liver fat content did not differ between genotypes. Yet, during intraperitoneal glucose tolerance tests (ipGTT) insulin excursions and HOMA-IR were lower in hKST-TG (4.42 ± 0.87 AU, WT vs. 2.20 ± 0.27 AU, hKST-TG, p < 0.05). Hyperinsulinemic euglycemic clamp studies with tracer-labeled glucose infusion confirmed improved insulin sensitivity by higher glucose infusion rates in hKST-TG mice (31.5 ± 1.78 mg/kg/min, hKST-TG vs. 18.1 ± 1.67 mg/kg/min, WT, p < 0.05). Improved insulin sensitivity was driven by reduced hepatic insulin resistance (clamp hepatic glucose output: 7.7 ± 1.9 mg/kg/min, hKST-TG vs 12.2 ± 0.8 mg/kg/min, WT, p < 0.05), providing evidence for direct insulin sensitizing effects of KST for the first time. Insulin sensitivity was differentially affected in skeletal muscle and adipose tissue. Mechanistically, we observed reduced Wnt signaling in the liver but not in skeletal muscle, which may explain the effect. CONCLUSIONS: KST expression increases after weight loss in sWAT from people with obesity. Furthermore, human KST ameliorates diet-induced hepatic insulin resistance in mice, while differentially affecting skeletal muscle and adipose tissue insulin sensitivity. Thus, KST may be an interesting, yet challenging, therapeutic target for patients with obesity and insulin resistance.

Case Report: Methotrexate and hydroxychloroquine in combination for the treatment of NOD2-mutation-associated Blau syndrome.

Mutations in nucleotide binding oligomerization domain containing 2 receptor (NOD2) are associated with Blau syndrome (also known as early-onset sarcoidosis)-a rare autosomal dominant, chronic granulomatous disease that typically presents before 5 years of age. Blau syndrome is characterized by the clinical triad of arthritis, granulomatous dermatitis, and recurrent uveitis. Here, we report a case of NOD2-mutation-associated early-onset sarcoidosis in which a combination of methotrexate and hydroxychloroquine was used to achieve improvement in arthritis, granulomatous dermatitis, and uveitis. A 13-month-old boy presented with a sudden-onset cutaneous eruption affecting the face, trunk, and extremities that initially mimicked papular atopic dermatitis but progressively worsened despite topical steroid therapy. The patient had no other known medical comorbidities or abnormalities except for heterochromia of the right eye. However, prior to presentation to dermatology, the patient began experiencing frequent falls, conjunctival injection, and apparent eye and joint pain. Skin biopsy from the right shoulder demonstrated rounded aggregates of epithelioid histiocytes and multinucleated giant cells without a significant lymphocytic component ("naked granulomas"), consistent with sarcoidal granulomatous dermatitis. Given the concern for Blau syndrome, the patient was sent for evaluation by ophthalmology and was found to have bilateral subconjunctival nodules. Our patient underwent genetic testing and was found to have a mutation in codon 1000 C > T (protein R334W) in the NOD2 gene. The patient responded to oral prednisolone 2 mg/kg/day for 8 weeks, but quickly relapsed, requiring a second 8-week course with taper upon starting methotrexate 7.5 mg subcutaneously weekly with 1 mg folic acid orally daily. After 8 weeks on methotrexate, due to persistent arthritis, conjunctival injection, and pruritus, and in consultation with rheumatology, the patient was started on hydroxychloroquine 75 mg orally daily along with continuation of 7.5 mg methotrexate subcutaneously weekly for 8 weeks, achieving significant reduction in arthritis, pruritus, and uveitis. After 8 weeks of this combination therapy, due to concerns of long-term macular toxicity, hydroxychloroquine was discontinued in favor of continuing methotrexate alone. The patient has remained free of significant side effects and stable with good disease control on 7.5 mg methotrexate weekly injected subcutaneously.

Abnormal thrombosis and neutrophil activation increase hospital-acquired sacral pressure injuries and morbidity in COVID-19 patients.

Hospitalized patients have an increased risk of developing hospital-acquired sacral pressure injury (HASPI). However, it is unknown whether SARS-CoV-2 infection affects HASPI development. To explore the role of SARS-CoV-2 infection in HASPI development, we conducted a single institution, multi-hospital, retrospective study of all patients hospitalized for ≥5 days from March 1, 2020 to December 31, 2020. Patient demographics, hospitalization information, ulcer characteristics, and 30-day-related morbidity were collected for all patients with HASPIs, and intact skin was collected from HASPI borders in a patient subset. We determined the incidence, disease course, and short-term morbidity of HASPIs in COVID-19(+) patients, and characterized the skin histopathology and tissue gene signatures associated with HASPIs in COVID-19 disease. COVID-19(+) patients had a 63% increased HASPI incidence rate, HASPIs of more severe ulcer stage (OR 2.0, p<0.001), and HASPIs more likely to require debridement (OR 3.1, p=0.04) compared to COVID-19(-) patients. Furthermore, COVID-19(+) patients with HASPIs had 2.2x increased odds of a more severe hospitalization course compared to COVID-19(+) patients without HASPIs. HASPI skin histology from COVID-19(+) patients predominantly showed thrombotic vasculopathy, with the number of thrombosed vessels being significantly greater than HASPIs from COVID-19(-) patients. Transcriptional signatures of a COVID-19(+) sample subset were enriched for innate immune responses, thrombosis, and neutrophil activation genes. Overall, our results suggest that immunologic dysregulation secondary to SARS-CoV-2 infection, including neutrophil dysfunction and abnormal thrombosis, may play a pathogenic role in development of HASPIs in patients with severe COVID-19.

Effect of IMU location on estimation of vertical ground reaction force during jumping.

Introduction: Several investigations have examined utilizing inertial measurement units (IMU) to estimate ground reaction force (GRF) during exercise. The purpose of this investigation was to determine the effect of inertial measurement units location on the estimation of ground reaction force during vertical jumping. Methods: Eight male subjects completed a series of ten countermovement jumps on a force plate (FP). The subjects had an inertial measurement units attached to the sacrum, back and chest. Ground reaction force was estimated from data from the individual inertial measurement units and by using a two-segment model and combined sensor approach. Results: The peak ground reaction force values for the sacrum, back, chest and combined inertial measurement units were 1,792 ± 278 N, 1,850 ± 341 N, 2,054 ± 346 N and 1,812 ± 323 N, respectively. The sacral inertial measurement units achieved the smallest differences for ground reaction force estimates providing a root mean square error (RMSE) between 88 N and 360 N. The inertial measurement units on the sacrum also showed significant correlations in peak ground reaction force (p < 0.001) and average ground reaction force (p < 0.001) using the Bland-Altman 95% Limits of Agreement (LOA) when in comparison to the force plate. Discussion: Based on assessment of bias, Limits of Agreement, and RMSE, the inertial measurement units located on the sacrum appears to be the best placement to estimate both peak and average ground reaction force during jumping.

Offset Loading in a Bilateral Squatting Movement Pattern Influences Ground-Reaction Force and Muscle Activity in the Dominant and Nondominant Limb.

PURPOSE: The purpose of this study was to explore whether offset loading in the barbell squat altered ground-reaction force (GRF) and muscle activation in the dominant (D) and nondominant (ND) lower limb compared to traditional squats. METHODS: Twelve well-trained men (age 26.4 [3.2] y; 10.3 [1.9] y experience) performed 3 sets of 10 repetitions at 60% of their previously measured 1-repetition maximum. Sets were quasi-randomized between traditional loading (TDL), dominant-side offset loading (OS-D), and nondominant-side offset loading (OS-ND). All repetitions were performed on a dual force plate with electromyography sensors on the prime mover muscles of the squat. GRF symmetry was assessed using the symmetry index (SI) to determine the direction (D [+] or ND [-]) and magnitude (%) of the asymmetry. Finally, the first 3 and final 3 repetitions of each set were compared for compensatory changes in symmetry. RESULTS: OS-D induced a significant change in limb SI relative to TDL (5.21% vs 1.44%; P = .011); however, no significant difference in limb SI was seen between TDL and OS-ND (-0.66% vs 1.44%; P = .278). No asymmetries between D and ND muscle activation were present in any condition. TDL and OS-D squats exhibited significant improvements in limb SI between the first 3 and final 3 repetitions (P = .035 and .011, respectively); however, no such improvement was seen in OS-ND. CONCLUSIONS: OS-D is capable of significantly altering GRF limb SI in a bilateral squat; however, OS-ND appears to exhibit no GRF or electromyography effects relative to TDL. Thus, the results of this study do not support the use of OS-ND in the pursuit of strengthening a weaker limb, suggesting that unilateral training may be a preferred mode of exercise for this desired outcome.

Vitiligo in a Patient With Kabuki Syndrome: Case Study and Review of the Literature.

Kabuki Syndrome (KS) is a rare genetic disorder characterized by dysmorphic facial features, skeletal anomalies, dermatoglyphic abnormalities, intellectual disability, and short stature. Autoimmune disease can be seen more frequently in this patient population. Vitiligo is an autoimmune disease that is uncommonly reported in patients with KS. This report describes a case of vitiligo manifesting in a patient with KS and discusses the use of Janus kinase inhibitors as treatment.

The effect of mesenchymal stem cells improves the healing of burn wounds: a phase 1 dose-escalation clinical trial.

Background: Stem cell therapy holds promise to improve healing and stimulate tissue regeneration after burn injury. Preclinical evidence has supported this; however, clinical studies are lacking. We examined the application of bone marrow-derived mesenchymal stem cells (BM-MSC) to deep second-degree burn injuries using a two-dose escalation protocol. Methods: Ten individuals aged 18 years or older with deep second-degree burn wounds were enrolled. The first five patients were administered 2.5 × 10³ BM-MSC/cm2 to their wounds. After safety of the initial dose level was assessed, a second group of five patients was treated with a higher concentration of 5 × 10³ allogeneic BM-MSC/cm2. Safety was assessed clinically and by evaluating cytokine levels in mixed recipient lymphocyte/donor BM-MSC reactions (INFγ, IL-10 and TNFα). At each visit, we performed wound measurements and assessed wounds using a Patient and Observer Scar Assessment Scale (POSAS). Results: All patients responded well to treatment, with 100% closure of wounds and minimal clinical evidence of fibrosis. No adverse reactions or evidence of rejection were observed for both dose levels. Patients receiving the first dose concentration had a wound closure rate of 3.64 cm2/day. Patients receiving the second dose concentration demonstrated a wound closure rate of 10.47 cm2/day. The difference in healing rates between the two groups was not found to be statistically significant (P = 0.17). Conclusion: BM-MSC appear beneficial in optimising wound healing in patients with deep second-degree burn wounds. Adverse outcomes were not observed when administering multiple doses of allogeneic BM-MSC. Lay Summary: Thermal injuries are a significant source of morbidity and mortality, constituting 5%-20% of all injuries and 4% of all deaths. Despite overall improvements in the management of acutely burned patients, morbidities associated with deeper burn injuries remain commonplace. Burn patients are too often left with significant tissue loss, scarring and contractions leading to physical loss of function and long-lasting psychological and emotional impacts.In previous studies, we have demonstrated the safety and efficacy of administering bone marrow-derived mesenchymal stem cells (BM-MSC) to chronic wounds with substantial improvement in healing and evidence of tissue regeneration. In this report, we have examined the application of BM-MSC to deep second-degree burn injuries in patients.The aim of the present phase I/II clinical trial was to examine the safety and efficacy of administering allogeneic BM-MSC to deep second-degree burns. We utilised two different dose levels at concentrations 2.5 × 103 and 5 × 103 cells/cm2. Patients with deep second-degree burn wounds up to 20% of the total body surface area were eligible for treatment. Allogeneic BM-MSC were applied to burn wounds topically or by injection under transparent film dressing <7 days after injury. Patients were followed for at least six months after treatment.Using two dose levels allowed us to gain preliminary information as to whether different amounts of BM-MSC administered to burn wounds will result in significant differences in safety/ clinical response. Once the safety and dose-response analysis were completed, we evaluated the efficacy of allogeneic stem cell therapy in the treatment of deep second-degree burn wounds.In this study, we examined the role of allogeneic BM-MSC treatment in patients with deep second-degree burn injuries, in a dose-dependent manner. No significant related adverse events were reported. Safety was evaluated both clinically and by laboratory-based methods. Efficacy was assessed clinically through evidence of re-pigmentation, hair follicle restoration and regenerative change. While these findings are encouraging, more studies will be needed to better establish the benefit of BM-MSC in the treatment of burn injuries.

Erratum: In vivo PS-OCT needle probe scan of human skeletal muscle: publisher's note.

[This corrects the article on p. 1386 in vol. 13, PMID: 35414965.].

In vivo PS-OCT needle probe scan of human skeletal muscle.

Polarization-sensitive optical coherence tomography (PS-OCT) derived birefringence values effectively identify skeletal muscle structural disruption due to muscular dystrophy and exercise-related muscle damage in animal models in ex vivo tissue. The purpose of this investigation was to determine if a PS-OCT needle probe inserted into the leg of a human subject could accurately identify various anatomical structures with implications for use as a diagnostic tool for the determination of skeletal muscle pathology. A healthy middle-aged subject participated in this study. A custom-built PS-OCT system was interfaced with a side-viewing fiber-optic needle probe inserted into the subject's vastus lateralis muscle via a motorized stage for 3D data acquisition via rotation and stepwise pullback. The deepest recorded PS-OCT images correspond to a depth of 6 mm beneath the dermis with structural images showing uniform, striated muscle tissue. Multiple highly birefringent band-like structures with definite orientation representing connective tissue of the superficial aponeurosis appeared as the depth of the needle decreased. Superficial to these structures the dominating appearance was that of adipose tissue and low birefringent but homogeneous scattering tissue. The data indicate that a PS-OCT needle probe can be inserted into live human skeletal muscle for the identification of relevant anatomical structures that could be utilized to diagnose significant skeletal muscle pathology.

Comparison of Flywheel and Pneumatic Training on Hypertrophy, Strength, and Power in Professional Handball Players.

Purpose: The mechanical properties of resistance-training machines are a variable that may help to optimize sports performance and injury prevention protocols. The purpose of this study was to examine two non-gravity-dependent training modalities on muscle structure and function. Methods: Eighteen professional handball players were randomly divided into two experimental groups: 1) iso-inertial flywheel training (FW) and 2) pneumatic resistance training (PN). Participants in both groups completed twelve training sessions in six weeks consisting of three movements (lateral raise, internal and external rotation). Four sets of seven repetitions for each movement were performed during each session. Before and after training subscapularis and deltoid (anterior, middle, posterior) muscle thickness was measured. Isokinetic torque and power during internal and external rotation at 60, 180, and 240 deg·s-1 was measured as well. Throwing speed was assessed before and after training while both sitting and standing situations. Results: Both groups showed similar significant increases in throwing speed and internal and external rotation peak torque, average and peak power at all angular velocities. Anterior and middle deltoid muscle thickness changes were greater after training in FW (20 and 22%) in comparison to PN (14 and 7%, respectively). Conclusions: In summary, both flywheel and pneumatic training resulted in similar increases in shoulder strength and power and throwing speed. However, flywheel training appeared to possibly result in a slightly greater level of muscle hypertrophy of the anterior and middle deltoid. Non-gravity dependent training appears to induce changes that would be beneficial to sports performance and perhaps injury prevention.

Preferentially expressed antigen in melanoma and p16 expression in acral melanocytic neoplasms.

Acral melanocytic neoplasms often pose diagnostic difficulty. Preferentially expressed antigen in melanoma (PRAME) expression and loss of p16 expression have diagnostic utility in melanocytic tumors. We examined PRAME and p16 expression in 30 acral melanocytic neoplasms (n = 11 nevi; n = 2 dysplastic nevi; n = 7 Spitz nevi; n = 10 acral melanomas). PRAME was scored as % positive nuclei: negative = 0%; 1% to 25% = 1+; 25% to 50% = 2+; 50% to 75% = 3+, or positive: 75% to 100% = 4+. p16 expression was defined as retained (homogeneous or checkerboard) or lost (complete or partial/regionally). PRAME expression was negative in all benign, dysplastic, and Spitz nevi. Conversely, all acral melanomas were diffusely (4+) positive for PRAME expression. p16 expression was retained in all benign acral nevi (8/11 homogeneous, 3/11 checkerboard), completely lost in one dysplastic nevus, and retained in all acral Spitz nevi (3/7 homogeneous, 4/7 checkerboard). p16 was retained in five of 10 acral melanomas (3/10 homogeneous; 2/10 checkerboard), and negative in five of 10 acral melanomas (absent in 3/10, partially lost in 2/10). Our data suggest that 4+ PRAME expression is highly sensitive and specific in the setting of acral melanomas and is a more predictive diagnostic tool compared with p16 immunohistochemistry.

Proteomic analysis of bone marrow-derived mesenchymal stem cell extracellular vesicles from healthy donors: implications for proliferation, angiogenesis, Wnt signaling, and the basement membrane.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown therapeutic potential in various in vitro and in vivo studies in cutaneous wound healing. Furthermore, there are ubiquitous studies highlighting the pro-regenerative effects of BM-MSC extracellular vesicles (BM-MSC EVs). The similarities and differences in BM-MSC EV cargo among potential healthy donors are not well understood. Variation in EV protein cargo is important to understand, as it may be useful in identifying potential therapeutic applications in clinical trials. We hypothesized that the donors would share both important similarities and differences in cargo relating to cell proliferation, angiogenesis, Wnt signaling, and basement membrane formation-processes shown to be critical for effective cutaneous wound healing. METHODS: We harvested BM-MSC EVs from four healthy human donors who underwent strict screening for whole bone marrow donation and further Good Manufacturing Practices-grade cell culture expansion for candidate usage in clinical trials. BM-MSC EV protein cargo was determined via mass spectrometry and Proteome Discoverer software. Corresponding proteomic networks were analyzed via the UniProt Consortium and STRING consortium databases. RESULTS: More than 3000 proteins were identified in each of the donors, sharing > 600 proteins among all donors. Despite inter-donor variation in protein identities, there were striking similarities in numbers of proteins per biological functional category. In terms of biologic function, the proteins were most associated with transport of ions and proteins, transcription, and the cell cycle, relating to cell proliferation. The donors shared essential cargo relating to angiogenesis, Wnt signaling, and basement membrane formation-essential processes in modulating cutaneous wound repair. CONCLUSIONS: Healthy donors of BM-MSC EVs contain important similarities and differences among protein cargo that may play important roles in their pro-regenerative functions. Further studies are needed to correlate proteomic signatures to functional outcomes in cutaneous repair.

A rare case of syringocystadenocarcinoma papilliferum of the breast: An institutional retrospective case review and brief literature review.

Syringocystadenocarcinoma papilliferum (SCACP) is a rare cutaneous adnexal tumor thought to originate from its benign counterpart, syringocystadenoma papilliferum. These tumors are predominantly located on the head and neck with their location on the breast extraordinarily reported; mammary localization poses a great diagnostic dilemma to the practicing pathologist. Herein, we report an unusual case of an 85-year-old woman with an outside diagnosis on a core needle biopsy of metaplastic mammary carcinoma. Upon consultative review of the partial mastectomy specimen, SCACP was identified. Herein, we review SCACP and the diagnostic challenge it poses, especially when localized to the breast. Furthermore, we perform a retrospective review of institutional pathology reports and identified four additional cases of SCACP diagnosed at our institution within the last decade. Finally, we briefly review the literature of SCACP. The entity of SCACP should be well known to pathologists to avoid misdiagnosis.

Development of sacral/buttock retiform purpura as an ominous presenting sign of COVID-19 and clinical and histopathologic evolution during severe disease course.

Retiform purpura has been described as a relatively frequent cutaneous finding in patients with coronavirus disease 2019 (COVID-19). The etiology is hypothesized to be related to thrombotic vasculopathy based on lesional biopsy specimen findings, but the pathogenesis of the vasculopathy is not completely understood. Here, we present a case of a retiform purpuric patch on the sacrum/buttocks in a hospitalized patient prior to subsequent diagnosis of COVID-19 and an eventual fatal disease course. Two lesional biopsy specimens at different time points in the disease course revealed thrombotic vasculopathy, despite therapeutic anticoagulation. Detailed histopathologic evaluation using immunohistochemical markers suggest the etiology of the vasculopathy involves both persistent complement activation and platelet aggregation, which possibly promote ongoing thrombus formation. This case highlights that sacral/buttock retiform purpuric patches may be a presenting sign of infection with SARS-CoV-2 virus and may represent an ominous sign supporting a future severe disease course. In addition, biopsy specimen findings at separate time points demonstrate that cutaneous vasculopathy may persist despite adequate systemic anticoagulation, possibly due to the combination of persistent complement and platelet activation. Finally, occlusive thrombi in sacral/buttock retiform purpuric patches may contribute to future ulceration and significant cutaneous morbidity in patients who survive COVID-19.

Muscle Actuators, Not Springs, Drive Maximal Effort Human Locomotor Performance.

The current investigation examined muscle-tendon unit kinematics and kinetics in human participants asked to perform a hopping task for maximal performance with variational preceding milieu. Twenty-four participants were allocated post-data collection into those participants with an average hop height of higher (HH) or lower (LH) than 0.1 m. Participants were placed on a customized sled at a 20º angle while standing on a force plate. Participants used their dominant ankle for all testing and their knee was immobilized and thus all movement involved only the ankle joint and corresponding propulsive unit (triceps surae muscle complex). Participants were asked to perform a maximal effort during a single dynamic countermovement hop (CMH) and drop hops from 10 cm (DH10) and 50 cm (DH50). Three-dimensional motion analysis was performed by utilizing an infrared camera VICON motion analysis system and a corresponding force plate. An ultrasound probe was placed on the triceps surae muscle complex for muscle fascicle imaging. HH hopped significantly higher in all hopping tasks in comparison to LH. In addition, the HH group concentric ankle work was significantly higher in comparison to LH during all of the hopping tasks. Active muscle work was significantly higher in HH in comparison to LH as well. Tendon work was not significantly different between HH and LH. Active muscle work was significantly correlated with hopping height (r = 0.97) across both groups and hopping tasks and contributed more than 50% of the total work. The data indicates that humans primarily use a motor-driven system and thus it is concluded that muscle actuators and not springs maximize performance in hopping locomotor tasks in humans.

Biological system energy algorithm reflected in sub-system joint work distribution movement strategies: influence of strength and eccentric loading.

To better understand and define energy algorithms during physical activity as it relates to strength and movement strategy of the hip, knee and ankle, a model of increasing eccentric load was implemented in the current investigation utilizing a countermovement jump and a series of drop jumps from different heights (15, 30, 45, 60, 75 cm). Twenty-one participants were grouped by sex (men, n = 9; women, n = 12) and muscle strength (higher strength, n = 7; moderate strength, n = 7; lower strength, n = 7) as determined by a maximal squat test. Force plates and 3D motion capture were utilized to calculate work for the center of mass (COM) of the whole body and individually for the hip, knee and ankle joints. Statistically significant lower net work of the COM was observed in women and lower strength participants in comparison to men and moderate strength and higher strength participants respectively (p ≤ 0.05). This was primarily due to higher negative to positive work ratios of the COM in women and lower strength participants during all jumps. Furthermore, the COM negative work was primarily dissipated at the knee joint in women and in the lower strength group, particularly during the higher drop jump trials, which are representative of a demanding eccentric load task. A definitive energy algorithm was observed as a reflection of altering joint work strategy in women and lower strength individuals, indicating a possible role in knee joint injury and modulation of such by altering muscular strength.

Use of an Instrumented Ankle Arthrometer and External Strain Gauge to Assess Ankle Dorsiflexion Motion and Plantarflexor Stiffness.

BACKGROUND: Ankle dorsiflexion motion and plantarflexor stiffness measurement offer clinical insight into the assessment and treatment of musculoskeletal and neurologic disorders. We aimed to determine reliability and concurrent validity of an ankle arthrometer in quantifying dorsiflexion motion and plantarflexor stiffness. METHODS: Ten healthy individuals were assessed for dorsiflexion motion and plantarflexor stiffness using an ankle arthrometer with a 6 degree-of-freedom kinematic linkage system and external strain gauge to apply dorsiflexion torque. Two investigators each performed five loads to the ankle at different combinations of loads (10 or 20 Nm), rates (2.5 or 5 Nm/sec), and knee angles (10° or 20°). Anteroposterior displacement and inversion-eversion rotation were also assessed with arthrometry, and functional dorsiflexion motion was assessed with the weightbearing lunge (WBL) test. RESULTS: Good-to-excellent intrarater reliability was observed for peak dorsiflexion (intraclass correlation coefficient [ICC][2,k] = 0.949-0.988) and plantarflexor stiffness (ICC[2,k] = 0.761-0.984). Interrater reliability was good to excellent for peak dorsiflexion (ICC[2,1] = 0.766-0.910) and poor to excellent for plantarflexor stiffness (ICC[2,1] = 0.275-0.914). Reliability was best for 20-Nm loads at 5 Nm/sec. Strong correlations were observed between peak dorsiflexion and anteroposterior displacement (r = 0.666; P = 0.035) and WBL distance (r = -0.681; P = 0.036). CONCLUSIONS: Using an ankle arthrometer to assess peak dorsiflexion and plantarflexor stiffness seems reliable when performed to greater torques with faster speeds; and offers consistency with functional measures. Use of this readily available tool may benefit clinicians attempting to quantify equinus and dorsiflexion deficits in pathological populations.

Evidence-based best practice advice for patients treated with systemic immunosuppressants in relation to COVID-19.

The emergence of the COVID-19 pandemic has led to significant uncertainty among physicians and patients about the safety of immunosuppressive medications used for the management of dermatologic conditions. We review available data on commonly used immunosuppressants and their effect on viral infections beyond COVID-19. Notably, the effect of some immunosuppressants on viruses related to SARS-CoV2, including SARS and MERS, has been previously investigated. In the absence of data on the effect of immunosuppressants on COVID-19, these data could be used to make clinical decisions on initiation and continuation of immunosuppressive medications during this pandemic. In summary, we recommend considering the discontinuation of oral Janus kinase (JAK) inhibitors and prednisone; considering the delay of rituximab infusion; and suggesting the careful continuation of cyclosporine, mycophenolate, azathioprine, methotrexate, and biologics in patients currently benefitting from such treatments.