Genome-informed trophic classification and functional characterization of virulence proteins from the maize tar spot pathogen Phyllachora maydis.

Phyllachora maydis is an ascomycete foliar fungal pathogen and the causal agent of tar spot in maize. Though P. maydis is considered an economically important foliar pathogens of maize, our general knowledge of the trophic lifestyle and functional role of effector proteins from this fungal pathogen remains limited. Here, we utilized a genome-informed approach to predict the trophic lifestyle of P. maydis and functionally characterized a subset of candidate effectors from this fungal pathogen. Leveraging the most recent P. maydis genome annotation and the CATAStrophy pipeline, we show this fungal pathogen encodes a predicted Carbohydrate-active enzymes (CAZymes) repertoire consistent with that of biotrophs. To investigate fungal pathogenicity, we selected 18 candidate effector proteins that were previously shown to be expressed during primary disease development. We assessed whether these putative effectors share predicted structural similarity with other characterized fungal effectors and determined whether any suppress plant immune responses. Using AlphaFold2 and Foldseek, we showed one candidate effector, PM02_g1115, adopts a predicted protein structure similar to that of an effector from Verticillium dahlia. Furthermore, transient expression of candidate effector-fluorescent protein fusions in Nicotiana benthamiana revealed two putative effectors, PM02_g378 and PM02_g2610, accumulated predominantly in the cytosol, and three candidate effectors, PM02_g1115, PM02_g7882, and PM02_g8240 consistently attenuated chitin-mediated reactive oxygen species production. Collectively, these results presented herein provide insights into the predicted trophic lifestyle and putative functions of effectors from P. maydis and will likely stimulate continued research to elucidate the molecular mechanisms used by P. maydis to induce tar spot.

USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF.

BACKGROUND: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts. METHODS: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells. We also evaluated the effects of USP7 inhibition on tumor growth inhibition in syngeneic models when dosed in combination with immune checkpoint inhibitors (ICIs). RESULTS: Abrogation of VEGF secretion from fibroblasts in response to USP7 inhibition resulted in inhibition of tumor neoangiogenesis and increased tumor recruitment of CD8-positive T-lymphocytes, leading to significantly improved sensitivity to immune checkpoint inhibitors. In syngeneic models, treatment with USP7 inhibitors led to striking tumor responses resulting in significantly improved survival. CONCLUSIONS: USP7-mediated reprograming of the TME is not linked to its previously characterized role in modulating MDM2 but does require p53 and UHRF1 in addition to the well-characterized VEGF transcription factor, HIF-1α. This represents a function of USP7 that is unique to fibroblasts, and which is not observed in cancer cells or other components of the TME. Given the potential for USP7 inhibitors to transform "immune desert" tumors into "immune responsive" tumors, this paves the way for a novel therapeutic strategy combining USP7 inhibitors with immune checkpoint inhibitors (ICIs).

Investigating effect of standardized total body skin examination using sequence-networks.

This study employs sequence-network analysis to investigate the influence of instructing a standardized procedure on total-body skin examination (TBSE) performance. A between-subjects study was conducted with thirty-one participants comprising medical students and attending physicians. Among these participants, fifteen were randomly assigned to the uninstructed group and sixteen to the instructed group. The participants' gaze and field of view were recorded using eye tracking glasses while performing TBSE on a male and a female standardized patient. The recordings were then transcribed to depict the examination process. The instructed group missed significantly fewer body parts (p = 0.045) and had higher time efficiency (p = 0.007) while examining the female patient, but no significant difference was observed for the male patient examination. Furthermore, the examination sequences of the instructed group contained lesser variability than the uninstructed group. Hence, implementing a standard optimal procedure to perform TBSE could minimize the likelihood of missing body parts, increase examination efficiency, and improve performance consistency. This study demonstrated the potential of sequence-network analysis to study human performance in sequential tasks.

Sarcoidosis: Evaluation and Treatment.

Sarcoidosis is a multisystem granulomatous inflammatory disease of unknown etiology that can involve any organ. Ongoing dyspnea and dry cough in a young to middle-aged adult should increase the suspicion for sarcoidosis. Symptoms can present at any age and affect any organ system; however, pulmonary sarcoidosis is the most common. Extrapulmonary manifestations often involve cardiac, neurologic, ocular, and cutaneous systems. Patients with sarcoidosis can exhibit constitutional symptoms such as fever, unintentional weight loss, and fatigue. The early recognition and diagnosis of sarcoidosis are challenging because there is no diagnostic standard for testing, initial symptoms vary, and patients may be asymptomatic. Consensus guidelines recommend a holistic approach when diagnosing sarcoidosis that focuses on clinical presentation and radiographic findings, biopsy with evidence of noncaseating granulomas, involvement of more than one organ system, and elimination of other etiologies of granulomatous disease. Corticosteroids are the initial treatment for active disease, with refractory cases often requiring immunosuppressive or biologic therapies. Transplantation can be considered for advanced and end-stage disease depending on organ involvement.

Cutaneous Lupus Erythematosus: Review and Considerations for Older Populations.

Though more common earlier in life, increasing attention is being focused on the development of cutaneous lupus erythematosus (CLE) in patients with advancing age. Studies show that CLE is more common in older populations than previously thought, and all CLE subtypes are possible in this group. Just like patients in the third or fourth decade of life, CLE may appear alongside or independent of systemic lupus erythematosus. Older populations manifesting CLE for the first time seem to have a lower risk of progression to systemic disease than younger peers, and are more commonly White. CLE must be carefully distinguished from other skin conditions that have a predilection for presentation in older populations, including rosacea, lichen planus, and other autoimmune conditions such as dermatomyositis or pemphigus/pemphigoid. It is thought that most CLE in older populations is drug-induced, with drug-induced subacute cutaneous lupus erythematosus being the most common subtype. Management of CLE in older patients focuses on eliminating unnecessary medications known to induce CLE, and otherwise treatment proceeds similarly to that in younger patients, with a few special considerations.

Obesity is an independent risk factor for cancer development following diagnosis of dermatomyositis.

Patients with dermatomyositis (DM) are at an increased risk of cancer development, especially around the time of diagnosis of DM. Obesity is also a risk factor in the general population for cancer development. This study aimed to assess the association between cancer in DM patients with and without obesity as defined by ICD code and BMI data. In this analysis of patients with DM, logistic regression modeling of the odds of cancer outcome was performed for patients with DM and obesity compared to those without obesity, adjusted for age and sex. A total of 12,722 patients with DM were identified, of whom 6,055 had available BMI data. DM patients who were coded obese at any point had significantly higher odds 1.98 (95 % Confidence interval (CI) 1.70, 2.30) of a subsequent cancer diagnosis. This association was also found in the subgroup analysis with available BMI where patients with obesity (BMI ≥30 kg/m2) had an increased odds of cancer 1.23 (1.02, 1.49) when compared to patients with BMI <30 kg/m2 with DM. In time to event analysis any obesity code was associated with a 16 % increased hazard of cancer (adjusted hazard ratio 1.16 [95 % CI 1.02, 1.31]). Overall, the most frequent type of cancer was breast cancer, however patients with DM and obesity had higher frequencies of lymphoma, colorectal, melanoma, uterine, renal cancers compared to patients with DM without obesity.

14-Gauge Coaxial Bone Needle Leads to Superior Results When Injecting Calcinosis Cutis.

Calcinosis cutis can occur idiopathically or be associated with injury, metabolic disease, and different rheumatologic diseases such as scleroderma and dermatomyositis. Calcinosis cutis is often treatment-resistant and leads to decreased quality of life and pain. Medical therapies, such as bisphosphonates, warfarin, tetracyclines, calcium channel blockers, colchicine, laser therapy and surgery, lithotripsy, and even stem cell transplantation have been used with varying success.1 Lesions of calcinosis cutis can persist even when systemic disease is adequately controlled leaving the patient with a painful reminder of their underlying disease.

Recombinant Zoster Vaccine Reduces 3-Year Cardiovascular Risk: Insights From a Multi-Centered Database.

BACKGROUND: Herpes zoster increases the risk for stroke and myocardial infarction. Zoster vaccination's impact on this risk is understudied. This retrospective work sought to determine if prophylactic herpes zoster vaccination may reduce the risk of stroke, myocardial infarction, and/or mortality. METHODS: A cohort analysis utilized TriNetX, a national, federated database. In one analysis, patients who received 2 doses of recombinant zoster vaccine (RZV) were compared to adults without RZV. A 1:1 propensity-score match analysis was conducted to adjust for demographics and comorbidities in calculating adjusted relative risks (aRR) with 95% confidence intervals. First-time incidences for myocardial infarction, stroke, and mortality were assessed after 3 years. A subgroup analysis between RZV and zoster vaccine live (ZVL) was also assessed. RESULTS: Matched cohorts of 7,657 patients revealed that adults who received 2 doses of RZV were at lower risk of MI (aRR [95% CI]) = (0.73 [0.55, 0.96]) and mortality (0.7 [0.57, 0.88]) while having similar risk for stroke (0.97 [0.75, 1.26]). Further subgroup analysis also revealed a reduced risk of 3-year mortality when compared to the ZVL cohort (0.84 [0.74, 0.95]). Sample size and comorbidities included in the analysis were limited by using a large database. CONCLUSIONS: RZV reduces the 3-year risk for myocardial infarction and mortality. J Drugs Dermatol. 2023;22(12):1178-1182. doi:10.36849/JDD.7415.

Uncovering the Infection Strategy of Phyllachora maydis during Maize Colonization: A Comprehensive Analysis.

Tar spot, a disease caused by the ascomycete fungal pathogen Phyllachora maydis, is considered one of the most significant yield-limiting diseases of maize (Zea mays L.) within the United States. P. maydis may also be found in association with other fungi, forming a disease complex which is thought to result in the characteristic fish eye lesions. Understanding how P. maydis colonizes maize leaf cells is essential for developing effective disease control strategies. Here, we used histological approaches to elucidate how P. maydis infects and multiplies within susceptible maize leaves. We collected tar spot-infected maize leaf samples from four different fields in northern Indiana at three different time points during the growing season. Samples were chemically fixed and paraffin-embedded for high-resolution light and scanning electron microscopy. We observed a consistent pattern of disease progression in independent leaf samples collected across different geographical regions. Each stroma contained a central pycnidium that produced asexual spores. Perithecia with sexual spores developed in the stomatal chambers adjacent to the pycnidium, and a cap of spores formed over the stroma. P. maydis reproductive structures formed around but not within the vasculature. We observed P. maydis associated with two additional fungi, one of which is likely a member of the Paraphaeosphaeria genus; the other is an unknown fungi. Our data provide fundamental insights into how this pathogen colonizes and spreads within maize leaves. This knowledge can inform new approaches to managing tar spot, which could help mitigate the significant economic losses caused by this disease.

14-Gauge Coaxial Bone Needle Leads to Superior Results When Injecting Calcinosis Cutis.

Calcinosis cutis can occur idiopathically or be associated with injury, metabolic disease, and different rheumatologic diseases such as scleroderma and dermatomyositis.

Cancer Screening for Dermatomyositis: A Survey of Indirect Costs, Burden, and Patient Willingness to Pay.

Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy (IIM) associated with an increased risk for malignancy. Although cancer screening is recommended, no consensus guidelines currently exist. Whole-body positron emission tomography/ computed tomography (PET/CT) has similar cost and efficacy to a more traditional conventional cancer screening panel (CSP). Our study sought to characterize patients' perspective of cancer screening and the indirect costs to patients. We conducted a survey of patients recently diagnosed with DM who were undergoing or had recently undergone a CSP. Patient values and indirect costs need to be considered in choosing a screening modality. This study contributes to a greater understanding of patients' experience of cancer screening in DM, which should be taken into consideration when developing consensus guidelines for cancer screening.

Higher Odds of Adverse Cutaneous Reactions in Patients With Dermatomyositis Treated With Hydroxychloroquine Compared With Methotrexate.

OBJECTIVE: Hydroxychloroquine (HCQ) use for the treatment of dermatomyositis (DM) has been associated with adverse cutaneous reactions. We applied a new user, active comparator, retrospective design to assess differences in adverse cutaneous reactions or hospitalizations between HCQ and methotrexate (MTX) use among patients with DM. METHODS: We used a national network of data from insurance registries (TriNetX), enrolling patients with two International Classification of Diseases (ICD) codes for DM separated by 6 months or more who had a prescription for either (but not both) HCQ or MTX on or after DM diagnosis. Outcomes were adverse cutaneous reactions (ICD codes) or hospital admission (Current Procedural Terminology (CPT) codes) within 4 months from the prescription dispense date. Logistic regression was used to produce adjusted odds ratios (aORs) and 95% confidence intervals (CIs) comparing outcomes in the HCQ group (n = 1364) and the MTX group (n = 1400), adjusted for age at first DM diagnosis, year of birth, sex, and time from DM diagnosis to first prescription. RESULTS: Overall, we found no significant difference in odds of hospitalization in those taking HCQ (aOR 1.05; 95% CI: 0.79-1.39) compared with those on MTX. Patients with DM on HCQ had 30% higher odds of adverse cutaneous reaction diagnosis compared with patients on MTX (aOR 1.30; 95% CI: 1.02-1.59). Age at DM diagnosis was an effect modifier of this association, with higher odds of adverse cutaneous reaction among patients taking HCQ who were younger at diagnosis. CONCLUSION: Compared with MTX use, HCQ use, especially in younger patients, may result in higher odds of adverse cutaneous reactions.

Respecting Conversational Norms Improves Reception of Expert Messages Among Unvaccinated Individuals.

The association of medical experts with politically left-leaning cities and states early in the COVID-19 pandemic may have exacerbated vaccine hesitancy in right-leaning states of the US. Criticism from outside experts violates rules of communication between social groups (i.e. an intergroup sensitivity effect), leading to rejection of messages promoting vaccine safety and efficacy. In two studies, we document the effects of shared geographical group membership for medical expert messages promoting vaccination. We also found evidence that satisfying conversational norms against intergroup criticism reduces message rejection. Specifically, an invitation from ingroup political elites for a doctor to speak reduced the negative effects of unshared group identity.

Rapid-onset ulcerative hand nodule.

Was this an infectious abscess, or something less common?