Treatment of calcinosis cutis associated with autoimmune connective tissue diseases.

Calcinosis cutis is a condition that is commonly associated with autoimmune connective tissue diseases. It is characterized by the deposition of insoluble calcium salts in the skin and subcutaneous tissue, which can cause pain, impair function, and have significant impacts on quality of life. Calcinosis cutis is difficult to manage because there is no generally accepted treatment: evidence supporting treatments is mostly comprised of case reports and case series, sometimes yielding mixed findings. Both pharmacologic and procedural interventions have been proposed to improve calcinosis cutis, and each may be suited to different clinical scenarios. This review summarizes current treatment options for calcinosis cutis, with discussion of recommendations based on patient-specific factors and disease severity.

Prevalence and Risk Factors for Renal Insufficiency among Adults Living with HIV in Tanzania: Results from a Cross-Sectional Study in 2020-2021.

With improved survival, adults living with HIV (ALHIV) are increasingly likely to experience age-related and HIV-related comorbidities, including renal insufficiency. Other risk factors for renal insufficiency (high blood pressure (BP), obesity, diabetes, and dyslipidemia) are also growing more common among ALHIV. To determine the prevalence of renal insufficiency (defined as an eGFR < 60 mL/min/1.73 m2) and factors associated with reduced eGFR, we conducted a cross-sectional study at six HIV clinics in Dar-es-Salaam, Tanzania. We applied multivariable (MV) ordinal logistic regression models to identify factors associated with reduced eGFR and examined the interaction of age with BP levels. Among the 450 ALHIV on ART analyzed [26% males; median age 43 (IQR: 18-72) years; 89% on tenofovir-containing ART; 88% HIV viral load ≤50 copies/mL], 34 (7.5%) had renal insufficiency. Prevalence was higher among males (12%) vs. females (6%), p = 0.03; ALHIV ≥50 (21%) vs. <50 years (2.5%), p < 0.001; those with high [≥130/80 mmHg (15%)] vs. normal [<120/80 mmHg (4%)] BP, p < 0.01 and those with dyslipidemia (10%) vs. those without (4.5%), p < 0.03. After adjusting for covariates, age (in years) was the only covariate with a statistically significant association with reduced eGFR (OR = 1.09 (1.07-1.12), p < 0.001). No significant interaction between age and BP was found. Interventions to increase routine screening for renal insufficiency, especially among older ALHIV, and improve BP control are critical to reducing kidney disease-related morbidity and mortality.

Proton therapy induces a local microglial neuroimmune response.

BACKGROUND AND PURPOSE: Although proton therapy is increasingly being used in the treatment of paediatric and adult brain tumours, there are still uncertainties surrounding the biological effect of protons on the normal brain. Microglia, the brain-resident macrophages, have been shown to play a role in the development of radiation-induced neurotoxicity. However, their molecular and hence functional response to proton irradiation remains unknown. This study investigates the effect of protons on microglia by comparing the effect of photons and protons as well as the influence of age and different irradiated volumes. MATERIALS AND METHODS: Rats were irradiated with 14 Gy to the whole brain with photons (X-rays), plateau protons, spread-out Bragg peak (SOBP) protons or to 50 % anterior, or 50 % posterior brain sub-volumes with plateau protons. RNA sequencing, validation of microglial priming gene expression using qPCR and high-content imaging analysis of microglial morphology were performed in the cortex at 12 weeks post irradiation. RESULTS: Photons and plateau protons induced a shared transcriptomic response associated with neuroinflammation. This response was associated with a similar microglial priming gene expression signature and distribution of microglial morphologies. Expression of the priming gene signature was less pronounced in juvenile rats compared to adults and slightly increased in rats irradiated with SOBP protons. High-precision partial brain irradiation with protons induced a local microglial priming response and morphological changes. CONCLUSION: Overall, our data indicate that the brain responds in a similar manner to photons and plateau protons with a shared local upregulation of microglial priming-associated genes, potentially enhancing the immune response to subsequent inflammatory challenges.

"I only seek treatment when I am ill": experiences of hypertension and diabetes care among adults living with HIV in urban Tanzania.

BACKGROUND: For adults living with HIV (ALHIV) and comorbidities, access to comprehensive healthcare services is crucial to achieving optimal health outcomes. This study aims to describe lived experiences, challenges, and coping strategies for accessing care for hypertension and/or diabetes (HTN/DM) in HIV care and treatment clinics (CTCs) and other healthcare settings. METHODOLOGY: We conducted a qualitative study that employed a phenomenological approach between January and April 2022 using a semi-structured interview guide in six HIV CTCs in Dar es Salaam, Tanzania. We purposively recruited 33 ALHIV with HTN (n = 16), DM (n = 10), and both (n = 7). Thematic content analysis was guided by the 5As framework of access to care. FINDINGS: The majority of the participants were females, between the ages of 54-73, and were recruited from regional referral hospitals. HIV CTCs at regional referral hospitals had more consistent provision of HTN screening services compared to those from district hospitals and health centers. Participants sought HTN/DM care at non-CTC health facilities due to the limited availability of such services at HIV CTCs. However, healthcare delivery for these conditions was perceived as unaccommodating and poorly coordinated. The need to attend multiple clinic appointments for the management of HTN/DM in addition to HIV care was perceived as frustrating, time-consuming, and financially burdensome. High costs of care and transportation, limited understanding of comorbidities, and the perceived complexity of HTN/DM care contributed to HTN/DM treatment discontinuity. As a means of coping, participants frequently monitored their own HTN/DM symptoms at home and utilized community pharmacies and dispensaries near their residences to check blood pressure and sugar levels and obtain medications. Participants expressed a preference for non-pharmaceutical approaches to comorbidity management such as lifestyle modification (preferred by young participants) and herbal therapies (preferred by older participants) because of concerns about side effects and perceived ineffectiveness of HTN/DM medications. Participants also preferred integrated care and focused patient education on multimorbidity management at HIV CTCs. CONCLUSION: Our findings highlight significant barriers to accessing HTN/DM care among ALHIV, mostly related to affordability, availability, and accessibility. Integration of NCD care into HIV CTCs, could greatly improve ALHIV health access and outcomes and align with patient preference.

Radiotherapy induces persistent innate immune reprogramming of microglia into a primed state.

Over half of patients with brain tumors experience debilitating and often progressive cognitive decline after radiotherapy treatment. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults, microglia can develop innate immune memory (IIM), which can either enhance (priming or training) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigate whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats show a stronger immune response to a secondary inflammatory insult, demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of postmortem normal-appearing non-tumor brain tissue of patients with glioblastoma indicates that radiation-induced microglial priming is likely conserved in humans. Targeting microglial priming or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity.

Effect of nicotine expectancy and nicotine dose reduction on cigarette demand, withdrawal alleviation, and puff topography.

BACKGROUND: Current FDA plans include proposed nicotine reduction mandates by the end of 2023. Most research on reduced nicotine cigarettes has been dose-blinded, while a mandate would be known to the public. Few laboratory studies have examined specifically how low nicotine content labeling impacts behavioral response. The purpose of this within-subject, balanced-placebo, human laboratory study was to evaluate the main and interactive effects of nicotine dose expectancy and dose reduction on cigarette reinforcement, withdrawal alleviation, and puff topography. METHODS: Participants who smoke daily (N=21; 9 female) completed one practice and four experimental sessions in which expectancy (labeled "average" versus "very low" nicotine) and nicotine dose (0.80mg versus 0.03mg yield) were manipulated. Participants in acute withdrawal sampled experimental cigarettes followed by withdrawal alleviation and puff topography measures. Cigarette demand was measured using an incentivized purchase task. Analyses evaluated main and interactive effects of expectancy and nicotine dose. RESULTS: Nicotine dose manipulation produced expected physiological effects (e.g., heart rate increases) and both reduced nicotine dose and expectation manipulations reduced perceived nicotine content. Expectation of reduced nicotine alone or in combination with reduced nicotine dose did not alter demand, withdrawal alleviation, or topography. Effective withdrawal alleviation was observed in all conditions. CONCLUSIONS: These data inform nicotine regulation policy by suggesting limited compensatory harms caused by reduced nicotine expectations. The minimal acute effects of reduced nicotine expectancy or exposure on demand suggests that reduced nicotine standards are likely to generate their greatest public health benefit through the slowing of newly initiating cigarette smoking.

Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12 + dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19 + IL4I1 + fibroblasts, and clonally expanded IL13 + IL22 + IL26 + T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13 + IL22 + IL26 + T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.

The Architecture of Object-Based Attention.

The allocation of attention to objects raises several intriguing questions: What are objects, how does attention access them, what anatomical regions are involved? Here, we review recent progress in the field to determine the mechanisms underlying object-based attention. First, findings from unconscious priming and cueing suggest that the preattentive targets of object-based attention can be fully developed object representations that have reached the level of identity. Next, the control of object-based attention appears to come from ventral visual areas specialized in object analysis that project downward to early visual areas. How feedback from object areas can accurately target the object's specific locations and features is unknown but recent work in autoencoding has made this plausible. Finally, we suggest that the three classic modes of attention may not be as independent as is commonly considered, and instead could all rely on object-based attention. Specifically, studies show that attention can be allocated to the separated members of a group-without affecting the space between them-matching the defining property of feature-based attention. At the same time, object-based attention directed to a single small item has the properties of space-based attention. We outline the architecture of object-based attention, the novel predictions it brings, and discuss how it works in parallel with other attention pathways.

Guidelines for Optimal Patient Outcomes Using Calcium Hydroxylapatite for Jawline Contour.

Background: Calcium hydroxylapatite (CaHA(+); Radiesse(+) [Merz North America, Inc., Raleigh, NC]) is the first FDA-approved injectable filler for subdermal and/or supraperiosteal injection to improve moderate-to-severe loss of jawline contour. CaHA has been recognized in the past for its ability to provide contour and support overlying tissues and utilized for jawline augmentation well before this recent indication; however, with recent FDA approval of CaHA(+) for jawline contour improvement, it is important that clinicians are aware of best practices for patient selection, treatment planning and injection, as well as safety considerations and postprocedure care. Objectives: To provide guidance on best practices for patient assessment and on-label use of CaHA(+) for jawline rejuvenation and augmentation. Methods: As part of a 2-h roundtable discussion, 5 clinicians with expertise in both the use of CaHA(+) and jawline treatment discussed patient selection, CaHA(+) injection technique, and important safety measures, with the purpose of developing guidance to support optimal clinical use. Results: The most common applications of CaHA(+) in the jawline are rejuvenation of the prejowl sulcus, recontouring the jawline, and providing definition to the gonial angle. Improving the gonial angle is of particular interest as it is a procedure sought by patients of all genders and ages. Variations in technique are discussed and case studies are presented. Conclusions: Jawline augmentation is a procedure with wide-ranging appeal for a diverse array of patients. CaHA(+) is an ideal filler for jawline augmentation due to its rheologic properties (high G') and ability to achieve defined contours and angles. Appropriate injection technique permits effective treatment and outcomes associated with high patient satisfaction.

The Blinded-Dose Purchase Task: assessing hypothetical demand based on cocaine, methamphetamine, and alcohol administration.

RATIONALE: Behavioral economic drug purchase tasks quantify the reinforcing value of a drug (i.e., demand). Although widely used to assess demand, drug expectancies are rarely accounted for and may introduce variability across participants given diverse drug experiences. OBJECTIVES: Three experiments validated and extended previous hypothetical purchase tasks by using blinded drug dose as a reinforcing stimulus, and determined hypothetical demand for experienced effects while controlling for drug expectancies. METHODS: Across three double-blind, placebo-controlled, within-subject experiments, cocaine (0, 125, 250 mg/70 kg; n=12), methamphetamine (0, 20, 40 mg; n=19), and alcohol (0, 1 g/kg alcohol; n=25) were administered and demand was assessed using the Blinded-Dose Purchase Task. Participants answered questions regarding simulated purchasing of the blinded drug dose across increasing prices. Demand metrics, subjective effects, and self-reported real-world monetary spending on drugs were evaluated. RESULTS: Data were well modeled by the demand curve function, with significantly higher intensity (purchasing at low prices) for active drug doses compared to placebo for all experiments. Unit-price analyses revealed more persistent consumption across prices (lower α) in the higher compared to lower active dose condition for methamphetamine (a similar non-significant finding emerged for cocaine). Significant associations between demand metrics, peak subjective effects, and real-world spending on drugs also emerged across all experiments. CONCLUSIONS: Orderly demand curve data revealed differences across drug and placebo conditions, and relations to real-world measures of drug spending, and subjective effects. Unit-price analyses enabled parsimonious comparisons across doses. Results lend credence to the validity of the Blinded-Dose Purchase Task, which allows for control of drug expectancies.