Hidradenitis Suppurativa: New Targets and Emerging Treatments.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can be challenging to treat. Biologics and targeted small molecules have become an increasingly popular area of investigation for therapeutic development for moderate-to-severe HS, though only three biologics-adalimumab, secukinumab, and bimekizumab-have received US Food and Drug Administration (FDA) or European Medicines Evaluation Agency approval for treating HS. Promising agents under investigation are targeting interleukin 17A/F, JAK/STAT pathway, interleukin 36, interleukin 1, and more.

A Pearl for Pretibial and Forearm Repair Following Mohs Micrographic Surgery.

Wound repair of the pretibial and forearm regions presents a challenge during dermatologic surgery as these areas are under significant tension and exhibit increased skin fragility. Various methodologies have been proposed for the closure and repair of such wounds, however, the use of the bilayered suture technique may be simpler and more effective than other techniques such as the pinch stitch, pully stitch, slip-knot stitch, pulley set-back dermal suture, horizontal mattress suture, pully stitch, and tandem pulley stitch. Our objective was to describe a novel method for the repair of pretibial and forearm wounds following Mohs micrographic surgery utilizing bilayered closure followed by tissue adhesive application.  J Drugs Dermatol. 2024;23(5):380.     doi:10.36849/JDD.7139  .

Aging in Place and 'The Little Things': Prioritizing Mobile Health and Social Care in Rural Communities.

Older adults are more frequently wanting to age in place. Governments are seeking cost-effective and efficient methods of supporting aging populations. Older adults who want to stay in their homes for as long as possible encounter multiple barriers, including struggling to maintain their homes, inadequate levels of social and healthcare support, and the lack of financial capacity to pay for home support services. The Mobile Seniors' Wellness Network (MSWN), a multi-disciplinary and person-centered mobile health and social support intervention study was designed to investigate and support aging in place for older adults living in rural New Brunswick, Canada. Secondary analysis of case notes and exit interviews using content analysis revealed concerns with the lack of affordable and mobile care services for vulnerable rural older adults. Older adults revealed that their needs include "the little things" rather than grand gestures or sweeping policies to age in place such as assistance with grounds and home maintenance, in addition to relational and person-centered health and social care in the home. Reliance on private service delivery and volunteer organizations can increase the likelihood that older adults will experience a breakdown of social support networks tied together loosely by friends, family, and their communities. When services are unattainable aging in place becomes an unreachable goal.

Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy.

Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously "undruggable" targets for biologic-based therapy.

Slipped-strand mispairing within a polycytidine tract in transcriptional regulator mga leads to M protein phase variation and Mga length polymorphism in Group A Streptococcus.

The M protein, a major virulence factor of Group A Streptococcus (GAS), is regulated by the multigene regulator Mga. An unexplained phenomena frequently occurring with in vitro genetic manipulation or culturing of M1T1 GAS strains is the loss of M protein production. This study was aimed at elucidating the basis for the loss of M protein production. The majority of M protein-negative (M-) variants had one C deletion at a tract of 8 cytidines starting at base 1,571 of the M1 mga gene, which is designated as c.1571C[8]. The C deletion led to a c.1571C[7] mga variant that has an open reading frame shift and encodes a Mga-M protein fusion protein. Transformation with a plasmid containing wild-type mga restored the production of the M protein in the c.1571C[7] mga variant. Isolates producing M protein (M+) were recovered following growth of the c.1571C[7] M protein-negative variant subcutaneously in mice. The majority of the recovered isolates with reestablished M protein production had reverted back from c.1571C[7] to c.1571C[8] tract and some M+ isolates lost another C in the c.1571C[7] tract, leading to a c.1571C[6] variant that encodes a functional Mga with 13 extra amino acid residues at the C-terminus compared with wild-type Mga. The nonfunctional c.1571C[7] and functional c.1571C[6] variants are present in M1, M12, M14, and M23 strains in NCBI genome databases, and a G-to-A nonsense mutation at base 1,657 of M12 c.1574C[7] mga leads to a functional c.1574C[7]/1657A mga variant and is common in clinical M12 isolates. The numbers of the C repeats in this polycytidine tract and the polymorphism at base 1,657 lead to polymorphism in the size of Mga among clinical isolates. These findings demonstrate the slipped-strand mispairing within the c.1574C[8] tract of mga as a reversible switch controlling M protein production phase variation in multiple GAS common M types.

Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management.

BACKGROUND: Cutaneous immune-related adverse events (cirAEs) remain a prevalent and common sequelae of immune checkpoint inhibitor (ICI) therapy, often necessitating treatment interruption and prolonged immune suppression. Treatment algorithms are still poorly defined, based on single-institution case reports without adequate safety assessments, and subject to publication bias. METHODS: Data in this registry were collected through a standardized REDCap form distributed to dermatologists via email listserv. RESULTS: Ninety-seven cirAEs were reported from 13 institutions in this registry. Topical and systemic steroids were the most common treatments used; however, targeted treatment matched to disease morphology was identified at numerous sites. Novel cirAE therapy uses that to our knowledge have not been previously described were captured including tacrolimus for the treatment of follicular, bullous, and eczematous eruptions and phototherapy for eczematous eruptions. Moreover, further evidence of cirAE treatment applications sparsely described in literature were also captured in this study including dupilumab and rituximab for bullous eruptions, phototherapy for lichenoid and psoriasiform eruptions, and acitretin for psoriasiform eruptions, among others. No serious adverse events were reported. Numerous targeted therapeutics including dupilumab, rituximab, and psoriasis biologics, among others, were associated with a cirAE grade improvement of ≥2 grades in every patient treated. CONCLUSION: This study suggests that a multi-institutional registry of cirAEs and management is not only feasible but that the information collected can be used to detect, evaluate, and rigorously assess targeted treatments for cirAEs. Further expansion and modification to include treatment progression may allow for sufficient data for specific treatment recommendations to be made.

A framework for the targeted recruitment of crop-beneficial soil taxa based on network analysis of metagenomics data.

BACKGROUND: The design of ecologically sustainable and plant-beneficial soil systems is a key goal in actively manipulating root-associated microbiomes. Community engineering efforts commonly seek to harness the potential of the indigenous microbiome through substrate-mediated recruitment of beneficial members. In most sustainable practices, microbial recruitment mechanisms rely on the application of complex organic mixtures where the resources/metabolites that act as direct stimulants of beneficial groups are not characterized. Outcomes of such indirect amendments are unpredictable regarding engineering the microbiome and achieving a plant-beneficial environment. RESULTS: This study applied network analysis of metagenomics data to explore amendment-derived transformations in the soil microbiome, which lead to the suppression of pathogens affecting apple root systems. Shotgun metagenomic analysis was conducted with data from 'sick' vs 'healthy/recovered' rhizosphere soil microbiomes. The data was then converted into community-level metabolic networks. Simulations examined the functional contribution of treatment-associated taxonomic groups and linked them with specific amendment-induced metabolites. This analysis enabled the selection of specific metabolites that were predicted to amplify or diminish the abundance of targeted microbes functional in the healthy soil system. Many of these predictions were corroborated by experimental evidence from the literature. The potential of two of these metabolites (dopamine and vitamin B12) to either stimulate or suppress targeted microbial groups was evaluated in a follow-up set of soil microcosm experiments. The results corroborated the stimulant's potential (but not the suppressor) to act as a modulator of plant beneficial bacteria, paving the way for future development of knowledge-based (rather than trial and error) metabolic-defined amendments. Our pipeline for generating predictions for the selective targeting of microbial groups based on processing assembled and annotated metagenomics data is available at https://github.com/ot483/NetCom2 . CONCLUSIONS: This research demonstrates how genomic-based algorithms can be used to formulate testable hypotheses for strategically engineering the rhizosphere microbiome by identifying specific compounds, which may act as selective modulators of microbial communities. Applying this framework to reduce unpredictable elements in amendment-based solutions promotes the development of ecologically-sound methods for re-establishing a functional microbiome in agro and other ecosystems. Video Abstract.

Subnational Gender Inequality and Childhood Immunization: An Ecological Analysis of the Subnational Gender Development Index and DTP Coverage Outcomes across 57 Countries.

The role of gender inequality in childhood immunization is an emerging area of focus for global efforts to improve immunization coverage and equity. Recent studies have examined the relationship between gender inequality and childhood immunization at national as well as individual levels; we hypothesize that the demonstrated relationship between greater gender equality and higher immunization coverage will also be evident when examining subnational-level data. We thus conducted an ecological analysis examining the association between the Subnational Gender Development Index (SGDI) and two measures of immunization-zero-dose diphtheria-tetanus-pertussis (DTP) prevalence and 3-dose DTP coverage. Using data from 2010-2019 across 702 subnational regions within 57 countries, we assessed these relationships using fractional logistic regression models, as well as a series of analyses to account for the nested geographies of subnational regions within countries. Subnational regions were dichotomized to higher gender inequality (top quintile of SGDI) and lower gender inequality (lower four quintiles of SGDI). In adjusted models, we find that subnational regions with higher gender inequality (favoring men) are expected to have 5.8 percentage points greater zero-dose prevalence than regions with lower inequality [16.4% (95% confidence interval (CI) 14.5-18.4%) in higher-inequality regions versus 10.6% (95% CI 9.5-11.7%) in lower-inequality regions], and 8.2 percentage points lower DTP3 immunization coverage [71.0% (95% CI 68.3-73.7%) in higher-inequality regions versus 79.2% (95% CI 77.7-80.7%) in lower-inequality regions]. In models accounting for country-level clustering of gender inequality, the magnitude and strength of associations are reduced somewhat, but remain statistically significant in the hypothesized direction. In conjunction with published work demonstrating meaningful associations between greater gender equality and better childhood immunization outcomes in individual- and country-level analyses, these findings lend further strength to calls for efforts towards greater gender equality to improve childhood immunization and child health outcomes broadly.

Toward a holistic view of orchard ecosystem dynamics: A comprehensive review of the multiple factors governing development or suppression of apple replant disease.

Replant diseases are a common occurrence in perennial cropping systems. In apple, progress toward the development of a universally effective disease management strategy, beyond the use of broad-spectrum soil fumigants, is impeded by inconsistencies in defining replant disease etiology. A preponderance of evidence attributes apple replant disease to plant-induced changes in the soil microbiome including the proliferation of soilborne plant pathogens. Findings from alternative studies suggest that the contribution of abiotic factors, such as the accumulation of phenolic detritus from previous orchard plantings, may play a part as well. Engineering of the resident soil microbiome using resource-based strategies is demonstrating potential to limit activity of replant pathogens and improve productivity in newly established orchards. An understanding of factors promoting the assembly of a disease-suppressive soil microbiome along with consideration of host factors that confer disease tolerance or resistance is imperative to the developing a more holistic view of orchard ecosystem dynamics. Here, we review the literature concerning the transition of orchard soil from a healthy state to a replant disease-conducive state. Included in the scope of this review are studies on the influence of soil type and geography on the apple replant pathogen complex. Furthermore, several tolerance and innate resistance mechanisms that have been described in apple to date, including the role of root chemistry/exudates are discussed. Finally, the interplay between apple rootstock genotype and key resource-based strategies which have been shown to "reshape" the plant holobiont in favor of a more prophylactic or disease-suppressive state is highlighted.

The Association between Childhood Immunization and Gender Inequality: A Multi-Country Ecological Analysis of Zero-Dose DTP Prevalence and DTP3 Immunization Coverage.

This study explores the association between childhood immunization and gender inequality at the national level. Data for the study include annual country-level estimates of immunization among children aged 12-23 months, indicators of gender inequality, and associated factors for up to 165 countries from 2010-2019. The study examined the association between gender inequality, as measured by the gender development index and the gender inequality index, and two key outcomes: prevalence of children who received no doses of the DTP vaccine (zero-dose children) and children who received the third dose of the DTP vaccine (DTP3 coverage). Unadjusted and adjusted fractional logit regression models were used to identify the association between immunization and gender inequality. Gender inequality, as measured by the Gender Development Index, was positively and significantly associated with the proportion of zero-dose children (high inequality AOR = 1.61, 95% CI: 1.13-2.30). Consistently, full DTP3 immunization was negatively and significantly associated with gender inequality (high inequality AOR = 0.63, 95% CI: 0.46-0.86). These associations were robust to the use of an alternative gender inequality measure (the Gender Inequality Index) and were consistent across a range of model specifications controlling for demographic, economic, education, and health-related factors. Gender inequality at the national level is predictive of childhood immunization coverage, highlighting that addressing gender barriers is imperative to achieve universal coverage in immunization and to ensure that no child is left behind in routine vaccination.

Fish oil blunts lung function decrements induced by acute exposure to ozone in young healthy adults: A randomized trial.

BACKGROUND: Over one-third of the U.S. population is exposed to unsafe levels of ozone (O3). Dietary supplementation with fish oil (FO) or olive oil (OO) has shown protection against other air pollutants. This study evaluates potential cardiopulmonary benefits of FO or OO supplementation against acute O3 exposure in young healthy adults. METHODS: Forty-three participants (26 ± 4 years old; 47% female) were randomized to receive 3 g/day of FO, 3 g/day OO, or no supplementation (CTL) for 4 weeks prior to undergoing 2-hour exposures to filtered air and 300 ppb O3 with intermittent exercise on two consecutive days. Outcome measurements included spirometry, sputum neutrophil percentage, blood markers of inflammation, tissue injury and coagulation, vascular function, and heart rate variability. The effects of dietary supplementation and O3 on these outcomes were evaluated with linear mixed-effect models. RESULTS: Compared with filtered air, O3 exposure decreased FVC, FEV1, and FEV1/FVC immediately post exposure regardless of supplementation status. Relative to that in the CTL group, the lung function response to O3 exposure in the FO group was blunted, as evidenced by O3-induced decreases in FEV1 (Normalized CTL -0.40 ± 0.34 L, Normalized FO -0.21 ± 0.27 L) and FEV1/FVC (Normalized CTL -4.67 ± 5.0 %, Normalized FO -1.4 ± 3.18 %) values that were on average 48% and 70% smaller, respectively. Inflammatory responses measured in the sputum immediately post O3 exposure were not different among the three supplementation groups. Systolic blood pressure elevations 20-h post O3 exposure were blunted by OO supplementation. CONCLUSION: FO supplementation appears to offer protective effects against lung function decrements caused by acute O3 exposure in healthy adults.

Defining the Opioid Requirement in Anterior Cruciate Ligament Reconstruction.

INTRODUCTION: The amount and duration of opioids necessary after anterior cruciate ligament reconstruction (ACLR) are inadequately defined. This study sought to prospectively (1) define the amount and duration of opioid consumption, (2) investigate the relationship between preoperative pain expectation and postoperative satisfaction with pain management, and (3) identify risk factors for increased opioid use after ACLR. METHODS: One hundred eight patients undergoing primary ACLR with hamstring graft were prospectively analyzed for preoperative pain expectation, using visual analog scale (VAS) rating, and postoperative satisfaction with pain management. Univariate and multivariate analyses were done to identify patient characteristics associated with satisfaction and/or amount and duration of opioid use. RESULTS: Mean duration and cumulative intake of opioid consumption after ACLR were 5.3 days and 15.3 tablets, respectively. Patients expected moderate postoperative pain: mean preoperative VAS = 68.9. The preoperative VAS rating was associated with a significantly greater amount (P = 0.0265) and longer duration (P = 0.0212) of opioid consumption. Baseline opioid users took opioids for twice as long postoperatively (10.0 versus 5.0 days; P = 0.0149) and consumed twice as many tablets (29.3 versus 14.8 tablets; P = 0.0280) compared with opioid-naive patients. DISCUSSION: This study demonstrated on average 15.3 opioid tablets over 5.3 days provided satisfactory pain management after ACLR. Risk factors for increased opioid consumption included preoperative opioid use.

Development and Application of a Semi quantitative Scoring Method for Ultrastructural Assessment of Acute Stress in Pancreatic Islets.

BACKGROUND: Pancreas and islet transplantation outcomes are negatively impacted by injury to the endocrine cells from acute stress during donor death, organ procurement, processing, and transplant procedures. Here, we report a novel electron microscopy scoring system, the Newcastle Pancreas Endocrine Stress Score (NPESS). METHODS: NPESS was adapted and expanded from our previously validated method for scoring pancreatic exocrine acinar cells, yielding a 4-point scale (0-3) classifying ultrastructural pathology in endocrine cell nuclei, mitochondria, endoplasmic reticulum, cytoplasmic vacuolization, and secretory granule depletion, with a maximum additive score of 15. We applied NPESS in a cohort of deceased organ donors after brainstem (DBD) and circulatory (DCD) death with a wide range of cold ischemic times (3.6-35.9 h) including 3 donors with type 1 and 3 with type 2 diabetes to assess islets in situ (n = 30) in addition to pancreata (n = 3) pre- and postislet isolation. RESULTS: In DBD pancreata, NPESS correlated with cold ischemic time (head: r = 0.55; P = 0.02) and mirrored exocrine score (r = 0.48; P = 0.01). When stratified by endocrine phenotype, cells with granules of heterogeneous morphology had higher scores than α, ß, and δ cells (P < 0.0001). Cells of mixed endocrine-exocrine morphology were observed in association with increased NPESS (P = 0.02). Islet isolation was associated with improved NPESS (in situ: 8.39 ± 0.77 [Mean ± SD]; postisolation: 5.44 ± 0.31; P = 0.04). CONCLUSIONS: NPESS provides a robust method for semiquantitative scoring of subcellular ultrastructural changes in human pancreatic endocrine cells in situ and following islet isolation with utility for unbiased evaluation of acute stress in organ transplantation research.