Disorders in the regulatory arm of the adaptive immune system result in autoimmune‐mediated diseases. While systemic immunosuppression is the prevailing approach to manage them, it fails to achieve ...long‐lasting remission due to concomitant suppression of the regulatory arm and carries the risk of heightened susceptibility to infections and malignancies. Alopecia areata is a condition characterized by localized hair loss due to autoimmunity. The accessibility of the skin allows local rather than systemic intervention to avoid broad immunosuppression. It is hypothesized that the expansion of endogenous regulatory T cells (Tregs) at the site of antigen encounter can restore the immune balance and generate a long‐lasting tolerogenic response. A hydrogel microneedle (MN) patch is therefore utilized for delivery of CCL22, a Treg‐chemoattractant, and IL‐2, a Treg survival factor to amplify them. In an immune‐mediated murine model of alopecia, local bolstering of Treg numbers is shown, leading to sustained hair regrowth and attenuation of inflammatory pathways. In a humanized skin transplant mouse model, expansion of Tregs within human skin is confirmed without engendering peripheral immunosuppression. The patch offers high‐loading capacity and shelf‐life stability for prospective clinical translation. By harmonizing immune responses locally, the aim is to reshape the landscape of autoimmune skin disease management.
Alopecia areata is a condition characterized by hair loss due to autoimmunity. Expansion of endogenous regulatory T cells (Tregs) at the site of antigen encounter can restore the skin immune balance. Here, a hydrogel microneedle is utilized to amplify Tregs in a murine model of alopecia leading to sustained hair regrowth without engendering peripheral immunosuppression. This approach could reshape the landscape of autoimmune skin disease management.
Purpose
Cancer survivors face higher rates of unemployment compared with individuals without a history of cancer. Compared to other cancer types, head and neck cancer (HNC) survivors face unique ...disease and treatment-specific issues that may limit return to work (RTW). This review aimed to determine employment outcomes of HNC survivors post-treatment and identify factors associated with RTW.
Methods
A systematic search was conducted in MEDLINE, CINAHL and PsycINFO in December 2021. Inclusion criteria included adults (≥ 18 years); completed treatment for HNC; data available on RTW post-treatment. Both quantitative and qualitative studies were considered. Studies were critically appraised and data synthesised narratively.
Results
Twenty-nine publications were included: 22 quantitative, four qualitative and three mixed methods. The proportion of HNC survivors who RTW ranged from 32 to 90%, with participants taking 3.6–11 months to RTW. Working in a professional role and having a supportive work environment were positively associated with RTW.
Conclusions
The proportion of HNC survivors who RTW varies significantly which may be due to the heterogeneity between the studies including difference in clinical characteristics of the participants and/or sample size. Future studies that are longitudinal, adequately powered and measure a range of clinical and demographic variables are needed to better understand the RTW experience and assist development of effective RTW strategies.
Implications for Cancer Survivors
This review suggests potential areas for intervention, including enhanced symptom management and engaging with employers to foster supportive work environments to support RTW of HNC survivors.
The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the ...combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib.
This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination.
Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs.
Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST.
NCT01468688.
El Niño resilience farming on the north coast of Peru Caramanica, Ari; Mesia, Luis Huaman; Morales, Claudia R. ...
Proceedings of the National Academy of Sciences - PNAS,
09/2020, Letnik:
117, Številka:
39
Journal Article
Recenzirano
Odprti dostop
El Niño–Southern Oscillation has been treated as a disruptor of environmental and socioeconomic equilibrium both in ancient times and in modern-day Peru. Recent work in the coastal desert plain, ...known as the Pampa de Mocan, challenges this view by demonstrating that prehispanic irrigation systems were designed to incorporate floods and convert them into productive waters. Archaeological investigations in this landscape reveal a 2,000-y history of floodwater farming embedded in conventional canal systems. Together with a pollen record recovered from a prehispanic well, these data suggest that the Pampa de Mocan was a flexible landscape, capable of taking advantage of El Niño floodwaters as well as river water. In sharp contrast to modern-day flood mitigation efforts, ancient farmers used floodwaters to develop otherwise marginal landscapes, such as the Pampa de Mocan, which in turn mitigated risk during El Niño years. These archaeological data speak to contemporary policy debates in the face of increasingly intense and frequent natural disasters and question whether El Niño Southern Oscillation events should be approached as a form of temporary disorder or as a form of periodic abundance.
Human immunodeficiency virus (HIV) drug resistance increases mortality and morbidity and antiretroviral therapy (ART) costs. We describe Paraguay's first nationally representative survey on ...pretreatment drug resistance (PDR) conducted among persons who initiated or reinitiated ART in 2019. We conducted a cross‐sectional survey of antiretroviral (ARV) drug resistance in Paraguay in 2019. Participants were sampled at four comprehensive care clinics where 90% of patients with HIV in Paraguay initiate ART. Patients included were adults ≥18 years old who initiated first‐line ART or reinitiated the same first‐line ART regimen after ≥3 months of discontinuation. Of 208 patients, 93.8% had no prior ART exposure, 3.8% reinitiated the same regimen, 2.4% had unknown prior ART exposure; and 31.3% had a CD4 count <200 cells/µl. Mutations associated with resistance were present in 15.4% of patients. Mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors (NNRTI) were present in 13.0% of patients, nucleoside reverse transcriptase inhibitors in 4.3%, and integrase inhibitors in 3.4%. Mutations associated with resistance to tenofovir were present in 1.0% of patients and emtricitabine/lamivudine in 1.4%. Nearly one in six patients had PDR in Paraguay's first nationally representative sample. High NNRTI PDR prevalence underscores the need to accelerate the transition to dolutegravir‐based first‐line ART. The low PDR prevalence of tenofovir and emtricitabine is reassuring as these ARVs are part of the World Health Organization (WHO)‐recommended oral pre‐exposure prophylaxis regimen. The high proportion of individuals initiating ART at a late disease stage highlights the need to improve treatment linkage strategies and implement WHO rapid ART initiation recommendations.
To explore the capability of very high-frequency ultrasound (US; 50-71 MHz) to detect the normal morphologic characteristics of the hair follicles and tracts, sebaceous glands, Montgomery glands, ...apocrine glands, and arrector pili muscles.
A retrospective study, approved by the Institutional Review Board, evaluated the normal US morphologic characteristics of the hair and adnexal structures in a database of very high-frequency US images extracted from the perilesional or contralateral healthy skin of 1117 consecutive patients who underwent US examinations for localized lesions of the skin and 10 healthy individuals from December 2017 to June 2018. These images were matched with their counterparts from the database of normal histologic images according to the corporal region. The Cohen concordance test and regional mean diameters of the hair follicles and adnexal structures were analyzed.
The normal hair follicles and tracts, sebaceous glands, Montgomery glands, apocrine glands, and arrector pili muscles were observed on US images and matched their histological counterparts in all the corporal regions. There was significant US concordance (κ = 0.82; P = .0001) among observers. Regional mean diameters (millimeters) of the hair follicles, sebaceous glands, and apocrine glands are provided.
The hair follicles and tracts, sebaceous glands, Montgomery glands, apocrine glands, and arrector pili muscles are detectable with very high-frequency US, including some regional and anatomic variants. Knowledge of their normal US appearances is a requisite for detecting subclinical changes, understanding the physiopathologic characteristics, and supporting the early diagnosis and management of common dermatologic diseases.
Evolutionary analyses of viral sequences can provide insights into transmission dynamics, which in turn can optimize prevention interventions. Here, we characterized the dynamics of HIV transmission ...within the Mexico City metropolitan area. HIV
sequences from persons recently diagnosed at the largest HIV clinic in Mexico City (between 2016 and 2021) were annotated with demographic/geographic metadata. A multistep phylogenetic approach was applied to identify putative transmission clades. A data set of publicly available sequences was used to assess international introductions. Clades were analyzed with a discrete phylogeographic model to evaluate the timing and intensity of HIV introductions and transmission dynamics among municipalities in the region. A total of 6,802 sequences across 96 municipalities (5,192 from Mexico City and 1,610 from the neighboring State of Mexico) were included (93.6% cisgender men, 5.0% cisgender women, and 1.3% transgender women); 3,971 of these sequences formed 1,206 clusters, involving 78 municipalities, including 89 clusters of ≥10 sequences. Discrete phylogeographic analysis revealed (i) 1,032 viral introductions into the region, over one-half of which were from the United States, and (ii) 354 migration events between municipalities with high support (adjusted Bayes factor of ≥3). The most frequent viral migrations occurred between northern municipalities within Mexico City, i.e., Cuauhtémoc to Iztapalapa (5.2% of events), Iztapalapa to Gustavo A. Madero (5.4%), and Gustavo A. Madero to Cuauhtémoc (6.5%). Our analysis illustrates the complexity of HIV transmission within the Mexico City metropolitan area but also identifies a spatially active transmission area involving a few municipalities in the north of the city, where targeted interventions could have a more pronounced effect on the entire regional epidemic.
Phylogeographic investigation of the Mexico City HIV epidemic illustrates the complexity of HIV transmission in the region. An active transmission area involving a few municipalities in the north of the city, with transmission links throughout the region, is identified and could be a location where targeted interventions could have a more pronounced effect on the entire regional epidemic, compared with those dispersed in other manners.
Abstract
Background
Evolutionary analyses of well-annotated human immunodeficiency virus (HIV) sequence data can provide insights into viral transmission patterns and associated factors. Here, we ...explored the transmission dynamics of the HIV-1 subtype B epidemic across the San Diego (US) and Tijuana (Mexico) border region to identify factors that could help guide public health policy.
Methods
HIV pol sequences were collected from people with HIV in San Diego County and Tijuana between 1996–2018. A multistep phylogenetic approach was used to characterize the dynamics of spread. The contributions of geospatial factors and HIV risk group to the local dynamics were evaluated.
Results
Phylogeographic analyses of the 2034 sequences revealed an important contribution of local transmission in sustaining the epidemic, as well as a complex viral migration network across the region. Geospatial viral dispersal between San Diego communities occurred predominantly among men who have sex with men, with central San Diego being the main source (34.9%) and recipient (39.5%) of migration events. HIV migration was more frequent from San Diego county towards Tijuana than vice versa. Migrations were best explained by the driving time between locations.
Conclusions
The US-Mexico border may not be a major barrier to the spread of HIV, which may stimulate coordinated transnational intervention approaches. Whereas a focus on central San Diego has the potential to avert most spread, the substantial viral migration independent of central San Diego shows that county-wide efforts will be more effective. Combined, this work shows that epidemiological information gleaned from pathogen genomes can uncover mechanisms that underlie sustained spread and, in turn, can be a building block of public health decision-making.
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•General guidelines for sarcomas are of limited value or even not applicable for some uncommon sarcomas.•Specific clinical and molecular characteristics of uncommon sarcoma subtypes ...imply specific diagnostic and therapeutic approaches.•New multikinase inhibitors recently developed provide new therapeutic opportunities to some vascular and fibroblastic sarcomas.•Patients suffering from these uncommon tumors deserve the same opportunities as other patients with more prevalent diseases, so specific clinical research in these subtypes should be promoted and supported.
WHO has developed a global HIV-drug resistance surveillance strategy, including assessment of pretreatment HIV-drug resistance. We aimed to do a nationally representative survey of pretreatment ...HIV-drug resistance in Mexico using WHO-recommended methods.
Among 161 Ministry of Health antiretroviral therapy (ART) clinics in Mexico, the largest, including 90% of ART initiators within the Ministry of Health (66 in total), were eligible for the survey. We used a probability-proportional-to-size design method to sample 25 clinics throughout the country. Consecutive ART-naive patients with HIV about to initiate treatment were invited to participate in the survey; individuals with previous exposure to ART were excluded. We assessed pretreatment HIV-drug resistance by Sanger sequencing and next-generation sequencing of viruses from plasma specimens from eligible participants with Stanford University HIV Drug Resistance Database methods. We obtained follow-up data for a median of 9·4 months (range 6-12) after enrolment. We investigated possible relations between demographic variables and pretreatment drug resistance with univariate and multivariate logistic regression.
Between Feb 3 and July 30, 2015, we screened 288 patients in 25 clinics, from whom 264 provided successfully sequenced viruses with no evidence of current exposure to antiretroviral drugs. With the Sanger method, of these 264 participants, 41 (15·5%, 95% CI 11·4-20·5) had pretreatment resistance to any antiretroviral drug and 28 (10·6%, 7·2-15·0) had pretreatment resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs). At least low-level pretreatment resistance (Stanford penalty score ≥15) was noted in 13 (4 · 9%) of participants to efavirenz and in 23 (8·7%) to the combination tenofovir plus emtricitabine plus efavirenz. With next-generation sequencing, of 264 participants, 38 (14·4%, 95% CI 10·4-19·2) had pretreatment resistance to any antiretroviral drug and 26 (9·8%, 6·5-14·1) had pretreatment resistance to NNRTIs. After median follow-up of 8 months (IQR 6·5-9·4, range 5-11) after ART initiation, 97 (72%) of 135 NNRTI initiators achieved viral suppression (<50 copies per mL) compared with ten (40%) of 25 individuals who started with protease inhibitor-based regimens (p=0·0045). After multivariate regression considering pretreatment resistance and initial ART regimen as composite variables, people starting NNRTIs with pretreatment drug resistance achieved significantly lower viral suppression (odds ratio 0·24, 95% CI 0·07-0·74; p=0·014) than patients without NNRTI resistance.
High levels of pretreatment drug resistance were noted in Mexico, and NNRTI pretreatment drug resistance significantly reduced the effectiveness of first-line ART regimens based on these drugs. Baseline HIV-drug resistance testing for initial ART follow-up and decision making should be considered.
The Mexican Government and Consejo Nacional de Ciencia y Tecnología.
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