Characteristics and rates of infection by HIV in people receiving non-occupational post-exposure prophylaxis (nPEP) against HIV.

INTRODUCTION/OBJECTIVES: The use of non-occupational post-exposure prophylaxis (nPEP) emerges as a strategic intervention to reduce HIV infection risk following sexual encounters in our setting. Notwithstanding, there is a scarcity of contemporary data regarding adherence to this treatment, its effectiveness and tolerance. Our study aims to delve into these factors among individuals who have resorted to nPEP after high-risk sexual encounters. METHODS: We conducted a retrospective observational study of cases administered nPEP for HIV from 1 January 2018 to 31 December 2021 at a tertiary hospital in Madrid. The study included all adults over 18 years who sought care at the emergency department of the Fundación Jiménez Díaz Hospital following a risky sexual encounter and were subsequently recommended HIV nPEP treatment. RESULTS: 878 individuals received nPEP for HIV and underwent initial serological tests. Of these, 621 had comprehensive follow-ups. The prescribed regimen for all was raltegravir (RAL) 1200 mg combined with tenofovir/emtricitabine (TDF/FTC) 245/200 mg daily for 28 days. The study revealed a 1.1% rate (n=10) of previously undetected infection and a 0.16% (n=1) failure rate of nPEP. Regarding regimen tolerability, 5.6% (n=35) experienced symptoms linked to the treatment, yet none necessitated discontinuation of the regimen. On the contrary, six per cent (n=53) reported symptoms consistent with an STI during one of the medical visits; specifically, 4.4% had urethritis, and 1.6% had proctitis. CONCLUSION: nPEP with RAL/TDF/FTC demonstrates high efficacy and safety, contingent on proper adherence. There is an observed increase in STI prevalence in this cohort, with nearly half of the participants not engaging in appropriate follow-up after initiating nPEP.

Multidisciplinary Panel Consensus for the Management of Patients with Type 2 Diabetes: A Delphi Study.

AIM: To reach a multidisciplinary consensus on managing patients with type 2 diabetes among specialists in family medicine, cardiology, endocrinology, internal medicine, and nephrology. METHODS: A two-round Delphi study was conducted using a questionnaire with 68 positive/negative statements distributed in four thematic blocks on diabetes management: early diagnosis and prediabetes, referral criteria, treatment and comorbidities, and clinical management. The expert panel was composed of 105 physicians from different specialties (family medicine, cardiology, endocrinology, internal medicine, and nephrology) with experience in managing patients with diabetes and who were members of a diabetes-related society. RESULTS: Response rates for the first and second rounds were 86.7 and 75.2%, respectively. After both rounds, a consensus was reached on 52 (76.5%) items. The recommendations with the highest degree of consensus (median = 10, IQR = 0.00) were related to anti-smoking education, cardiovascular risk factor target control, and diabetic kidney disease. There were significant differences between family physicians and other specialties for some items. CONCLUSIONS: This study provides a set of recommendations for diabetes management agreed upon by specialists from different healthcare settings.

Incidence and Risk Factors for Development of Cardiac Toxicity in Adult Patients with Newly Diagnosed Acute Myeloid Leukemia.

The incidence of cardiac morbimortality in acute myeloid leukemia (AML) is not well known. We aim to estimate the cumulative incidence (CI) of cardiac events in AML patients and to identify risk factors for their occurrence. Among 571 newly diagnosed AML patients, 26 (4.6%) developed fatal cardiac events, and among 525 treated patients, 19 (3.6%) experienced fatal cardiac events (CI: 2% at 6 months; 6.7% at 9 years). Prior heart disease was associated with the development of fatal cardiac events (hazard ratio (HR) = 6.9). The CI of non-fatal cardiac events was 43.7% at 6 months and 56.9% at 9 years. Age ≥ 65 (HR = 2.2), relevant cardiac antecedents (HR = 1.4), and non-intensive chemotherapy (HR = 1.8) were associated with non-fatal cardiac events. The 9-year CI of grade 1-2 QTcF prolongation was 11.2%, grade 3 was 2.7%, and no patient had grade 4-5 events. The 9-year CI of grade 1-2 cardiac failure was 1.3%, grade 3-4 was 15%, and grade 5 was 2.1%; of grade 1-2, arrhythmia was 1.9%, grade 3-4 was 9.1%, and grade 5 was 1%. Among 285 intensive therapy patients, median overall survival decreased in those experiencing grade 3-4 cardiac events (p < 0.001). We observed a high incidence of cardiac toxicity associated with significant mortality in AML.

Evaluation of the inter and intraobserver reproducibility of the "defect coverage index method", a new computed tomography assessment method of sagittal graft positioning in arthroscopic bone block procedures.

PURPOSE: To assess the reproducibility of a new 2-dimensional computed tomography (CT) method of assessing graft positioning in arthroscopic bone block procedure. METHODS: This is a prospective observational study. Twenty-seven patients, (all men, mean [Standard deviation] age at surgery 30.9 [8.49] years) were included. Vertical graft position was assessed on the sagittal view by measuring the amount of glenoid bone defect covered by the graft. The length of the bone defect and the amount of graft covering the defect were measured. Positioning of the graft on the sagittal plane was classified as accurate if the graft covered at least 90% of the defect. Intraobserver and interobserver reproducibility was analyzed using intraclass correlation coefficients (ICC) and Kappa coefficient with 95% confidence. RESULTS: Excellent intraobserver reproducibility was found, with an ICC of 0.94 (CI 95%, 0.86-0.97). Interobserver reproducibility was good, with the ICC value of 0.71, ranging from 0.45 to 0.86 (CI 95%). CONCLUSION: This new method of assessing graft positioning in arthroscopic bone block procedures on 2-dimensional computed tomography scans is reliable, with an excellent intraobserver and good interobserver reproducibility. LEVEL OF EVIDENCE: III.

Relato de experiência de educação em saúde para pessoas vivendo com hiv: integração ensino e serviço / Experience report on health education for people living with hiv: integration teaching and service / Informe de experiencia en educación en salud para personas que viven con vih: enseñanza y servicio de integración

A educação em saúde e o acesso à informação são ferramentas estratégicas para a promoção do autocuidado de pessoas vivendo com HIV. Apesar dos grandes avanços científicos, sobretudo quanto ao uso da TARV, ainda existem desafios a serem enfrentados como o preconceito, o estigma e a desinformação da população. Nesse sentido, tal estratégia contribui com a adesão ao tratamento, por meio do esclarecimento de dúvidas a cerca da infecção pelo HIV. Trata-se de um relato de experiência referente às ações de educação em saúde realizadas em serviços especializados de saúde para o tratamento de pessoas vivendo com HIV. Os participantes do projeto foram capacitados e realizaram ações de educação em saúde, para abordar temas relacionados ao HIV/Aids e para o esclarecimento de dúvidas a respeito da terapia antirretroviral. Conclui-se que a integração dos serviços de saúde com as instituições de ensino se constitui com uma importante estratégia para o desenvolvimento de reflexões críticas acerca da temática, bem como para auxiliar nos cuidados direcionados às pessoas que vivem com HIV. PALAVRAS-CHAVE: Educação em Saúde; HIV; Terapia Antirretroviral; Adesão ao Tratamento.

Health education and access to information are strategic tools for promoting self-care for people living with HIV. Despite the great scientific advances, especially regarding the use of ART, there are still challenges to be faced, such as prejudice, stigma and misinformation of the population. In this sense, such a strategy contributes to adherence to treatment, by clarifying doubts about HIV infection. This is an experience report regarding health education actions carried out in specialized health services for the treatment of people living with HIV. Project participants were trained and carried out health education actions to address issues related to HIV/AIDS and to clarify doubts about antiretroviral therapy. It is concluded that the integration of health services with educational institutions constitutes an important strategy for the development of critical reflections on the subject, as well as to assist in the care directed to people living with HIV.

La educación sanitaria y el acceso a la información son herramientas estratégicas para promover el autocuidado de las personas que viven con VIH. Apesar de los grandes avances científicos, especialmente en lo que respecta al uso de las TAR, todavía quedan desafíos por afrontar, como los prejuicios, el estigma y la desinformación de la población. En este sentido, dicha estrategia contribuye a la adherencia al tratamiento, al aclarar dudas sobre la infección por VIH. Este es un relato de experiencia sobre acciones de educación en salud realizadas en servicios de salud especializados para el tratamiento de personas que viven con VIH. Los participantes del proyecto fueron capacitados y realizaron acciones de educación en salud para abordar temas relacionados con el VIH/SIDA y aclarar dudas sobre la terapia antirretroviral. Se concluye que la integración de los servicios de salud con las instituciones educativas constituye una estrategia importante para el desarrollo de reflexiones críticas sobre el tema, así como para coadyuvar en la atención dirigida a las personas que viven con VIH.

Sulforaphane covalently interacts with the transglutaminase 2 cancer maintenance protein to alter its structure and suppress its activity.

Type 2 transglutaminase (TG2) functions as an important cancer cell survival protein in a range of cancers including epidermal squamous cell carcinoma. TG2 exists in open and closed conformations each of which has a distinct and mutually exclusive activity. The closed conformation has GTP-binding/GTPase activity while the open conformation functions as a transamidase to catalyze protein-protein crosslinking. GTP-binding/GTPase activity is required for TG2 maintenance of the aggressive cancer phenotype. Thus, identifying agents that convert TG2 from the closed to the open GTP-binding/GTPase inactive conformation is an important cancer prevention/treatment strategy. Sulforaphane (SFN) is an important diet-derived cancer prevention agent that is known to possess a reactive isothiocyanate group and has potent anticancer activity. Using a biotin-tagged SFN analog (Biotin-ITC) and kinetic analysis we show that SFN covalently and irreversibly binds to recombinant TG2 to inhibit transamidase activity and shift TG2 to an open/extended conformation, leading to a partial inhibition of GTP binding. We also show that incubation of cancer cells or cancer cell extract with Biotin-ITC results in formation of a TG2/Biotin-ITC complex and that SFN treatment of cancer cells inhibits TG2 transamidase activity and shifts TG2 to an open/extended conformation. These findings identify TG2 as a direct SFN anticancer target in epidermal squamous cell carcinoma.

Detección de Leishmania (viannia) braziliensis en piel de oreja de Rattus rattus que habitan área urbana de la ciudad de Corrientes

Resumen La leishmaniasis cutánea es una enfermedad zoonótica que se transmite al hombre y a los animales a través de la picadura de insectos dípteros de los géneros Phlebotomus y Lutzomyia infectados con diferentes especies de protozoos del género Leishmania. En América Latina el principal agente etiológico responsable de esta parasitosis es la especie L. braziliensis. Si bien se han identificado numerosas especies de mamíferos infectados naturalmente con especies de Leishmania, los roedores cumplirían un rol importante en el ciclo de transmisión de la enfermedad. El presente trabajo tuvo como objetivo la identificación de especie de leishmania que circula en roedores sinantrópicos que habitan el área urbana de la ciudad de Corrientes. Se trabajó con muestras de piel de oreja de roedores a los que se les aplicó las técnicas de Nested PCR para la identificación de Leishmania spp y PCR Simple para la detección de L. braziliensis. Se analizó un total de 30 muestras de roedores de la especie Rattus rattus de los cuales 2 muestras resultaron detectables a Nested PCR. Seguidamente, a las muestras detectables a Leishmania spp. se les aplicó PCR Simple a L. braziliensis resultando ambas detectables a esta especie. Si bien los valores obtenidos en este trabajo no son altos para poder considerarlos como reservorios, si se evidencia una infección natural que no afecta clínicamente a los roedores estudiados con circulación del parásito en piel, particularmente de la especie L. braziliensis.

Abstract Cutaneous leishmaniasis is a zoonotic disease that is transmitted to man and animals through the bite of dipteran insects of the genera Phlebotomus and Lutzomyia infected with different species of protozoa of the genus Leishmania. In Latin America the main etiological agent responsible for this parasitosis is the species L. braziliensis. Although numerous species of mammals have been identified naturally infected with Leishmania species, rodents would play an important role in the transmission cycle of the disease. The present work aimed to identify the species of leishmania that circulates in synanthropic rodents that inhabit the urban area of the city of Corrientes. We worked with rodent ear skin samples to which the Nested PCR techniques were applied for the identification of Leishmania spp and Simple PCR for the detection of L. braziliensis. A total of 30 rodent samples of the species Rattus rattus were analyzed, of which 2 samples were detectable by Nested PCR. Next, the samples detectable to Leishmania spp. Simple PCR was applied to L. braziliensis, both of which were detectable in this species. Although the values obtained in this work are not high to be considered as reservoirs, there is evidence of a natural infection that does not clinically affect the rodents studied with circulation of the parasite on the skin, particularly of the L. braziliensis species.

An Extract of Taro (Colocasia esculenta) Mediates Potent Inhibitory Actions on Metastatic and Cancer Stem Cells by Tumor Cell-Autonomous and Immune-Dependent Mechanisms.

The taro plant, Colocasia esculenta, contains bioactive proteins with potential as cancer therapeutics. Several groups have reported anti-cancer activity in vitro and in vivo of taro-derived extracts (TEs). We reported that TE inhibits metastasis in a syngeneic murine model of Triple-Negative Breast Cancer (TNBC). PURPOSE: We sought to confirm our earlier studies in additional models and to identify novel mechanisms by which efficacy is achieved. METHODS: We employed a panel of murine and human breast and ovarian cancer cell lines to determine the effect of TE on tumor cell viability, migration, and the ability to support cancer stem cells. Two syngeneic models of TNBC were employed to confirm our earlier report that TE potently inhibits metastasis. Cancer stem cell assays were employed to determine the ability of TE to inhibit tumorsphere-forming ability and to inhibit aldehyde dehydrogenase activity. To determine if host immunity contributes to the mechanism of metastasis inhibition, efficacy was assessed in immune-compromised mice. RESULTS: We demonstrate that viability of some, but not all cell lines is inhibited by TE. Likewise, tumor cell migration is inhibited by TE. Using 2 immune competent, syngeneic models of TNBC, we confirm our earlier findings that tumor metastasis is potently inhibited by TE. We also demonstrate, for the first time, that TE directly inhibits breast cancer stem cells. Administration of TE to mice elicits expansion of several spleen cell populations but it was not known if host immune cells contribute to the mechanism by which TE inhibits tumor cell dissemination. In novel findings, we now show that the ability of TE to inhibit metastasis relies on immune T-cell-dependent, but not B cell or Natural Killer (NK)-cell-dependent mechanisms. Thus, both tumor cell-autonomous and host immune factors contribute to the mechanisms underlying TE efficacy. Our long-term goal is to evaluate TE efficacy in clinical trials. Most of our past studies as well as many of the results reported in this report were carried out using an isolation protocol described earlier (TE). In preparation for a near future clinical trial, we have now developed a strategy to isolate an enriched taro fraction, TE-method 2, (TE-M2) as well as a more purified subfraction (TE-M2F1) which can be scaled up under Good Manufacturing Practice (GMP) conditions for evaluation in human subjects. We demonstrate that TE-M2 and TE-M2F1 retain the anti-metastatic properties of TE. CONCLUSIONS: These studies provide further support for the continued examination of biologically active components of Colocasia esculenta as potential new therapeutic entities and identify a method to isolate sufficient quantities under GMP conditions to conduct early phase clinical studies.

The effect of omitting axillary dissection and the impact of radiotherapy on patients with breast cancer sentinel node macrometastases: a cohort study following the ACOSOG Z0011 and AMAROS trials.

PURPOSE: To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted. METHODS: A retrospective cohort study of T1-T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan-Meyer curves and Cox-regression, respectively. RESULTS: 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13-50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45-9.98%). CONCLUSIONS: Our study confirms that omitting ALND is safe and has high survival rates in patients with T1-T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity.

The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile.

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

Engineering subtilisin proteases that specifically degrade active RAS.

We describe the design, kinetic properties, and structures of engineered subtilisin proteases that degrade the active form of RAS by cleaving a conserved sequence in switch 2. RAS is a signaling protein that, when mutated, drives a third of human cancers. To generate high specificity for the RAS target sequence, the active site was modified to be dependent on a cofactor (imidazole or nitrite) and protease sub-sites were engineered to create a linkage between substrate and cofactor binding. Selective proteolysis of active RAS arises from a 2-step process wherein sub-site interactions promote productive binding of the cofactor, enabling cleavage. Proteases engineered in this way specifically cleave active RAS in vitro, deplete the level of RAS in a bacterial reporter system, and also degrade RAS in human cell culture. Although these proteases target active RAS, the underlying design principles are fundamental and will be adaptable to many target proteins.

Geometric border as a marker for melanoma diagnosis: Study of 200 consecutive melanocytic lesions.

The ABCD rule has long been proposed as a guidance for malignant melanoma (MM) diagnosis. We aimed to define a new simple, straightforward tool that could be useful in early melanoma detection and must be validated in further studies. We conducted a prospective historic cohort study of 200 melanocytic lesions classifying them according to the presence of geometric borders. Sixty-four percent of the MM and 31% of the melanocytic nevi presented with geometric borders. Lesions with two straight borders that formed a noncurvilinear angle presented a 2.1-fold higher risk of being malignant after excision. When comparing melanomas with geometric and nongeometric border, we found a tendency toward better prognostic markers in the geometric lesions. Lesions located in the extremities and melanoma subtype SSM were more common in the geometric group. Regarding pathologic features, a deeper Breslow (mean, 3.8 vs 1.4 mm), presence of ulceration (25% vs 5%) and a higher number of mitosis was found in the nongeometric group. On the other hand, more regression was found in the geometric group while both groups showed similar degree of lymphovascular infiltration. We propose geometric border as another clinical criterion to take into account when suspecting MM, which must be validated in further studies. The ABCDE rule could be completed with a G for geometry.

Primary gastric adenocarcinoma in a patient with Peutz-Jeghers syndrome.

We present the case of a 42-year-old female under study due to dyspepsia without response to empirical treatment, with perioral mucocutaneous pigmentation. A gastroscopy revealed a 5 cm gastric tumor in the antrum, as well as multiple sessile gastric and duodenal polyps smaller than 1 cm. Large-capacity forceps biopsies were obtained and a well-differentiated adenocarcinoma with gastric origin was diagnosed, with over expression of the HER2/neu without microsatellite instability in the context of a hamartomatous polyposis. The genomic study confirmed an alteration in the STK11 gene translated to a truncated protein product, compatible with a Peutz-Jeghers syndrome (PJS).

Desmoid fibromatosis of the esophagogastric junction.

Desmoid fibromatosis is a mesenchymal clonal proliferation, which lacks metastatic potential. Nevertheless, it has an infiltrative growth and thus implies a high morbidity1. Although the etiology remains unclear, mutations in the B-catenin or APC genes are involved. Some risk factors include pregnancy, hormonal exposure or surgery. Desmoid fibromatosis can be sporadic (80%) or FAP-associated2. In sporadic cases, it is caused by mutations in the B-catenin (CTNNB1) gene. Whether it is FAP-associated or not should be determined, as the treatment for each condition is different. A radiologic test is essential for diagnosis, although a biopsy is necessary for confirmation. With regard to treatment, there is a wide range of different alternatives such as observation only, medical treatment or even surgery3. However, a recurrence rate that ranges from 30% to 40% have been reported in the major published series4 and thus, conservative treatment is more common nowadays. We present the case of an 82-year-old male with constitutional syndrome. A computed tomography was performed, which identified a 69 x 52mm mass in the oesophago-gastric union. A computed tomography guided biopsy was performed and the histological analysis identified a fusocellular tumor compatible with desmoid fibromatosis. Treatment was started with indomethacin. However, a control computed tomography 3 months later showed that the mass had grown. Thus, indomethacin treatment was stopped and tamoxifen treatment was started. The patient has had an excellent performance status since symptom presentation. In conclusion, desmoid tumors are rare and most are sporadic. However, they may also be associated with familial adenomatous polyposis syndrome. It must be emphasized that our patient did not have any risk factors and the anatomical location in the oesophago-gastric union is not a common location. Desmoid fibromatosis supposes a clinical challenge for diagnosis and treatment and thus, management should be individualized.

Kröhnke pyridines: Rapid and facile access to Mcl-1 inhibitors.

The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 α-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of α-pyridinium methyl ketone salts and α,ß-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Kröhnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 α-helix.

Enteral stent for the treatment of a urinary fistula associated with a biological mesh following a Bricker-type procedure.

Postoperative fistula results in increased morbidity and a longer hospital stay. While surgery is the most common treatment, the endoscopic approach is an increasingly used alternative. A 57-year-old woman underwent surgery for colonic adenocarcinoma, which relapsed as peritoneal carcinomatosis and was managed with chemotherapy and surgery, a biological Permacol™ mesh was used for abdominal wall closure.