Tumor analysis of MMR genes in Lynch-like syndrome: Challenges associated with results interpretation.

BACKGROUND: Up to 70% of suspected Lynch syndrome patients harboring MMR deficient tumors lack identifiable germline pathogenic variants in MMR genes, being referred to as Lynch-like syndrome (LLS). Previous studies have reported biallelic somatic MMR inactivation in a variable range of LLS-associated tumors. Moreover, translating tumor testing results into patient management remains controversial. Our aim is to assess the challenges associated with the implementation of tumoral MMR gene testing in routine workflows. METHODS: Here, we present the clinical characterization of 229 LLS patients. MMR gene testing was performed in 39 available tumors, and results were analyzed using two variant allele frequency (VAF) thresholds (≥5% and ≥10%). RESULTS AND DISCUSSION: More biallelic somatic events were identified at VAF ≥ 5% than ≥10% (35.9% vs. 25.6%), although the rate of nonconcordant results regarding immunohistochemical pattern increased (30.8% vs. 20.5%). Interpretation difficulties question the current utility of the identification of MMR somatic hits in the diagnostic algorithm of suspected LS cases.

Cognitive Training to Reduce Memory Disturbance Associated With Postoperative Cognitive Impairment After Elective Noncardiac Surgery: An Experimental Study.

PURPOSE: Assess the efficiency of a cognitive training program using an artificial intelligence application to optimize cognitive reserve and reduce memory disturbance in patients aged 55 to 75 after Class II-III elective noncardiac surgery. DESIGN: Experimental with random assignment. METHODS: The study was conducted on 80 patients undergoing surgery at the Teknon Medical Center Hospital in Barcelona, from April 2018 to June 2021. Both groups were evaluated with cognitive tests before surgery and 7 and 30 days after surgery. The experimental group was subjected to cognitive training for 10 days before surgery to improve their cognitive reserve. FINDINGS: Significant differences were found between the study groups 30 days after surgery in the three screening tests (Mini-Cog, T@M, and MFE). The intervention group presented with fewer cognitive and memory alterations. Age and pre-existing comorbidities were not correlated with an impact on memory impairment or cognitive function. CONCLUSIONS: A cognitive training program based on artificial intelligence, prescribed and monitored by anesthesia nurses has a positive impact on increasing cognitive reserve and reducing memory disturbance in patients aged 55 to 75 undergoing Class II to III elective, noncardiac surgery. This intervention may serve as a prehabilitation strategy in patients with a risk of cognitive dysfunction evaluated by anesthesia nurses for the purpose of preserving their cognitive function and optimizing their recovery.

Hypouricemia with hypercalciuria: Longitudinal study and review of the topic.

BACKGROUND AND OBJECTIVE: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20ml/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. PATIENTS AND METHODS: Retrospective longitudinal study in which the medical records of eight patients (5V, 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V, 22M). RESULTS: In the hypouricemia group baseline urate levels were 1.9 (0.3) mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05) mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20ml/100ml FGR. The z-DMO values were less than -1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower. CONCLUSION: Our patients with hypercalciuria and hypouricemia would be affected by a variant of idiopathic hypercalciuria in which, due to an unknown cause, the proximal tubular reabsorption of urate is modestly reduced and improves over time. Hypouricemia with hypercalciuria and decreased bone density may not be a specific entity.

Hipouricemia con hipercalciuria. Estudio longitudinal y revisión del tema / Hypouricemia with hypercalciuria: Longitudinal study and review of the topic

Antecedentes y objetivo: La asociación de hipouricemia e hipercalciuria es poco frecuente. En 1974 se describió un nuevo síndrome nominado Hipouricemia con hipercalciuria y reducción de la densidad ósea. Posteriormente, se publicaron algunos casos con esa asociación en los que la excreción fraccional de urato era superior a 20/100ml FGR. Hemos analizado una serie de niños que fueron diagnosticados de hipouricemia e hipercalciuria y que fueron controlados evolutivamente. El objetivo del trabajo es intentar conocer si nuestros pacientes podrían estar afectos del síndrome antes mencionado o ser portadores de una variante de hipercalciuria idiopática. Pacientes y métodos: Estudio retrospectivo longitudinal en el que se estudiaron las historias clínicas de 8 pacientes (5V y 3M) diagnosticados de hipouricemia e hipercalciuria en la infancia. Se anotaron la clínica al diagnóstico, los hallazgos ecográficos y densitométricos, y determinadas variables bioquímicas, con especial hincapié en el manejo tubular renal del urato. Los resultados se compararon con los de 36 niños afectos de hipercalciuria idiopática sin hipouricemia (14V y 22M). Resultados: En el grupo con hipouricemia los niveles iniciales de uricemia fueron 1,9 (0,3) mg/dl (rango: 1,5-2) y los del cociente calcio/creatinina en primera orina del día, 0,27 (0,05) mg/mg (rango: 0,23-0,31). En todos los casos la excreción fraccional de urato fue inferior a 20ml/100ml FGR. Los valores de z-DMO fueron menores de −1 en 4/8 casos. En el último control, solo en 3 casos persistía el cociente calcio/creatinina elevado, y en todos la uricemia era superior a 2mg/dl. El valor de z-DMO había mejorado en 5 casos y empeorado en otros 3... (AU)

Background and objective: The association of hypouricemia and hypercalciuria is rare. In 1974 a new syndrome named Hypouricemia with hypercalciuria and decreased bone density was described. Afterwards, some cases with such association were published in which the fractional excretion of urate was higher than 20/100ml FGR. We have analyzed a series of children who were diagnosed with hypouricemia and hypercalciuria and who were monitored. The aim of this study was to determine whether our patients could be affected by the aforementioned syndrome or be carriers of a variant of idiopathic hypercalciuria. Patients and methods: Retrospective longitudinal study in which the medical records of eight patients (5V and 3M) diagnosed with hypouricemia and hypercalciuria in childhood. Clinical features at diagnosis, ultrasound and densitometric findings and selected biochemical variables were noted, with special emphasis on renal tubular handling of urate. Results were compared with 36 children with idiopathic hypercalciuria without hypouricemia (14V and 22M). Results: In the hypouricemia group baseline urate levels were 1.9 (0.3)mg/dl (range: 1.5-2) and first day urine calcium/creatinine ratio 0.27 (0.05)mg/mg (range: 0.23-0.31). In all cases fractional urate excretion was less than 20/100ml FGR. The z-DMO values were less than −1 in 4/8 cases. At the last follow-up only three cases still had an elevated calcium/creatinine ratio and in all of them the urates levels was greater than 2mg/dl. The z-DMO value had improved in five cases and worsened in three others. In relation to the group without hypouricemia, no differences were observed between the various parameters studied including the z-DMO value, with the exception of fractional excretion and tubular urate reabsorption although plasmatic uric acid levels were still significantly lower... (AU)

Proton Pump Inhibitors in Pediatric Gastroesophageal Reflux Disease: A Systematic Review of Randomized Controlled Trials.

This systematic review was conducted with the objective of understanding the efficacy and safety of proton pump inhibitors (PPIs) in the pediatric population. We used PubMed to identify randomized controlled trials (RCTs) published between 1 June 2010 and 30 June 2023, performed in patients from birth to 18 years old with gastroesophageal reflux disease (GERD) who received treatment with any PPI. This literature search yielded 76 articles and 13 of these met the inclusion criteria. For infants, PPIs were equal to placebos in reducing GERD symptoms in four articles. In one article, the numbers of GER episodes and esophageal acid exposures were lower in infants who received PPIs in the left lateral position, but there was generally no significant improvement in symptoms. In another publication, the combination of PPIs and feeding modifications (FMs) was not more effective than PPIs alone. For children and adolescents, PPIs were effective in improving symptoms and achieving endoscopic healing, which was subsequently maintained. To conclude, PPIs are not effective in reducing the symptoms related to GERD in infants but are effective in older children, where histological remission can be seen. Generally, PPIs are well tolerated, but it is important to remember the possible adverse events (AEs), especially if PPIs are used for an extended period.

Using the photon isoeffective dose formalism to compare and combine BNCT and CIRT in a head and neck tumour.

Boron Neutron Capture Therapy (BNCT) is a radiotherapy technique based on the enrichment of tumour cells with suitable 10-boron concentration and on subsequent neutron irradiation. Low-energy neutron irradiation produces a localized deposition of radiation dose caused by boron neutron capture reactions. Boron is vehiculated into tumour cells via proper borated formulations, able to accumulate in the malignancy more than in normal tissues. The neutron capture releases two high-LET charged particles (i.e., an alpha particle and a lithium ion), losing their energy in a distance comparable to the average dimension of one cell. Thus BNCT is selective at the cell level and characterized by high biological effectiveness. As the radiation field is due to the interaction of neutrons with the components of biological tissues and with boron, the dosimetry requires a formalism to express the absorbed dose into photon-equivalent units. This work analyzes a clinical case of an adenoid cystic carcinoma treated with carbon-ion radiotherapy (CIRT), located close to optic nerve and deep-seated as a practical example of how to apply the formalism of BNCT photon isoeffective dose and how to evaluate the BNCT dose distribution against CIRT. The example allows presenting different dosimetrical and radiobiological quantities and drawing conclusions on the potential of BNCT stemming on the clinical result of the CIRT. The patient received CIRT with a dose constraint on the optic nerve, affecting the peripheral part of the Planning Target Volume (PTV). After the treatment, the tumour recurred in this low-dose region. BNCT was simulated for the primary tumour, with the goal to calculate the dose distribution in isoeffective units and a Tumour Control Probability (TCP) to be compared with the one of the original treatment. BNCT was then evaluated for the recurrence in the underdosed region which was not optimally covered by charged particles due to the proximity of the optic nerve. Finally, a combined treatment consisting in BNCT and carbon ion therapy was considered to show the consistency and the potential of the model. For the primary tumour, the photon isoeffective dose distribution due to BNCT was evaluated and the resulted TCP was higher than that obtained for the CIRT. The formalism produced values that are consistent with those of carbon-ion. For the recurrence, BNCT dosimetry produces a similar TCP than that of primary tumour. A combined treatment was finally simulated, showing a TCP comparable to the BNCT-alone with overall dosimetric advantage in the most peripheral parts of the treatment volume. Isoeffective dose formalism is a robust tool to analyze BNCT dosimetry and to compare it with the photon-equivalent dose calculated for carbon-ion treatment. This study introduces for the first time the possibility to combine the dosimetry obtained by two different treatment modalities, showing the potential of exploiting the cellular targeting of BNCT combined with the precision of charged particles in delivering an homogeneous dose distribution in deep-seated tumours.

Moderate-High Blood Eosinophilia Is Associated with Increased Hospitalization and Other Asthma Comorbidities.

(1) Background: Eosinophilia has traditionally been linked to eosinophilic asthma, for which it is the gold-standard prognostic biomarker. However, the association between eosinophilia and the presence of other diseases and comorbidities is yet unclear. (2) Methods: For this retrospective study, we reviewed the electronic medical records of 49,909 subjects with blood eosinophilia to gather data on the presence of asthma, COPD, sleep apnea, tuberculosis, dyslipidemia, hypertension, and other cardiovascular diseases and severe CRSwNP among these subjects. Demographic features including age, sex, and smoking habits were collected, as well as the number of hospitalizations and emergency department visits. T-tests, ANOVA, Fisher test, and logistic regression models were used. (3) Results: For all age groups studied, eosinophilia was significantly more prevalent among asthmatic subjects than nonasthmatics, especially in patients also presenting CRSwNP, hypertension, and dyslipidemia. The likelihood of developing asthma, COPD, and CRSwNP, and hospitalization, was increased when BEC was above 600 eosinophils/µL. The association between asthma, CRSwNP, and BEC was corroborated by multiple logistic regressions models. (4) Conclusions: We demonstrated the association of having over 600 blood eosinophils/µL with a higher number of hospitalizations and comorbidities (CRSwNP and COPD), which proves that BEC is a highly useful parameter to consider in subjects who present blood eosinophilia.

Evolutionary-Related High- and Low-Virulent Classical Swine Fever Virus Isolates Reveal Viral Determinants of Virulence.

Classical swine fever (CSF) has been eradicated from Western and Central Europe but remains endemic in parts of Central and South America, Asia, and the Caribbean. CSF virus (CSFV) has been endemic in Cuba since 1993, most likely following an escape of the highly virulent Margarita/1958 strain. In recent years, chronic and persistent infections with low-virulent CSFV have been observed. Amino acid substitutions located in immunodominant epitopes of the envelope glycoprotein E2 of the attenuated isolates were attributed to positive selection due to suboptimal vaccination and control. To obtain a complete picture of the mutations involved in attenuation, we applied forward and reverse genetics using the evolutionary-related low-virulent CSFV/Pinar del Rio (CSF1058)/2010 (PdR) and highly virulent Margarita/1958 isolates. Sequence comparison of the two viruses recovered from experimental infections in pigs revealed 40 amino acid differences. Interestingly, the amino acid substitutions clustered in E2 and the NS5A and NS5B proteins. A long poly-uridine sequence was identified previously in the 3' untranslated region (UTR) of PdR. We constructed functional cDNA clones of the PdR and Margarita strains and generated eight recombinant viruses by introducing single or multiple gene fragments from Margarita into the PdR backbone. All chimeric viruses had comparable replication characteristics in porcine monocyte-derived macrophages. Recombinant PdR viruses carrying either E2 or NS5A/NS5B of Margarita, with 36 or 5 uridines in the 3'UTR, remained low virulent in 3-month-old pigs. The combination of these elements recovered the high-virulent Margarita phenotype. These results show that CSFV evolution towards attenuated variants in the field involved mutations in both structural and non-structural proteins and the UTRs, which act synergistically to determine virulence.

Shock score for prediction of clinical outcomes among stable patients with acute symptomatic pulmonary embolism.

BACKGROUND: The Composite Pulmonary Embolism Shock (CPES) score has been developed to identify normotensive patients with acute pulmonary embolism (PE) and a low cardiac index (referred to as normotensive shock). We aimed to externally assess the validity of this model for predicting a complicated course among hemodynamically stable patients with acute PE. METHODS: Using prospectively collected data from the PROgnosTic valuE of Computed Tomography scan (PROTECT) study, we calculated the CPES score for each patient and the proportion of patients with a score > 3. We calculated the test performance characteristics to predict a complicated course (i.e., death from any cause, hemodynamic collapse, or recurrent PE) and the discriminatory power using the area under the receiver operating characteristic curve. RESULTS: Sixty-three of the 848 (7.4 %) patients had a complicated course during the 30-day follow-up period. Of the 848 enrolled patients, the CPES score was positive (i.e., score > 3) in 78 (9.2 %). The specificity was 92.1 % (723/785), the positive predictive value was 20.5 % (16/78), and the positive likelihood ratio was 3.22 for a complicated course. The areas under the receiver operating characteristic curve for a complicated course were 0.71 (95 % confidence interval [CI], 0.65-0.78). With the higher score risk classification threshold (cutoff score > 4), the proportion of patients designated as positive was 2.1 %, and the specificity was 98.1 %. When echocardiographic right ventricle (RV) dysfunction was replaced by computed tomographic RV enlargement, the specificity was 85.4 %, the positive predictive value was 14.2 %, and the positive likelihood ratio was 2.06 for a complicated course. When analyses were restricted to the subgroup of patients with intermediate-risk PE, the specificity and the positive predictive value for a complicated course were identical to the overall cohort. CONCLUSIONS: The CPES score has acceptable C-statistic, excellent specificity, and low positive predictive value for identification of hemodynamic deterioration in normotensive patients with PE. CLINICALTRIALS: gov number: NCT02238639.

High-Sensitivity vs Conventional Troponin Cutoffs for Risk Stratification in Patients With Acute Pulmonary Embolism.

Importance: High-sensitivity troponin tests can detect even milder cardiac troponin elevations in plasma, beyond the threshold of conventional troponin tests. Whether detection of low-grade cardiac troponin elevation is associated with outcomes of patients with hemodynamically stable pulmonary embolism (PE) and helps with risk stratification is unknown. Objective: To determine the association between high-sensitivity cardiac troponin I (hs-cTnI) compared with conventional cardiac troponin I (cTnI) and PE risk designations according to the European Society of Cardiology (ESC) 2019 classification scheme and clinical outcomes in patients with hemodynamically stable PE. Design, Setting, and Participants: This is a post hoc analysis of data from the prospective Prognostic Value of Computed Tomography (PROTECT) multicenter cohort study enrolling patients from 12 hospital emergency departments in Spain. In this analysis, cTnI and hs-cTnI were compared with respect to ESC risk designation, and the association between troponin values and a complicated course after PE diagnosis was evaluated. Of 848 patients enrolled in PROTECT, 834 (98.3%) had hsTnI and cTnI values available and were included in the present analysis. Data were analyzed from May to December 2022. Exposures: Troponin blood testing with cTnI (threshold of >0.05 ng/mL) vs hs-cTnI (threshold of >0.029 ng/mL) assays at the time of PE diagnosis. Main Outcomes: Complicated course, defined as hemodynamic collapse, recurrent PE, or all-cause death, within 30 days after PE. Results: Of 834 patients (mean [SEM] age, 67.5 [0.6] years; 424 [50.8%] female), 139 (16.7%) had elevated cTnI and 264 (31.7%) elevated hs-TnI, respectively. During follow-up, 62 patients (7.4%; 95% CI, 5.7-9.4) had a complicated course. Analyzing troponin elevation as a binary variable, elevated cTnI (odds ratio [OR], 2.84; 95% CI, 1.62-4.98) but not hs-cTnI (OR, 1.12; 95% CI, 0.65-1.93) was associated with increased odds of a complicated course. Of 125 patients who had elevated hs-cTnI but normal cTnI, none (0; 95% CI, 0.0-2.9) developed a complicated course. Using the 2019 ESC risk stratification scheme, hs-TnI classified fewer patients as low risk compared with cTnI. Among 78 patients designated as ESC low risk when using cTnI but not with hsTnI, none (0; 95% CI, 0.0-4.6) had a complicated course. Conclusions and Relevance: In this study of patients with hemodynamically stable PE, hs-cTnI identified modest elevations in cardiac troponin levels. However, the results did not provide additive clinical value compared with cTnI. These findings suggest that use of hs-cTnI may result in overestimation of the risk in patients with stable PE.

Phenolic profile changes of grapevine leaves infected with Erysiphe necator.

BACKGROUND: Powdery mildew in grapevine is caused by Erysiphe necator and its control requires many chemical treatments. Numerous efforts are being made to improve disease management to achieve crop sustainability goals. The exogenous induction of plant immune responses is one of the most encouraging strategies currently being developed. The objective of this research was to analyse differences in phenolic compound concentrations in E. necator-infected leaves of two varieties of Vitis vinifera, Tempranillo and Tempranillo Blanco, using ultra performance liquid chromatography coupled with mass spectrometry. To understand the susceptibility of the varieties, in vitro assays using whole leaves were done. RESULTS: Differences in susceptibility between varieties were found in the early stage of the disease. In both varieties, total phenolic compounds were higher in infected leaves; however, hydroxycinnamic acid, anthocyanins and stilbenes were higher only in Tempranillo. Twenty-six compounds showed differential responses to the fungal disease in Tempranillo, but only two in Tempranillo Blanco: syringa resinol, which was not detected in diseased leaves; and gallocatechin, which increased at 5 days post inoculation. In Tempranillo, four anthocyanidins, six hydroxycinnamic acids, mainly feruloyl derivates, and epigallocatechin gallate were higher in infected leaves at the beginning of the infection, whereas (-)-epicatechin and protocatechuic hexoside contents were lower. CONCLUSION: Disease-induced changes in phenolic compound biosynthesis were found. The increase in anthocyanidin content and flavan-3-ol galloylation could have a role in delaying E. necator growth in Tempranillo. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Asymmetrical nucleosomal DNA signatures regulate transcriptional directionality.

Despite the symmetrical structure of nucleosomes, in vitro studies have shown that transcription proceeds with different efficiency depending on the orientation of the DNA sequence around them. However, it is unclear whether this functional asymmetry is present in vivo and whether it could regulate transcriptional directionality. Here, we report that the proximal and distal halves of nucleosomal DNA contribute differentially to nucleosome stability in the genome. In +1 nucleosomes, this asymmetry facilitates or hinders transcription depending on the orientation of its underlying DNA, and this difference is associated with an asymmetrical interaction between DNA and histones. These properties are encoded in the DNA signature of +1 nucleosomes, since its incorporation in the two orientations into downstream nucleosomes renders them asymmetrically accessible to MNase and inverts the balance between sense and antisense transcription. Altogether, our results show that nucleosomal DNA endows nucleosomes with asymmetrical properties that modulate the directionality of transcription.

Suitability of machine learning for atrophy and fibrosis development in neovascular age-related macular degeneration.

PURPOSE: To assess the suitability of machine learning (ML) techniques in predicting the development of fibrosis and atrophy in patients with neovascular age-related macular degeneration (nAMD), receiving anti-VEGF treatment over a 36-month period. METHODS: An extensive analysis was conducted on the use of ML to predict fibrosis and atrophy development on nAMD patients at 36 months from start of anti-VEGF treatment, using only data from the first 12 months. We use data collected according to real-world practice, which includes clinical and genetic factors. RESULTS: The ML analysis consistently identified ETDRS as a relevant factor for predicting the development of atrophy and fibrosis, confirming previous statistical analyses. Also, it was shown that genetic variables did not demonstrate statistical relevance in the prediction. Despite the complexity of predicting macular degeneration, our model was able to obtain a balance accuracy of 63% and an AUC of 0.72 when predicting the development of atrophy or fibrosis at 36 months. CONCLUSION: This study demonstrates the potential of ML techniques in predicting the development of fibrosis and atrophy in nAMD patients receiving long-term anti-VEGF treatment. The findings highlight the importance of clinical factors, particularly ETDRS (early treatment diabetic retinopathy study) visual acuity test, in predicting these outcomes. The lessons learned from this research can guide future ML-based prediction tasks in the field of ophthalmology and contribute to the design of data collection processes.

Precocious Puberty in Hypothyroidism: Mini-Review of Van Wyk-Grumbach Syndrome.

Severe hypothyroidism can affect a variety of organs and can develop atypical manifestations. Peripheral precocious puberty may be secondary to other endocrinological diseases, which must be taken into account in the differential diagnosis in order to avoid unnecessary additional tests. Van Wyk-Grumbach syndrome is an infrequent manifestation characterized by severe hypothyroidism and incomplete precocious puberty. Diagnosis is made by clinical and complementary tests, and the main treatment goal is to achieve euthyroidism through hormone replacement. Prognosis is good once the treatment is established. The aim of this study is to review the available literature about Van Wyk-Grumbach syndrome following the PRISMA statement, and to present the first clinical case published in Spain. We have included the articles published during the period from 1905 to week 40 of 2022. A total of 68 articles have been selected for study and analysis, within which there are 99 published clinical cases. Girls accounted for 92.1% of cases (median age at the diagnosis 8.5 years). Metrorrhagia was the most prevalent symptom, present in 80.5% of the girls. Abdominal ultrasound was performed in 93.3% of the girls and 97.8% of them had at least one ovarian cyst. All cases were treated with levothyroxine, responding satisfactorily after the first doses of treatment. To conclude, Van Wyk-Grumbach syndrome is characterized by severe hypothyroidism and incomplete precocious puberty, which is important to keep in mind in order to avoid complementary exams and unnecessary surgical interventions.

Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up.

PURPOSE: Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. METHODS: We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004-2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. RESULTS: Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. CONCLUSION: Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.

Assesment of Hypoderma infestation in a wild population of Cervus elaphus from mountains Atlantic ecosystems in southwestern Europe (Spain).

Hypodermosis in Cervus elaphus was studied in the Riaño Regional Hunting Reserve, Province of León, north-western Spain. One hundred and ten red deer were examined for the presence of warble fly larvae. They were analyzed by PCR analysis of the COI region of mt-DNA and identified as Hypoderma actaeon. The prevalence of larvae was 42.7% with a mean intensity of 12.5 ± 18 (range 1-80) warbles/deer infested. The distribution of larvae in the infested animals showed an aggregated/overdispersed pattern (aggregation index = 25.84), where the larvae are not randomly or uniformly distributed, but strongly aggregated among their hosts. Larvae were found in all three states. First and second-instars were observed mainly in the autumn until the end of winter (November-March) and third-instars in late winter until mid-spring (March-May). The adult animals and the males had a higher prevalence than the young and the females, finding statistically significant differences only according to the sex of the animals. Seasonal variations were observed in the prevalence with the highest number of infested animals in winter and autumn, but not in terms of the mean intensity of parasites. Additionally, we assessed the presence of anti-Hypoderma antibodies in serum by means of indirect ELISA tests, using a crude larval extract (CLE) and a purified fraction the hypodermin C (HyC) obtained from first instars of Spanish isolates of Hypoderma lineatum (cattle). These findings confirm that H. actaeon is widely distributed in northern Spain, and provide new information about its chronobiology in mountainous Atlantic ecosystems from southwestern Europe.

Contribution to the Knowledge of Gastrointestinal Nematodes in Roe Deer (Capreolus capreolus) from the Province of León, Spain: An Epidemiological and Molecular Study.

A study of gastrointestinal nematodes in roe deer was carried out in the regional hunting reserves of Riaño and Mampodre, Province of León, Spain, to provide information on their prevalence and intensity of infection in relation to the sampling areas, age of the animals, and body weight. Through a regulated necropsy of the animals, all of them harbored gastrointestinal nematodes in their digestive tract, with a mean intensity of parasitism of 638 ± 646.1 nematodes/infected animal. Eleven genera were found and 18 species of gastrointestinal nematodes were identified, three of them polymorphic: Trichostrongylus axei, Trichostrongylus vitrinus, Trichostrongylus capricola, Trichostrongylus colubriformis, Haemonchus contortus, Spiculopteragia spiculoptera/Spiculopteragia mathevossiani, Ostertagia leptospicularis/Ostertagia kolchida, Ostertagia (Grosspiculopteragia) occidentalis, Teladorsagia circumcincta/Teladorsagia trifurcate, Marshallagia marshalli, Nematodirus europaeus, Cooperia oncophora, Capillaria bovis, Oesophagostomum venulosum, and Trichuris ovis. All of them have already been cited in roe deer in Europe, but Marshallagia marshalli, Capillaria bovis, and Ostertagia (Grosspiculopteragia) occidentalis are reported for the first time in Spain in this host. The abomasum was the intestinal section, where the prevalence (98.9%) and mean intensity (x¯ = 370.7 ± 374.4 worms/roe deer; range 3-1762) were significantly higher, but no statistically significant differences were found when comparing the sampling areas and age of animals. The animals with lower body weight had a higher parasite load than those in better physical condition, finding, in this case, statistically significant differences (p = 0.0020). Seven genera and 14 species were identified. In the small intestine, 88% of the animals examined presented gastrointestinal nematodes, with an average intensity of x¯ = 131.7 ± 225.6 parasites/infected animal, ranging between 4-1254 worms. No statistically significant differences were found when the three parameters studied were compared. Four genera and seven species were identified. In the large intestine/cecum, 78.3% of the examined roe deer presented adult worms, with an average intensity of 6.3 ± 5.5 worms/infected animal; range 1-26 worms. Only statistically significant differences were observed when considering the mean intensity of parasitism and the sampling area (p = 0.0093). Two genera and two species were identified. Several of the species found in the study were studied molecularly, and with the sequences obtained compared with those deposited in GenBank, phylogenetic trees were prepared to determine their taxonomic status. Using coprological techniques, the existing correlation in the shedding of gastrointestinal nematode eggs in roe deer was investigated with that of semi-extensive sheep farms in the same study area to verify the existence of cross-transmission of these parasites between wild and domestic animals. The high values found in the studied parameters show that northern Spain is an area of high-intensity infection for roe deer.

Reconstruction technique of multiligamentous knee injury in a patient with traumatic transtibial amputation.

Multiligamentary knee injuries associated with transtibial amputation is a pathologie with a low incidence, so their diagnosis and treatment represent a great challenge for the medical team, mainly due to the low rate of scientific publications on the matter. This article intends to present the treatment of a really infrequent pathology, presenting the clinical case of a polytraumatized patient who suffered a left transtibial amputation associated with a multiligament knee injury with dislocation of the proximal tibiofibular joint. After analyzing the multiple therapeutic options, a specific surgical planning is carried out for the specific case of a multiligament knee injury associated with an ipsilateral transtibial amputation, proceeding to the execution of the reconstruction of the injury with good results. For this, several specific surgical gestures are carried out, adapted to the patient's condition, which will facilitate the surgery and are explained in the surgical technique. In conclusion, we must know that in order to obtain satisfactory results in these patients, it is important to carry out an early diagnosis and treatment of the injury, analyzing the proximal tibiofibular stability and providing adequate stability through the execution of a precise surgical technique.

Hybrid Silica Xerogel and Titania/Silica Xerogel Dispersions Reinforcing Hydrophilicity and Antimicrobial Resistance of Leathers.

Four leather substrates from different animals were treated by dispersions containing hydrophilic composite silica-hyperbranched poly(ethylene imine) xerogels. Antimicrobial activity was introduced by incorporating silver nanoparticles and/or benzalkonium chloride. The gel precursor solutions were also infused before gelation to titanium oxide powders typically employed for induction of self-cleaning properties. The dispersions from these biomimetically premade xerogels integrate environmentally friendly materials with short coating times. Scanning electron microscopy (SEM) provided information on the powder distribution onto the leathers. Substrate and coating composition were estimated by infrared spectroscopy (IR) and energy-dispersive X-ray spectroscopy (EDS). Surface hydrophilicity and water permeability were assessed by water-contact angle experiments. The diffusion of the leather's initial components and xerogel additives into the water were measured by Ultraviolet-Visible (UV-Vis) spectroscopy. Protection against GRAM- bacteria was tested for Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae against GRAM+ bacteria for Staphylococcus aureus and Enterococcus faecalis and against fungi for Candida albicans. Antibiofilm capacity experiments were performed against Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, and Candida albicans. The application of xerogel dispersions proved an adequate and economically feasible alternative to the direct gel formation into the substrate's pores for the preparation of leathers intended for medical uses.

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.