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Polymyalgia rheumatica (PMR) is a chronic inflammatory disease characterized by shoulder and pelvic girdle pain. Its onset peaks around the age of 75; the prevalence increases until the age of 90 and it is more frequent in females. Diagnosis is mostly performed on the basis of symptoms. An increase of serum inflammatory markers is indicative, but not essential, while therapy is mainly based on glucocorticoids. Since there is no universal agreement about diagnostic criteria for PMR, its detection is still difficult. There are discordant opinions about the fact that PMR can be recognised and managed by general practitioners (GPs), while patients with atypical features need to be referred to the rheumatologist. In the Italian setting, the absence of recent epidemiological studies is associated with the total lack of a research protocol in primary care, from which relevant information could be derived. The out-of-hospital public rheumatologist is a peculiar figure of the Italian National Health System, who takes care of outpatients. Although differences between the different Italian regional health services exist, this professional figure has proved to be effective in reducing delay and increasing accuracy in PMR diagnosis.

The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.

Objective: To evaluate changes in hemoglobin A1c (HbA1c) levels and z-height over 3 years based on continuous glucose monitoring (CGM) usage among children with new-onset type 1 diabetes (T1DM) from various Latin American centers. Study design: Data on z-height, CGM access, and HbA1c (%) were collected for Latin American children aged 6 months to 18 years with T1DM onset from 19 centers in a retrospective analysis of medical records, from 2020 to 2023. A 2-way ANOVA method with repeated measures and multiple regression analyses were performed. Results: We included 433 children (46.0% female) aged 8.7 ± 3.7 years; 199 (45.9%) used CGM. The mean HbA1c was significantly lower in years 1, 2, and 3 than at baseline in children with CGM, but not those without CGM. The z-height decreased significantly with the years in both groups. However, the CGM users showed a significantly greater height in years 2 and 3 than the nonusers. Multiple linear regression analysis showed that CGM users exhibited a significantly lower incremental area under the curve (AUC) for HbA1c during follow-up than nonusers. Furthermore, a lower incremental AUC for HbA1c was associated with a smaller decremental AUC for z-height (R2 = 0.19). Multiple logistic regression analysis revealed that children with CGM were 80% more likely (OR, 0.22; 95% CI, 0.1-0.6) to achieve an HbA1c of

Abstract The Central and South‐Central Andes form a “two‐sided” mountain belt bounded by distinct zones of convergence in the forearc and backarc flanks. Previous geodetic interseismic deformation studies found that the forearc to backarc velocity field is better explained when elastic models allow reverse aseismic slip on the Andes eastern‐flank décollement faults. Here, we extend the earlier interpretation of interseismic motion and argue that normal aseismic creep of the Precordillera décollement is required to explain backarc Global Navigation Satellite System displacements during the co‐ and early postseismic phases of the 2015 Illapel, Chile, earthquake. This model significantly reduces the previously reported overlap between coseismic slip and afterslip on the megathrust of this earthquake, consistent with the expectation that these slip modes are spatially partitioned. These findings have direct implications for estimating recurrence interval and slip rate, and for probabilistic seismic hazard analysis on both sides of the orogen.

BackgroundIn 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern.MethodsINTERCOVID-2022 is a large, prospective, observational study, involving 41 hospitals across 18 countries. Each woman with real-time PCR or rapid test, laboratory-confirmed COVID-19 in pregnancy was compared with two unmatched women without a COVID-19 diagnosis who were recruited concomitantly and consecutively in pregnancy or at delivery. Mother and neonate dyads were followed until hospital discharge. Primary outcomes were maternal morbidity and mortality index (MMMI), severe neonatal morbidity index (SNMI), and severe perinatal morbidity and mortality index (SPMMI). Vaccine effectiveness was estimated, adjusted by maternal risk profile.FindingsWe enrolled 4618 pregnant women from Nov 27, 2021 (the day after WHO declared omicron a variant of concern), to June 30, 2022: 1545 (33%) women had a COVID-19 diagnosis (median gestation 36·7 weeks [IQR 29·0-38·9]) and 3073 (67%) women, with similar demographic characteristics, did not have a COVID-19 diagnosis. Overall, women with a diagnosis had an increased risk for MMMI (relative risk [RR] 1·16 [95% CI 1·03-1·31]) and SPMMI (RR 1·21 [95% CI 1·00-1·46]). Women with a diagnosis, compared with those without a diagnosis, also had increased risks of SNMI (RR 1·23 [95% CI 0·88-1·71]), although the lower bounds of the 95% CI crossed unity. Unvaccinated women with a COVID-19 diagnosis had a greater risk of MMMI (RR 1·36 [95% CI 1·12-1·65]). Severe COVID-19 symptoms in the total sample increased the risk of severe maternal complications (RR 2·51 [95% CI 1·84-3·43]), perinatal complications (RR 1·84 [95% CI 1·02-3·34]), and referral, intensive care unit (ICU) admission, or death (RR 11·83 [95% CI 6·67-20·97]). Severe COVID-19 symptoms in unvaccinated women increased the risk of MMMI (RR 2·88 [95% CI 2·02-4·12]) and referral, ICU admission, or death (RR 20·82 [95% CI 10·44-41·54]). 2886 (63%) of 4618 total participants had at least a single dose of any vaccine, and 2476 (54%) of 4618 had either complete or booster doses. Vaccine effectiveness (all vaccines combined) for severe complications of COVID-19 for all women with a complete regimen was 48% (95% CI 22-65) and 76% (47-89) after a booster dose. For women with a COVID-19 diagnosis, vaccine effectiveness of all vaccines combined for women with a complete regimen was 74% (95% CI 48-87) and 91% (65-98) after a booster dose.InterpretationCOVID-19 in pregnancy, during the first 6 months of omicron as the variant of concern, was associated with increased risk of severe maternal morbidity and mortality, especially among symptomatic and unvaccinated women. Women with complete or boosted vaccine doses had reduced risk for severe symptoms, complications, and death. Vaccination coverage among pregnant women remains a priority.FundingNone.

Background: Patients with metastatic colorectal cancer (mCRC) carrying a deficit in the mismatch repair system/microsatellite instability (dMMR/MSI) show great responses to immune checkpoint inhibitors. However, 30% of patients with dMMR/MSI are primarily immunoresistant, and another 30% develop secondary resistance. Thus several combinations such as anti-programmed cell death protein 1 (anti-PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) are being pursued. The combination of radiotherapy and immunotherapy is another avenue of research that can increase the release of neoantigens resulting in the abscopal effect. This phenomenon has demonstrated promising potential activity in colon cancer preclinical studies; nevertheless, clinical results are limited to just a few case series. Patients and methods: We conducted a prospective interventional single-institution study to assess the feasibility, safety, and disease control rate of the combination of pembrolizumab and stereotactic ablative radiotherapy (SABR) in a cohort of 14 consecutive patients with dMMR/MSI mCRC. Results: Among the 14 patients enrolled, 11 received SABR in combination with pembrolizumab as the first to the fourth line. The disease control rate was 50% in the intention-to-treat population, with six patients still maintaining the response after >15 months. Any-grade treatment-related adverse events occurred in 50% of patients, with grade 3 (G3) events in three patients; no treatment-related death occurred. Conclusions: Our findings convey no signal of enhanced systemic efficacy compared with historical data on pembrolizumab alone even if the local control rate is high. To our knowledge, this represents the largest study conducted in this population; further studies could extend the knowledge on the toxicity profile of this combination.

Forward genetics involves the identification of an unknown DNA sequence (genotype) associated with the expression of that sequence (phenotype). This is often done by generating variants (mutants) of that feature. One of the most practical methods is transposon mutagenesis, which facilitates the genotype-phenotype association through a sequence tag. This six-session laboratory practical illustrates the concept of forward genetics in bacteria using the random DNA target selection of the Tn5 mini-transposon to generate a mutant library. The target bacterium is "Pseudomonas chlororaphis" subsp. "aurantiaca" strain SMMP3, whose broad-spectrum fungal antagonism is largely due to a diffusible, orange-pigmented antibiotic of the phenazine class. The library is screened on appropriate media to select clones with reduced colony pigmentation. Upon qualitative and quantitative phenotype confirmation, a subset of mutants is subjected to an arbitrary PCR to identify the interrupted genes through an "in-silico" comparative analysis of the sequencing products in public genomic databases. Students thus identify previously described or novel biosynthetic and regulatory genes involved in phenazine production. Along with the objective of illustrating a forward genetics approach, the exercise emulates a real scientific activity in which supervised students pursue a path to interpret the phenotypic consequences of gene knockouts.

In the very recent years, cybersecurity attacks have increased at an unprecedented pace, becoming ever more sophisticated and costly. Their impact has involved both private/public companies and critical infrastructures. At the same time, due to the COVID-19 pandemic, the security perimeters of many organizations expanded, causing an increase in the attack surface exploitable by threat actors through malware and phishing attacks. Given these factors, it is of primary importance to monitor the security perimeter and the events occurring in the monitored network, according to a tested security strategy of detection and response. In this paper, we present a protocol tunneling detector prototype which inspects, in near real-time, a company’s network traffic using machine learning techniques. Indeed, tunneling attacks allow malicious actors to maximize the time in which their activity remains undetected. The detector monitors unencrypted network flows and extracts features to detect possible occurring attacks and anomalies by combining machine learning and deep learning. The proposed module can be embedded in any network security monitoring platform able to provide network flow information along with its metadata. The detection capabilities of the implemented prototype have been tested both on benign and malicious datasets. Results show an overall accuracy of 97.1% and an F1-score equal to 95.6%.

Introducción: estudios previos informaron un aumento de los debuts de diabetes mellitus tipo 1 (DM1) en niños residentes de las regiones gravemente afectadas por la pandemia de COVID-19. Objetivos: determinar las tasas y la severidad de los debuts por DM1 en poblaciones pediátricas de varios centros argentinos durante la pandemia de COVID-19 durante el confinamiento de 2020, y compararlos con la prepandemia (2018-2019) y la pospandemia (2021-2022). Materiales y métodos: revisión retrospectiva de historias clínicas donde se determinaron las tasas de debuts de DM1 en niños de 6 meses a 16 años durante el confinamiento (2020), la prepandemia (2018 y 2019) y la pospandemia (2021-2022) en 28 centros argentinos. Para determinar la tasa de debuts de DM1, se dividió el número de debuts de DM1 por año por la población proyectada. Resultados: se incluyeron 1997 casos (48,5% mujeres), el 50,1% tenía obra social. Los valores medios ± un desvío estándar fueron: edad 8,7±3,7 años, glucosa 468±184 mg/dL, HbA1c 11,3% ±2,5, pH 7,21±0,2 y bicarbonato 13,4±7,7. No hubo diferencias significativas en la edad, índice de masa corporal (IMC), glucosa y HbA1c entre 2018 y 2022. Sin embargo, el pH (7,19 versus 7,23) y el bicarbonato (12,5 versus 14,7 mEq/L) fueron significativamente más bajos en 2020 versus 2018. La tasa de debuts de DM1 por 100.000 habitantes fue mayor en 2020 (3,5) versus la prepandemia: 2,9 en 2018 y 3,2 en 2019. No obstante, durante 2021 y 2022 las tasas de DM1 fueron incluso superiores a la de 2020, con 4,4 y 4,0, respectivamente. Conclusiones: se ha registrado un aumento de debuts de DM1 en diferentes centros médicos de Argentina desde la pandemia. Los niveles de bicarbonato y pH de los debuts de DM1 fueron significativamente más bajos durante el confinamiento por la pandemia (2020) comparados con la prepandemia (2018).