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Abstract Arguably, the greatest threat to bacteria is phages. It is often assumed that those bacteria that escape phage infection have mutated or utilized phage‐defence systems; however, another possibility is that a subpopulation forms the dormant persister state in a manner similar to that demonstrated for bacterial cells undergoing nutritive, oxidative, and antibiotic stress. Persister cells do not undergo mutation and survive lethal conditions by ceasing growth transiently. Slower growth and dormancy play a key physiological role as they allow host phage defence systems more time to clear the phage infection. Here, we investigated how bacteria survive lytic phage infection by isolating surviving cells from the plaques of T2, T4, and lambda (cI mutant) virulent phages and sequencing their genomes. We found that bacteria in plaques can escape phage attack both by mutation (i.e. become resistant) and without mutation (i.e. become persistent). Specifically, whereas T4‐resistant and lambda‐resistant bacteria with over a 100,000‐fold less sensitivity were isolated from plaques with obvious genetic mutations (e.g. causing mucoidy), cells were also found after T2 infection that undergo no significant mutation, retain wild‐type phage sensitivity, and survive lethal doses of antibiotics. Corroborating this, adding T2 phage to persister cells resulted in 137,000‐fold more survival compared to that of addition to exponentially growing cells. Furthermore, our results seem general in that phage treatments with Klebsiella pneumonia and Pseudomonas aeruginosa also generated persister cells. Hence, along with resistant strains, bacteria also form persister cells during phage infection.

Telemedicine applications present virtually limitless prospects for innovating and enhancing established and new models of patient care in the field of Internal Medicine. Although there is a wide range of innovative technological solutions in Europe, there are overarching elements associated with such technologies when applied to the practices of Internal Medicine specialists. The European Federation of Internal Medicine (EFIM) strongly advocates for active leadership and influence from the Internal Medicine societies and specialist physicians across Europe in the development and application of telemedicine and digital technologies in healthcare. This position paper’s conclusions were drawn via Delphi method, which was developed collaboratively from July 2021 to December 2023. The panel, consisting of experts in clinical medicine, public health, health economics and statistics, assessed various aspects related to telemedicine. Participants assigned scores on a Likert scale reflecting perceived value and potential risks. The findings were consolidated in a comprehensive checklist aligning with relevant literature and a SWOT analysis. Specifically, key issues that need to be addressed include promoting the professional development of e-health competencies in the healthcare and medical workforce, using educational campaigns to promote digital literacy among patients and caregivers, designing and implementing telemedicine applications tailored to local conditions and needs and considering the ethical and legal contexts under which these applications are employed. Importantly, there is currently no consensus on care models or standardized protocols among European Internal Medicine specialists regarding the utilization of telemedicine. This position paper aims to outline the opportunities and challenges associated with the application of telemedicine in Internal Medical practice in Europe.

# Background Patients with chronic lung disease (CLD), such as asthma or chronic obstructive pulmonary disease, were expected to have an increased risk of clinical manifestations and severity of COVID-19. However, these comorbidities have been reported less frequently than expected. Chronic treatment with inhaled corticosteroids (ICS) may impact the clinical course of COVID-19. The main objective of this study is to know the influence of chronic treatment with ICS on the prognosis of COVID-19 hospitalized patients with CLD. # Methods A multicenter retrospective cohort study was designed, including patients hospitalized with COVID-19. Epidemiological and clinical data were collected at admission and at seven days, and clinical outcomes were collected. Patients with CLD with and without chronic treatment with ICS were compared. # Results Two thousand five hundred ninety-eight patients were included, of which 1,171 patients had a diagnosis of asthma and 1,427 of COPD (53.37% and 41.41% with ICS, respectively). No differences were found in mortality, transfer to ICU, or development of moderate-severe ARDS. Patients with chronic ICS had a longer hospital stay in both asthma and COPD patients (9 vs. 8 days, *p =* 0.031 in asthma patients), (11 vs. 9 days, *p =* 0.018 in COPD patients); although they also had more comorbidity burden. # Conclusions Patients with chronic inhaled corticosteroids had longer hospital stays and more chronic comorbidities, measured by the Charlson comorbidity index, but they did not have more severe disease at admission, evaluated with qSOFA and PSI scores. Chronic treatment with inhaled corticosteroids had no influence on the prognosis of patients with chronic lung disease and COVID-19.

Background: Muscle wasting is pronounced in patients with heart failure with preserved ejection fraction (HFpEF). The quadriceps femoris echotexture biomarkers assessed by ultrasound (US) have not been studied in these patients. Objective: To describe echotexture biomarkers assessed by the US and to assess their relationship with sex, age, body mass index (BMI), self-reported outcomes, muscle strength and physical function in older adults with HFpEF. Methods: A cross-sectional study was conducted. Patients 70 years and older with HFpEF were included. The sex, age, BMI, and self-reported outcomes were collected. The US assessed muscle and subcutaneous fat tissue contrast, correlation, energy, homogeneity, and entropy at rest and maximal voluntary isometrical contraction (MVIC). The six-minute walk test (6MWT), the short physical performance battery (SPPB), the timed up and go test (TUG), the usual pace gait speed test (UGS), and the fast pace gait speed test (FGS) were used to assess physical function. The five-repetitions sit-to-stand test (5-STS) was performed to assess muscle strength. Bivariant Pearson correlations and subsequent multivariate linear regression analyses were conducted. Results: Seventy-two older adults with HFpEF [81.06 years, 29.13 BMI, and 55.60% females] were recruited. In women, relaxed and MVIC muscle energy and entropy explained 35.40% of the TUG variance; relaxed muscle entropy and MVIC muscle energy shared 24.00% of the UGS variance; relaxed and MVIC muscle entropy, MVIC muscle contrast and MVIC muscle energy explained 32.60% of the FGS variance, adjusted all the models by age and BMI. Conclusions: Echotexture biomarkers are related to women's muscle strength and physical function, especially muscle energy, contrast, and entropy. Echotexture biomarkers assessed by the US could facilitate the management of older adults with HFpEF, monitor its progression and assess the effectiveness of treatments on the musculoskeletal structure. Trial registration: NCT03909919. April 10, 2019. Retrospectively registered.

Abstract In 2020, the COVID-19 pandemic followed a two-wave pattern in most countries. Hospital admission for COVID-19 in one wave or another could have affected mortality, especially among the older persons. The objective of this study was to evaluate whether the admission of older patients during the different waves, before SARS-CoV-2 vaccination was available, was associated with a different mortality. We compared the mortality rates of patients hospitalized during 2020 before (first wave) and after (second wave) July 7, 2020, included in the SEMI-COVID-19 Registry, a large, multicenter, retrospective cohort of patients admitted to 126 Spanish hospitals for COVID-19. A multivariate logistic regression analysis was performed to control for changes in either the patient or disease profile. As of December 26, 2022, 22,494 patients had been included (17,784 from the first wave and 4710 from the second one). Overall mortality was 20.4% in the first wave and 17.2% in the second wave (risk difference (RD) − 3.2%; 95% confidence interval (95% CI) − 4.4 to − 2.0). Only patients aged 70 and older (10,973 patients: 8571 in the first wave and 2386 in the second wave) had a significant reduction in mortality (RD − 7.6%; 95% CI − 9.7 to − 5.5) (unadjusted relative risk reduction: 21.6%). After adjusting for age, comorbidities, variables related to the severity of the disease, and treatment received, admission during the second wave remained a protective factor. In Spain, patients aged 70 years and older admitted during the second wave of the COVID-19 pandemic had a significantly lower risk of mortality, except in severely dependent persons in need of corticosteroid treatment. This effect is independent of patient characteristics, disease severity, or treatment received. This suggests a protective effect of a better standard of care, greater clinical expertise, or a lesser degree of healthcare system overload.

Introduction: Older patients are more likely to have cognitive dysfunction, and a great proportion of patients undergone surgical procedures are older adults. Postoperative cognitive dysfunction (POCD) has been shown as a consistent complication after major surgical procedures such as heart surgery. Aim: To determine the presence of long-term POCD in ≥65-year-old patients undergoing coronary artery bypass grafting and aortic valve replacement, and to establish related risk factors. Methods: We prospectively and sequentially included 44 patients with coronary disease and aortic stenosis scheduled for heart surgery. Follow-up of all patients was standardized and a neurocognitive evaluation were performed preoperatively and at 1, 6 and 12 months after surgery. Results: Patients experienced a significantly postoperative cognitive dysfunction (33.5%, 63.4% and 38.9% at 1, 6 and 12 months, respectively) from baseline (20.5%). Patient-associated aspects such as age (p

Summary: The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

Abstract Background Cardiovascular (CV) polypills are a useful baseline treatment to prevent CV diseases by combining different drug classes in a single pill to simultaneously target more than one risk factor. The aim of the present trial was to determine whether the treatment with the CNIC-polypill was at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDL-c) and systolic BP (SBP) values in subjects at high or very high risk without a previous CV event. Methods The VULCANO was an international, multicentre open-label trial involving 492 participants recruited from hospital clinics or primary care centres. Patients were randomised to the CNIC-polypill -containing aspirin, atorvastatin, and ramipril- or usual care. The primary outcome was the comparison of the mean change in LDL-c and SBP values after 16 weeks of treatment between treatment groups. Results The upper confidence limit of the mean change in LDL-c between treatments was below the prespecified margin (10 mg/dL) and above zero, and non-inferiority and superiority of the CNIC-polypill (p = 0.0001) was reached. There were no significant differences in SBP between groups. However, the upper confidence limit crossed the prespecified non-inferiority margin of 3 mm Hg. Significant differences favoured the CNIC-polypill in reducing total cholesterol (p = 0.0004) and non-high-density lipoprotein cholesterol levels (p = 0.0017). There were no reports of major bleeding episodes. The frequency of non-serious gastrointestinal disorders was more frequent in the CNIC-polypill arm. Conclusion The switch from conventional treatment to the CNIC-polypill approach was safe and appears a reasonable strategy to control risk factors and prevent CVD. Trial registration This trial was registered in the EU Clinical Trials Register (EudraCT) the 20th February 2017 (register number 2016-004015-13; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016-004015-13 ).

Abstract Heart failure (HF)-related factors potentially lead to sarcopenia. Ultrasound (US) assessment has all the advantages of being used in clinical practice to assess muscle architecture. This study aimed to assess the relationship between the quadriceps femoris (QF) muscle architecture with the gender, age, body mass index (BMI), muscle strength and physical function in older adults with HF with preserved ejection fraction (HFpEF) as well as to assess the difference in these relationships between the two genders. Patients 70 years and older with HFpEF were included. The gender, age and BMI were collected. The QF muscle thickness, the QF muscle echo-intensity, the subcutaneous fat tissue thickness (FT) and the subcutaneous fat tissue echo-intensity were assessed by the US. The six-minute walk test, the short physical performance battery (SPPB), the timed up and go test (TUG), and the gait speed test (UGS) were used to assess physical function. The five-repetitions sit-to-stand test (5-STS) was performed to assess muscle strength. Bivariant Pearson correlations and subsequent multivariate linear regression analysis were conducted. Seventy older adults with HFpEF [81.00 (5.97) years] were recruited. The FT showed a correlation between poor and moderate muscle strength and physical function in women with HFpEF. The FT explained 24.5% of the 5-STS variance, 32.4% of the SPPB variance, 31.5% of the TUG variance, 28.6% of the UGS variance, and 21.4% of the FGS variance in women. The US assessment could allow clinicians to assess muscle architecture biomarkers related to muscle strength and physical function in older adults with HFpEF. Trial registration NCT03909919. April 10, 2019. Retrospectively registered.

Background: The emergence of new SARS-CoV-2 variants with significant immune-evasiveness, the relaxation of measures for reducing the number of infections, the waning of immune protection (particularly in high-risk population groups), and the low uptake of new vaccine boosters, forecast new waves of hospitalizations and admission to intensive care units. There is an urgent need for easily implementable and clinically effective Early Warning Scores (EWSs) that can predict the risk of complications within the next 24–48 hr. Although EWSs have been used in the evaluation of COVID-19 patients, there are several clinical limitations to their use. Moreover, no models have been tested on geographically distinct populations or population groups with varying levels of immune protection. Methods: We developed and validated COVID-19 Early Warning Score (COEWS), an EWS that is automatically calculated solely from laboratory parameters that are widely available and affordable. We benchmarked COEWS against the widely used NEWS2. We also evaluated the predictive performance of vaccinated and unvaccinated patients. Results: The variables of the COEWS predictive model were selected based on their predictive coefficients and on the wide availability of these laboratory variables. The final model included complete blood count, blood glucose, and oxygen saturation features. To make COEWS more actionable in real clinical situations, we transformed the predictive coefficients of the COEWS model into individual scores for each selected feature. The global score serves as an easy-to-calculate measure indicating the risk of a patient developing the combined outcome of mechanical ventilation or death within the next 48 hr. Conclusions: The COEWS score predicts death or MV within the next 48 hr based on routine and widely available laboratory measurements. The extensive external validation, its high performance, its ease of use, and its positive benchmark in comparison with the widely used NEWS2 position COEWS as a new reference tool for assisting clinical decisions and improving patient care in the upcoming pandemic waves. Funding: University of Vienna.

We synthesized six new camphor-derived homochiral thioureas 1–6, from commercially available (1R)-(−)-camphorquinone. These new compounds 1–6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:β stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:β. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for β glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.

Abstract Background Old age is one of the most important risk factors for severe COVID-19. Few studies have analyzed changes in the clinical characteristics and prognosis of COVID-19 among older adults before the availability of vaccines. This work analyzes differences in clinical features and mortality in unvaccinated very old adults during the first and successive COVID-19 waves in Spain. Methods This nationwide, multicenter, retrospective cohort study analyzes unvaccinated patients ≥ 80 years hospitalized for COVID-19 in 150 Spanish hospitals (SEMI-COVID-19 Registry). Patients were classified according to whether they were admitted in the first wave (March 1-June 30, 2020) or successive waves (July 1-December 31, 2020). The endpoint was all-cause in-hospital mortality, expressed as the case fatality rate (CFR). Results Of the 21,461 patients hospitalized with COVID-19, 5,953 (27.7%) were ≥ 80 years (mean age [IQR]: 85.6 [82.3–89.2] years). Of them, 4,545 (76.3%) were admitted during the first wave and 1,408 (23.7%) during successive waves. Patients hospitalized in successive waves were older, had a greater Charlson Comorbidity Index and dependency, less cough and fever, and met fewer severity criteria at admission (qSOFA index, PO2/FiO2 ratio, inflammatory parameters). Significant differences were observed in treatments used in the first (greater use of antimalarials, lopinavir, and macrolides) and successive waves (greater use of corticosteroids, tocilizumab and remdesivir). In-hospital complications, especially acute respiratory distress syndrome and pneumonia, were less frequent in patients hospitalized in successive waves, except for heart failure. The CFR was significantly higher in the first wave (44.1% vs. 33.3%; -10.8%; p

Bacteriophages are the most abundant biological entity on the planet, having pivotal roles in bacterial ecology, animal and plant health, and in the biogeochemical cycles. Although, in principle, phages are simple entities that replicate at the expense of their bacterial hosts, due the importance of bacteria in all aspects of nature, they have the potential to influence and modify diverse processes, either in subtle or profound ways. Traditionally, the main application of bacteriophages is phage therapy, which is their utilization to combat and help to clear bacterial infections, from enteric diseases, to skin infections, chronic infections, sepsis, etc. Nevertheless, phages can also be potentially used for several other tasks, including food preservation, disinfection of surfaces, treatment of several dysbioses, and modulation of microbiomes. Phages may also be used as tools for the treatment of non-bacterial infections and pest control in agriculture; moreover, they can be used to decrease bacterial virulence and antibiotic resistance and even to combat global warming. In this review manuscript we discuss these possible applications and promote their implementation.