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The development of an automated and reproducible process for copper-mediated click reactions of alkynes and azides into 1,4-disubstituted 1,2,3-triazole products is described. This method utilizes prepacked capsules that contain all necessary reagents and materials for the reaction and purification processes. The reaction and product isolation steps are fully automated with no further user involvement, resulting in the triazole products in high purity. The effectiveness of capsule-based automated organic synthesis was further demonstrated by sequencing the automated synthesis of organic azides, followed by a second capsule for CuAAC with no intermediate purification.

Sepsis is defined as dysregulated host response to infection that leads to life-threatening organ dysfunction. Biomarkers characterising the dysregulated host response in sepsis are lacking. We aimed to develop host gene expression signatures to predict organ dysfunction in children with bacterial or viral infection.

The development of an automated process for Suzuki–Miyaura cross couplings is described, in which the complete reaction, workup, and product isolation are effected automatically with no user involvement, aside from loading of the starting materials and reaction capsule. This practical and simple method was successfully demonstrated to provide the desired biaryl products using a range of aryl bromides and boronic acids and is also effective for the late-stage functionalization of aryl halides in bioactive molecules.

Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h.

Purpose: Preliminary data suggested that bone mineral density (BMD) in transgender adults before initiating gender-affirming hormone therapy (GAHT) is lower when compared to cisgender controls. In this study, we analyzed bone metabolism in a sample of transgender adults before GAHT, and its possible correlation with biochemical profile, body composition and lifestyle habits (i.e., tobacco smoke and physical activity). Methods: Medical data, smoking habits, phospho-calcic and hormonal blood tests and densitometric parameters were collected in a sample of 125 transgender adults, 78 Assigned Females At Birth (AFAB) and 47 Assigned Males At Birth (AMAB) before GAHT initiation and 146 cisgender controls (57 females and 89 males) matched by sex assigned at birth and age. 55 transgender and 46 cisgender controls also underwent a complete body composition evaluation and assessment of physical activity using the International Physical Activity Questionnaire (IPAQ). Results: 14.3% of transgender and 6.2% of cisgender sample, respectively, had z-score values < -2 (p= 0.04). We observed only lower vitamin D values in transgender sample regarding biochemical/hormonal profile. AFAB transgender people had more total fat mass, while AMAB transgender individuals had reduced total lean mass as compared to cisgender people (53.94 ± 7.74 vs 58.38 ± 6.91, p< 0.05). AFAB transgender adults were more likely to be active smokers and tend to spend more time indoor. Fat Mass Index (FMI) was correlated with lumbar and femur BMD both in transgender individuals, while no correlations were found between lean mass parameters and BMD in AMAB transgender people. Conclusions: Body composition and lifestyle factors could contribute to low BMD in transgender adults before GAHT.

Origins of replication sites (ORIs) are crucial genomic regions where DNA replication initiation takes place, playing pivotal roles in fundamental biological processes like cell division, gene expression regulation, and DNA integrity. Accurate identification of ORIs is essential for comprehending cell replication, gene expression, and mutation-related diseases. However, experimental approaches for ORI identification are often expensive and time-consuming, leading to the growing popularity of computational methods. In this study, we present PLANNER (DeeP LeArNiNg prEdictor for ORI), a novel approach for species-specific and cell-specific prediction of eukaryotic ORIs. PLANNER uses the multi-scale k-tuple sequences as input and employs the DNABERT pre-training model with transfer learning and ensemble learning strategies to train accurate predictive models. Extensive empirical test results demonstrate that PLANNER achieved superior predictive performance compared to state-of-the-art approaches, including iOri-Euk, Stack-ORI, and ORI-Deep, within specific cell types and across different cell types. Furthermore, by incorporating an interpretable analysis mechanism, we provide insights into the learned patterns, facilitating the mapping from discovering important sequential determinants to comprehensively analysing their biological functions.

The Internet allows humans to effortlessly communicate with each other in novel ways and delivers instantaneous access to vast amounts of information and accumulated knowledge. Recently, several scholars have made the case that the Internet can enhance human cognition, while others are skeptical or disagree. Within the context of the wider debate around human enhancement, to what extent can it be argued that the Internet enhances human cognition? In an effort to resolve this question, we examine three critical assumptions: (1) the Internet fosters an active learning environment characterized by deep and constructive learning, (2) the current design of the Internet benefits users and promotes adaptive behaviors, and (3) the Internet improves cognitive function. Our analysis systematizes the evidence presented in recent scholarship that points to either an optimistic or pessimistic view on whether the Internet can function as a cognitive enhancement—with some evidence, such as the “Google effect,” being cited by either side of the debate. Moreover, we find a clash of differing ideological views, which risks polarizing both the academic and the public debate on the topic. In the effort to advance this debate toward a conclusion based on the available objective facts and evidence, we argue for a nuanced approach: to designate the Internet as a technologically enabled environment, not as a single technological intervention that can be reliably expected to enhance or decrease cognition.

Background: Proximal femur fractures have a negative impact on loss of functional autonomy and mortality. Objective: The aim of this retrospective study was to evaluate functional autonomy and mortality in a group of older adults with hip fractures managed in an orthogeriatric setting 12 months after discharge and to determine if gender affected outcome. Methods: In all participants, we assessed clinical history, functional pre-fracture status using activities of daily living (ADL) and in-hospital details. At 12 months after discharge, we evaluated functional status, place of residence, hospital readmissions and mortality. Results: We studied 361 women and 124 men and we observed a significant reduction in the ADL score at 6 months (1.15 ± 1.58/p < 0.001 in women and 1.45 ± 1.66/p < 0.001 in men). One-year mortality (33.1% in men and 14.7% in women) was associated with pre-fracture ADL score and reduction in ADL at 6 months (HR 0.68/95%, CI 0.48–0.97/p < 0.05 and HR 1.70/95%, CI 1.17–2.48/p < 0.01, respectively) in women, and new hospitalisations at 6 months and polypharmacy in men (HR 1.65/95%, CI 1.07–2.56/p < 0.05 and HR 1.40/95%, CI 1.00–1.96/p = 0.05, respectively) in Cox's regression model. Discussion and Conclusions: Our study suggests that functional loss in older adults hospitalised for proximal femur fractures is greatest in the first 6 months after discharge, and this increases the risk of death at 1 year. Cumulative mortality at 12 months is higher in men and appears to be related to polypharmacy and new hospital admissions 6 months after discharge.

Post-translational modification of proteins by Ubiquitin (Ub) and Ubiquitin-like proteins (Ubls) can be reversed by deconjugating enzymes, which have been implicated in different pathways and associated with various human diseases. To understand the activity and dynamics of deconjugating enzymes, multiple synthetic and semi-synthetic Ub/Ubl probes have been developed, and some of them have been applied to screen inhibitors of deconjugating enzymes. Since these Ub/Ubl probes are generally not cell-permeable, different strategies have been developed to deliver Ub/Ubl probes to live cells. However, till now, no Ub/Ubl probes can be expressed in live cells to directly report on the activities of deconjugating enzymes in the most relevant cellular environment. Here, we genetically encoded cross-linkable Ub/Ubl probes in live E. coliand HEK293T cells. These probes can cross-link with deconjugating enzymes in vitroand in vivo. Using these Ub probes combined with mass spectrometry, we have successfully identified endogenous deconjugating enzymes in live cells. We believe that these genetically encoded Ub/Ubl probes are valuable for investigating biological functions of deconjugating enzymes in physiological environments.

Background: This study analyzes the effect of frailty and Post-Operative Delirium (POD) on the functional status at hospital discharge and at 4-month follow-up in patients with hip fracture (HF). Methods: Multicenter prospective observational study of older patients with HF admitted to 12 Italian Orthogeriatric centers (July 2019-August 2022). POD was assessed using the 4AT. A 26-item Frailty Index (FI) was created using data collected on admission. The outcome measures were Cumulated Ambulation Score (CAS) ≤ 2 at discharge and a telephone-administered CAS ≤ 2 after 4 months. Poisson regression models were used to assess the effect of frailty and POD on outcomes. Results: 984 patients (median age 84 years, IQR = 79–89) were recruited: 480 (48.7%) were frail at admission, 311 (31.6%) developed POD, and 158 (15.6%) had both frailty and POD. In a robust Poisson regression, frailty alone (Relative Risk, RR = 1.56, 95% Confidence Intervals, CI 1.19–2.04, p = 0.001) and its combination with POD (RR = 2.57, 95% CI 2.02–3.26, p < 0.001) were associated with poor functional status at discharge. At 4-month follow-up, the combination of frailty with POD (RR 3.65, 95% CI 1.85–7.2, p < 0.001) increased the risk of poor outcome more than frailty alone (RR 2.38, 95% CI 1.21–4.66, p < 0.001). Conclusions: POD development exacerbates the negative effect that frailty exerts on functional outcomes in HF patients.

Background and aims: The most recent guidelines suggest treating patients whose FRAX 10-year fracture risk scores are ≥ 20%. However, this method of evaluation does not take into account parameters that are nonetheless relevant to the therapeutic choice. Our aim was to compare the therapeutic choices for treatment based on a wider assessment (real-world practice) with those based on FRAX scores, taking 20% as the cut-off score. Methods: We obtained the medical history, bone mineral density (BMD) values, and the presence of major fragility fractures in a sample of 856 postmenopausal women. The 10-year FRAX risk of major osteoporotic fracture was calculated, and patients were grouped into risk classes (“FRAX < 20%” = low, “FRAX ≥ 20%” = high); we then compared the treated and untreated patients in each class. After an average interval of 2.5 years, changes in lumbar and femoral BMD and appearances of new fragility fractures were recorded. Results: 83% of high-risk patients and 57% of low-risk patients were treated. The therapeutic decision was based mainly on densitometric values and the presence of vertebral fractures. At the 2.5 year follow-up, lumbar spine and femur BMD had decreased in the untreated group; 9.9% of the treated patients developed new vertebral fragility fractures, compared with 5.3% of the untreated patients. Discussion and conclusions: Our wider assessment designated as at high fracture risk a group of patients who had not been identified by the FRAX assessment. FRAX could underestimate the risk of fracture in older people, for which the therapeutic choice should consider a broader approach, also based on individual patient’s needs.

Background: Surgical aortic valve replacement (SAVR) is still the gold standard for treating aortic valve stenosis (AVS). Its effectiveness has been extensively examined in terms of perioperative mortality, but its impact on overall health has received much less attention. Aims: To assess the physical performance, cognitive status, and health-related quality of life of elderly patients undergoing SAVR, in the short, medium and long term. Methods: This single-center prospective study enrolled patients aged > 70 years who underwent isolated SAVR for severe AVS. Data were collected on each participant’s clinical status, physical performance, cognitive status, mood, and health-related quality of life. This multidimensional geriatric assessment was performed before surgery (T0), and again at 45 days (T1), 3 months (T2), 6 months (T3), and 12 months (T4) post-surgery. Baseline (T0) and follow-up (T2-T4) data were compared separately for patients grouped by gender using paired t-tests. Results: Data from a total of 35 patients were analyzed. Compared with the baseline (T0), nutritional status worsened at T1, then gradually improved through to T4. Physical performance, mood, and health-related quality of life improved significantly after surgery. Cognitive function showed no change through to T3, but then deteriorated at T4. Conclusions: Our results show that SAVR in patients over 70 years of age has a positive impact on nutrition, mood, and health-related quality of life. Cognitive function was not negatively affected in the short and medium term, although it deteriorated in the long term. SAVR also had a positive impact on the physical performance of our sample.

Background and aims: Atrial fibrillation (AF) is often complicated by disabling conditions in the elderly. COVID-19 has high mortality in older people. This study aimed at evaluating the relationship of pre-infection AF with characteristics and survival of older COVID-19 patients. Methods: We retrospectively analyzed inpatients aged ≥ 60 years enrolled in GeroCovid Observational, a multicenter registry endorsed by the Italian and the Norwegian Societies of Gerontology and Geriatrics. Pre-COVID-19 sociodemographic, functional, and medical data were systematically collected, as well as in-hospital mortality. Results: Between March and June 2020, 808 COVID-19 subjects were enrolled (age 79 ± 9 years; men 51.7%). The prevalence of AF was 21.8%. AF patients were older (82 ± 8 vs. 77 ± 9 years, p< 0.001), had a higher CHA2DS2-VASc score (4.1 ± 1.5 vs. 3.2 ± 1.5, p< 0.001) and were more likely to present almost all comorbidities. At multivariable analysis, advanced age, white blood cell count, the presence of heart and peripheral artery diseases were significantly associated with the presence of AF. In-hospital mortality was higher in AF patients (36.9 vs. 27.5%; OR = 1.55, 95% CI = 1.09–2.20; p= 0.015). A decision tree analysis showed that, in AF subjects, preserved functional status at admission was the most important factor associated with survival. In patients without AF, baseline COVID-19 severity was the most relevant variable related to clinical prognosis. Conclusions: AF is frequent in older patients with COVID-19, in whom it associates with clinical complexity and high mortality. Pre-infection disability shapes the prognosis of this extremely vulnerable segment of hospitalized subjects. Clinical trial registration: GeroCovid Observational was registered at www.clinicaltrials.gov(NCT04379440).

•International travel can expose one to health risks and represents an important Public Health Issue.•The compliance to prophylactic measures and behavioral advice given during pre-travel consultation are fundamental preventive measures.•Pre-travel consultation is the only way to make travellers aware of specific risks that could occur during their trip and recommend specific prophylaxis, including immunization.

Backgrounds: Acetylcholinesterase inhibitors (AChEI) and cognitive stimulation (CS) are the standard pharmacological and non-pharmacological treatments for Alzheimer’s disease (AD). Aims: The aim of this study was to investigate the effects of these treatments, alone or combined, on the neuropsychological profiles of patients with AD. Methods: Forty participants were assigned to three groups receiving either only AChEI (n= 14), AChEI + CS (n= 15), or only CS (n= 11). Cognition was evaluated at baseline and after three months. Linear mixed-effects models were used to investigate differences among the treatments in terms of changes in the patients’ neuropsychological profiles. Results: Results, although preliminary because of the small sample size, suggest that a general improvement was found in patients who received AChEI + CS and those who received only CS compared with those who received only AChEI. Interestingly, individuals who received only CS showed a significant improvement in immediate memory recall than those who received only AChEI. Furthermore, the group receiving AChEI + CS showed an improvement in delayed recall than the other two groups. Discussion: The combination of AChEI and CS seems to have the greatest benefit for patients with mild AD. More interestingly, CS alone is more effective than AChEI alone, even in improving memory, considered to be the “lost” cognitive domain in AD.

Despite advances in sequencing technologies, assembly of complex plant genomes remains elusive due to polyploidy and high repeat content. Here we report PolyGembler for grouping and ordering contigs into pseudomolecules by genetic linkage analysis. Our approach also provides an accurate method with which to detect and fix assembly errors. Using simulated data, we demonstrate that our approach is of high accuracy and outperforms three existing state-of-the-art genetic mapping tools. Particularly, our approach is more robust to the presence of missing genotype data and genotyping errors. We used our method to construct pseudomolecules for allotetraploid lawn grass utilizing PacBio long reads in combination with restriction site-associated DNA sequencing, and for diploid Ipomoea trifidaand autotetraploid potato utilizing contigs assembled from Illumina reads in combination with genotype data generated by single-nucleotide polymorphism arrays and genotyping by sequencing, respectively. We resolved 13 assembly errors for a published I. trifidagenome assembly and anchored eight unplaced scaffolds in the published potato genome.

Peptide ligands of class B G-protein-coupled receptors act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor–arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show that initial binding of the PTH C-terminal part constrains the conformation of the flexible PTH N-terminal signaling epitope before a second binding event occurs. A ‘hot-spot’ PTH residue, His9, that inserts into the PTHR transmembrane domain at this second step allosterically engages receptor–arrestin coupling. A conformational change in PTHR intracellular loop 3 permits favorable interactions with ß-arrestin’s finger loop. These results unveil structural determinants for PTHR–arrestin complex formation and reveal that the two-step binding mechanism proceeds via cooperative fluctuations between ligand and receptor, which extend to other class B G-protein-coupled receptors.

Described herein is the development of an automated and reproducible process for the conversion of primary amines to organic azides utilizing prepacked capsules containing all the required reagents, including imidazole-1-sulfonyl azide tetrafluoroborate. Apart from manually loading the primary amine into the reaction vessel, the entire reaction and product isolation process can be achieved automatically, with no further user involvement, and delivers the desired organic azide in high purity. This practical and simple automated capsule-based method offers a convenient and safe way of generating organic azides without handling or exposure of potentially explosive reagents.

•International travel can expose one to health risks and represents an important Public Health Issue.•The compliance to prophylactic measures and behavioral advice given during pre-travel consultation are fundamental preventive measures.•Pre-travel consultation is the only way to make travellers aware of specific risks that could occur during their trip and recommend specific prophylaxis, including immunization.

•The translation and cultural adaptation of the FOSQ-10 into Portuguese is valid and reliable.•The methodology of the study was grounded in the APA & NCME, 2014 guidelines proposed by the American Educational Research Association.•The missing values are non-random, associated with individuals not performing tasks (Questions 3, 4, and 10).•The total scores of FOSQ-10 P exhibited a significant negative correlation with the total scores of the Epworth Sleepiness Scale.