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The ATLAS collaboration will replace its tracking detector with new all silicon pixel and strip systems. This will allow to cope with the higher radiation and occupancy levels expected after the 5-fold increase in the luminosity of the LHC accelerator complex (HL-LHC). In the new tracking detector (ITk) pixel modules with increased granularity will implement to maintain the occupancy with a higher track density. In addition, both sensors and read-out chips composing the hybrid modules will be produced employing more radiation hard technologies with respect to the present pixel detector. Due to their outstanding performance in terms of radiation hardness, thin n-in-p sensors are promising candidates to instrument a section of the new pixel system. Recently produced and developed sensors of new designs will be presented. To test the sensors before interconnection to chips, a punch-through biasing structure has been implemented. Its design has been optimized to decrease the possible tracking efficiency losses observed. After irradiation, they were caused by the punch-through biasing structure. A sensor compatible with the ATLAS FE-I4 chip with a pixel size of 50x250 \\(\\mathrm{\\mu}\\)m\\(^{2}\\), subdivided into smaller pixel implants of 30x30 \\(\\mathrm{\\mu}\\)m\\(^{2}\\) size was designed to investigate the performance of the 50x50 \\(\\mathrm{\\mu}\\)m\\(^{2}\\) pixel cells foreseen for the HL-LHC. Results on sensor performance of 50x250 and 50x50 \\(\\mathrm{\\mu}\\)m\\(^{2}\\) pixel cells in terms of efficiency, charge collection and electric field properties are obtained with beam tests and the Transient Current Technique.

Atom transfer radical addition (ATRA) reactions are essential transformations in organic synthetic chemistry that enable the atom-economic difunctionalization of abundant olefin feedstocks. In this way, a rich chemical space can be opened up by well-planned combinations of simple starting materials. To build an efficient photocatalytic transformation, the reactivity of trichloromethanesulfenyl chloride toward alkenes and alkynes was investigated under photocatalytic Cu(I) reaction conditions. In this study, we found that trichloromethanesulfenyl chloride can be added to a series of olefins (such as styrenes and electron-rich and -poor olefins) in the presence of 1 mol% [Cu(dmp)2]BF4 photocatalyst and blue LED irradiation, producing α-chloro trichloromethylthioethers in good yields. Experimental and theoretical (DFT) mechanistic studies are consistent with the proposed radical chain mechanism of transformation. This study may serve as a valuable reference for the development of new coupling reactions that are economical and highly efficient processes.

Influenza A viruses that cause pandemics, as well as other harmful pathogens (e.g., SARS-CoV-2 variants), are known as the ‘silent bioterrorists’ of the 21st century. Due to high mutability, anti-influenza chemotherapeutic treatment is a vital defense strategy to combat both seasonal and pandemic influenza strains, especially when vaccines fail. Consequently, the development of novel therapies to combat this serious threat is of great concern. Hence, in this study, 3-(2-thienyl) acrylic acid (TA) was converted into amides of anti-influenza drugs (aminoadamantanes and oseltamivir) through TBTU-mediated coupling. The crystal structures of the thienyl-based amide hybrids (TA-Am (1), TA-Rim (2), TA-Os-OEt (3), and TA-OsC (4)) were also investigated using single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Moreover, the antiviral activities of the hybrids against influenza virus A/Fort Monmouth/1/1947 (H1N1), clinically isolated influenza strain A/Wuhan/359/1995 (H3N2), and oseltamivir-resistant A/Jinnan/15/2009 (H1N1) were evaluated in vitro. Amongst the tested thienyl-based amides, bisamide 8 (Boc-Os-Hda-TA) exhibited the most potent activity against influenza virus A (A/Wuhan/359/1995) with an IC50 value of 18.52 μg/mL and a selectivity index (SI) = 13.0.

BackgroundStatins are widely used to prevent cardiovascular disease (CVD). With advancing age, the risks of statins might outweigh the potential benefits. It is unclear which factors influence general practitioners’ (GPs) advice to stop statins in oldest-old patients.ObjectiveTo investigate the influence of a history of CVD, statin-related side effects, frailty and short life expectancy, on GPs’ advice to stop statins in oldest-old patients.DesignWe invited GPs to participate in this case-based survey. GPs were presented with 8 case vignettes describing patients > 80 years using a statin, and asked whether they would advise stopping statin treatment.Main MeasuresCases varied in history of CVD, statin-related side effects and frailty, with and without shortened life expectancy (< 1 year) in the context of metastatic, non-curable cancer. Odds ratios adjusted for GP characteristics (ORadj) were calculated for GPs’ advice to stop.Key ResultsTwo thousand two hundred fifty GPs from 30 countries participated (median response rate 36%). Overall, GPs advised stopping statin treatment in 46% (95%CI 45–47) of the case vignettes; with shortened life expectancy, this proportion increased to 90% (95CI% 89–90). Advice to stop was more frequent in case vignettes without CVD compared to those with CVD (ORadj 13.8, 95%CI 12.6–15.1), with side effects compared to without ORadj 1.62 (95%CI 1.5–1.7) and with frailty (ORadj 4.1, 95%CI 3.8–4.4) compared to without. Shortened life expectancy increased advice to stop (ORadj 50.7, 95%CI 45.5–56.4) and was the strongest predictor for GP advice to stop, ranging across countries from 30% (95%CI 19–42) to 98% (95% CI 96–99).ConclusionsThe absence of CVD, the presence of statin-related side effects, and frailty were all independently associated with GPs’ advice to stop statins in patients aged > 80 years. Overall, and within all countries, cancer-related short life expectancy was the strongest independent predictor of GPs’ advice to stop statins.

There is a critical need to develop novel antibiotics to combat antimicrobial resistance. Streptomyces species are very rich source of antibiotics, typically encoding 20–60 biosynthetic gene clusters (BGCs). However, under laboratory conditions, most are either silent or poorly expressed so that their products are only detectable at nanogram quantities, which hampers drug development efforts. To address this subject, we used comparative genome analysis of industrial Streptomyces rimosus strains producing high titers of a broad spectrum antibiotic oxytetracycline (OTC), developed during decades of industrial strain improvement. Interestingly, large-scale chromosomal deletions were observed. Based on this information, we carried out targeted genome deletions in the native strain S. rimosus ATCC 10970, and we show that a targeted deletion in the vicinity of the OTC BGC significantly induced expression of the OTC BGC, as well as some other silent BGCs, thus suggesting that this approach may be a useful way to identify new natural products.

Background General practitioners (GPs) should regularly review patients’ medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients’ health. However, deprescribing can be challenging for physicians. This study investigates GPs’ deprescribing decisions in 31 countries. Methods In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs’ deprescribing decisions. Results Of 3,175 invited GPs, 54% responded ( N  = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57). Interpretation The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.

A series of seventeen cinnamic acid hybrids (4ai–ci) were obtained through an amidation of aminoadamantanes (amantadine, rimantadine, and memantine) with mixed anhydride generated from different substituted cinnamic acid and ethyl chloroformate. 1H NMR, 13C NMR, IR, and HRMS were used for the confirmation of the structures of the synthesized hybrids. Moreover, the antioxidant profiles of amides were estimated as per five different in vitro methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid cation radical (ABTS⁺), ferric reducing antioxidant power (FRAP), cupric reducing antioxidant capacity (CUPRAC) assay, and inhibition of Fe(III)/asc induced lipid peroxidation (LP) in brain homogenate. For comparison, caffeic acid (CaffA), known as a potent naturally occurring antioxidant, was used as a reference compound in our study. The results revealed that the most prominent antioxidant activity was demonstrated by compound 4b2, with excellent CUPRAC, FRAP, scavenging ABTS+˙ potential, and inhibition of Fe/asc–induced LP, followed by 4c6 > 4a6 > CaffA > 4c5 and 4a5 > 4a7. Overall, the results suggest that the hybrids (4b2, 4c6, and 4a6) consisting of a caffeoyl moiety and lipophilic adamantane core endow the molecules with the higher antioxidant activity than their parent compound (caffeic acid), especially against LP. Thus, these promising antioxidants could have beneficial effects in various pathological conditions, where oxidative stress is implicated.

ObjectiveThe overall objective of this study was to examine the differences in ultrasound availability in primary care across Europe.DesignCross-sectional study.SettingPrimary care.ParticipantsPrimary care physicians (PCPs).Primary and secondary outcomes measuresThe primary aim was to describe the variation in in-house primary care ultrasonography availability across Europe using descriptive statistics. The secondary aim was to explore associations between in-house ultrasonography availability and the characteristics of PCPs and their clinics using a mixed-effects logistic regression model.ResultsWe collected data from 20 European countries. A total of 2086 PCPs participated, varying from 59 to 446 PCPs per country. The median response rate per country was 24.8%. The median (minimum–maximum) percentage of PCPs across Europe with access to in-house abdominal ultrasonography was 15.3% (0.0%–98.1%) and 12.1% (0.0%–30.8%) had access to in-house pelvic ultrasonography with large variations between countries. We found associations between in-house abdominal ultrasonography availability and larger clinics (OR 2.5, 95% CI 1.2 to 4.9) and clinics with medical doctors specialised in areas, which traditionally use ultrasonography (OR 2.1, 95% CI 1.1 to 3.8). Corresponding associations were found between in-house pelvic ultrasonography availability and larger clinics (OR 1.9, 95% CI 1.3 to 2.7) and clinics with medical doctors specialised in areas, which traditionally use ultrasonography (OR 3.0, 95% CI 1.8 to 5.1). Additionally, we found a negative association between urban clinics and in-house pelvic ultrasound availability (OR 0.5, 95% CI 0.2 to 0.9).ConclusionsAcross Europe, there is a large variation in PCPs’ access to in-house ultrasonography and organisational aspects of primary care seem to determine this variation. If evidence continues to support ultrasonography as a front-line point-of-care test, implementation strategies for increasing its availability in primary care are needed. Future research should focus on facilitators and barriers that may affect the implementation process.

Parkinson’s disease (PD) has emerged as the second most common form of human neurodegenerative disorders. However, due to the severe side effects of the current antiparkinsonian drugs, the design of novel and safe compounds is a hot topic amongst the medicinal chemistry community. Herein, a convenient peptide method, TBTU (O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), was used for the synthesis of the amide (E)-N-(2-methylcinnamoyl)-amantadine (CA(2-Me)-Am; 3)) derived from amantadine and 2-methylcinnamic acid. The obtained hybrid was studied for its antiparkinsonian activity in an experimental model of PD induced by MPTP. Mice (C57BL/6,male, 8 weeks old) were divided into four groups as follows: (1) the control, treated with normal saline (i.p.) for 12 consecutive days; (2) MPTP (30 mg/kg/day, i.p.), applied daily for 5 consecutive days; (3) MPTP + CA(2-Me)-Am, applied for 12 consecutive days, 5 days simultaneously with MPTP and 7 days after MPTP; (4) CA(2-Me)-Am +oleanoic acid (OA), applied daily for 12 consecutive days. Neurobehavioral parameters in all experimental groups of mice were evaluated by rotarod test and passive avoidance test. Our experimental data showed that CA(2-Me)-Am in parkinsonian mice significantly restored memory performance, while neuromuscular coordination approached the control level, indicating the ameliorating effects of the new compound. In conclusion, the newly synthesized hybrid might be a promising agent for treating motor disturbances and cognitive impairment in experimental PD.

(1) Background: The SARS-CoV-2 pandemic had a significant impact on the management of traumatic brain injury (TBI). We aimed to compare the clinical characteristics and outcomes of TBI patients before and during the SARS-CoV-2 pandemic.; (2) Methods: We analyzed depicted data from existing medical records on sex, age, mechanism of injury, clinical performance at admission and discharge, neuroimaging, laboratory values at admission, mortality, duration of hospitalization, and referrals after discharge from the traumatology department for all adult patients during the SARS-CoV-2 pandemic and a year before. Variables were compared using the Chi-square or t-test between both groups.; (3) Results: Most patients had mild (n = 477), followed by moderate (11) and severe (11) TBI. Mild TBI was less frequent during the SARS-CoV-2 period (n = 174 vs. n = 303). The incidence of high falls increased during the SARS-CoV-2 period (14.5% vs. 24.7%; p < 0.05) in the group with mild TBI. Patients had similar mean Glasgow Coma Scales (GCS), Glasgow Outcome Scales-Extended (GOSE), and glucose levels at admission before and during the pandemic. Serum ethanol levels were significantly lower during the SARS-CoV-2 period (1.3 ± 0.7 mmol/L vs. 0.7 ± 1.2 mmol/L; p < 0.001). At discharge, the mean GCS was significantly lower (14.7 ± 1.8 vs. 14.1 ± 0.5; p < 0.05) for patients treated during the SARS-CoV-2 period than before the SARS-CoV-2 period. There were no differences in GOSE; (4) Conclusions: our results demonstrated a significant impact of SARS-CoV-2 pandemic on the frequency, mechanism, and consequences of TBI, and may help improve care for our patients.