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BackgroundPersistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty.MethodsHuman venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury.ResultsExposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (p

BackgroundCOVID-19 patients may exhibit neurological symptoms due to direct viral damage, systemic inflammatory syndrome, or treatment side effects. Mechanical ventilation in patients with severe respiratory failure often requires sedation and neuromuscular blockade, hindering thorough clinical examinations. This study aimed to investigate neurological involvement through clinical and noninvasive techniques and to detect signs of intracranial hypertension in these patients.MethodWe conducted a prospective observational study on mechanically ventilated COVID-19 adult patients admitted to our ICU, following standard of care protocols for ventilation and permissive hypercapnia. Data were collected at three time points: admission day (T1), day seven (T7), and day fourteen (T14). At each time point, patients underwent multimodal noninvasive neurological monitoring, including clinical examination, pupillary reactivity, transcranial color doppler of the middle cerebral artery (MCA), and optic nerve sheath diameter (ONSD) assessed via ultrasound (US). Head computer tomography (CT) was performed at T1 and T14. A limited subset of patients had a follow-up examination six months after ICU discharge.ResultsSeventy-nine patients were recruited; most were under deep sedation and neuromuscular blockade at T1. Pupillary size, symmetry, and reactivity were normal, as was the MCA mean velocity. However, ONSD, assessed by both US and CT, appeared enlarged, suggesting raised intracranial pressure (ICP). In a subgroup of 12 patients, increased minute ventilation was associated with a significant decrease in US-ONSD, corresponding to a drop in paCO2. At follow-up, twelve patients showed no long-term neurological sequelae, and US-ONSD was decreased in all of them.Discussion and conclusionsIn this cohort, enlarged ONSD was detected during non-invasive neurological monitoring, suggesting a raised ICP, with hypercapnia playing a prominent role. Further studies are needed to explore ONSD behavior in other samples of mechanically ventilated, hypercapnic patients.

Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.

Sexually transmitted infections (STIs) have seen a considerable increase in the last years and given the health burden they may represent from both a personal and community perspective, they require surveillance and prevention programmes based on a timely and decentralized diagnosis. In this context, user-friendly rapid molecular tests may represent a good trade-off between diagnostic accuracy, accessibility and affordability. In this study we evaluated the diagnostic performance of a new real-time LAMP (Loop Mediated Isothermal Amplification) method for the rapid detection and differentiation of 7 major sexually transmissible pathogens by analysing real clinical samples (genital and extra-genital matrices) from individuals with suspected STIs. The assay showed good overall diagnostic performances in terms of sensitivity, specificity and concordance with a gold-standard PCR-based molecular method. This assay, not requiring specialised laboratory technicians or expensive instrumentation, but nonetheless capable of guaranteeing accurate results, is within the reach of outpatient settings, obstetrics, and gynaecology clinic, hence ensuring on-field access to early diagnosis.

BackgroundHair loss/thinning is a common side effect of tamoxifen in estrogen receptor (ER) positive breast cancer therapy. Some nutraceuticals known to promote hair growth are avoided during breast cancer therapy for fear of phytoestrogenic activity. However, not all botanical ingredients have similarities to estrogens, and in fact, no information exists as to the true interaction of these ingredients with tamoxifen. Therefore, this study sought to ascertain the effect of nutraceuticals (+/- estrogen/tamoxifen), on proliferation of breast cancer cells and the relative expression of ERα/β.MethodsKelp, Astaxanthin, Saw Palmetto, Tocotrienols, Maca, Horsetail, Resveratrol, Curcumin and Ashwagandha were assessed on proliferation of MCF7, T47D and BT483 breast cancer cell lines +/- 17β-estradiol and tamoxifen. Each extract was analysed by high performance liquid chromatography (HPLC) prior to use. Cellular ERα and ERβ expression was assessed by qRT-PCR and western blot. Changes in the cellular localisation of ERα:ERβ and their ratio following incubation with the nutraceuticals was confirmed by immunocytochemistry.ResultsEstradiol stimulated DNA synthesis in three different breast cancer cell lines: MCF7, T47D and BT483, which was inhibited by tamoxifen; this was mirrored by a specific ERa agonist in T47D and BT483 cells. Overall, nutraceuticals did not interfere with tamoxifen inhibition of estrogen; some even induced further inhibition when combined with tamoxifen. The ERα:ERβ ratio was higher at mRNA and protein level in all cell lines. However, incubation with nutraceuticals induced a shift to higher ERβ expression and a localization of ERs around the nuclear periphery.ConclusionsAs ERα is the key driver of estrogen-dependent breast cancer, if nutraceuticals have a higher affinity for ERβ they may offer a protective effect, particularly if they synergize and augment the actions of tamoxifen. Since ERβ is the predominant ER in the hair follicle, further studies confirming whether nutraceuticals can shift the ratio towards ERβ in hair follicle cells would support a role for them in hair growth. Although more research is needed to assess safety and efficacy, this promising data suggests the potential of nutraceuticals as adjuvant therapy for hair loss in breast cancer patients receiving endocrine therapy.

This article presents new archaeological observations and multidisciplinary research from Dor, Israel to establish a more reliable relative sea level for the Carmel Coast and Southern Levant between the Middle Bronze Age and the Roman period (ca. 3500-1800 y BP). Our record indicates a period of low relative sea level, around -2.5 m below present, from the Middle Bronze Age to the Hellenistic period (ca. 3500-2200 y BP). This was followed by a rapid rise to present levels, starting in the Hellenistic period and concluding during the Roman period (ca. 2200-1800 y BP). These Roman levels agree with other relative sea-level indications from Israel and other tectonically stable areas in the Mediterranean. Several relative sea-level reconstruction models carried out in the current study provide different predictions due to their parameters and do not model the changes observed from field data which points to a non-isostatic origin for the changes. Long-term low stable Iron Age relative sea level can be seen in Dor, where Iron Age harbor structures remain around the same elevation between ca. 3100-2700 y BP. A similar pattern occurs at Atlit, the Iron Age harbor to the north used continuously from ca. 2900 y BP to the beginning of the Hellenistic period (ca. 2200 y BP). An examination of historical and archaeological sources reveals decline and occasional disappearance of Hellenistic sites along the coast of Israel at ca. 2200 y BP (2nd century BCE), as in the case of Yavneh Yam, Ashdod Yam, Straton's Tower, and tel Taninim. In Akko-Ptolemais, the large harbor installations built in the Hellenistic period were never replaced by a substantial Roman harbor. The conclusions of this research are thus relevant for the sea-level research community and for the historical analyses of the Israeli and South Levantine coastline.

BACKGROUND: Heart rate is routinely measured as part of the clinical examination but is rarely acted upon unless it is well outside a population-based normal range. With wearable sensor technologies, heart rate can now be continuously measured, making it possible to accurately identify an individuals normal heart rate and potentially important variations in it over time. Our objective is to describe inter- and intra-individual variability in resting heart rate (RHR) collected over the course of two years using a wearable device, studying the variations of resting heart rate as a function of time of year, as well as individuals characteristics like age, sex, average sleep duration, and body mass index (BMI). METHODS AND FINDINGS: Our retrospective, longitudinal cohort study includes 92,457 de-identified individuals from the United States (all 50 states), who consistently-over at least 35 weeks in the period from March 2016 to February 2018, for at least 2 days per week, and at least 20 hours per day-wore a heart rate wrist-worn tracker. In this study, we report daily RHR and its association with age, BMI, sex, and sleep duration, and its variation over time. Individual daily RHR was available for a median of 320 days, providing nearly 33 million daily RHR values. We also explored the range in daily RHR variability between individuals, and the long- and short-term changes in the trajectory of an individuals daily RHR. Mean daily RHR was 65 beats per minute (bpm), with a range of 40 to 109 bpm among all individuals. The mean RHR differed significantly by age, sex, BMI, and average sleep duration. Time of year variations were also noted, with a minimum in July and maximum in January. For most subjects, RHR remained relatively stable over the short term, but 20% experienced at least 1 week in which their RHR fluctuated by 10 bpm or more. CONCLUSIONS: Individuals have a daily RHR that is normal for them but can differ from another individuals normal by as much as 70 bpm. Within individuals, RHR was much more consistent over time, with a small but significant seasonal trend, and detectable discrete and infrequent episodes outside their norms.

Excessive alcohol consumption contributes significantly to premature mortality, injuries and morbidity, and a range of U.S. state policies have been shown to reduce these behaviors. Monitoring state alcohol policy environments is essential, but methodologically challenging given that new laws may be passed (or repealed) each year, resulting in considerable variation across states. Existing measures have not been made public or have only a single year available. We develop a new replicable measure, the state alcohol policy score, for each state and year 2004-2009, that captures the essential features of a state's evidence-based alcohol policies. We evaluate its similarity to two existing alcohol policy measures and validate it by replicating findings from a previous study that used one of those measures to assess its relationship with several binge drinking outcomes. Estimates of the association between one-year lagged state alcohol policy scores and state binge drinking outcomes, obtained from the 2005-2010 Behavioral Risk Factor Surveillance System surveys (n = 440,951, 2010), were produced using Generalized Linear Models that controlled for state and individual-level co-variates, with fixed effects for year and region. We find a 10-percentage point increase in the state alcohol policy score was associated with a 9% lower odds of binge drinking (aOR = 0.91, 95% CI 0.89, 0.92; N = 1,992,086), a result consistent for men, women and for most age and race subgroups. We find that gender gaps in binge drinking behaviors narrowed in states with higher state alcohol policy scores. These results were nearly identical to those found in other studies using different scores obtained with the aid of expert opinions. We conclude that the score developed here is a valid measure that can be readily updated for monitoring and evaluating the variation and impact of state alcohol policies and make available our state scores for the years of the study.

Background: COVID-19 patients may exhibit neurological symptoms due to direct viral damage, systemic inflammatory syndrome, or treatment side effects. Mechanical ventilation in patients with severe respiratory failure often requires sedation and neuromuscular blockade, hindering thorough clinical examinations. This study aimed to investigate neurological involvement through clinical and noninvasive techniques and to detect signs of intracranial hypertension in these patients. Method: We conducted a prospective observational study on mechanically ventilated COVID-19 adult patients admitted to our ICU, following standard of care protocols for ventilation and permissive hypercapnia. Data were collected at three time points: admission day (T1), day seven (T7), and day fourteen (T14). At each time point, patients underwent multimodal noninvasive neurological monitoring, including clinical examination, pupillary reactivity, transcranial color doppler of the middle cerebral artery (MCA), and optic nerve sheath diameter (ONSD) assessed via ultrasound (US). Head computer tomography (CT) was performed at T1 and T14. A limited subset of patients had a follow-up examination six months after ICU discharge. Results: Seventy-nine patients were recruited; most were under deep sedation and neuromuscular blockade at T1. Pupillary size, symmetry, and reactivity were normal, as was the MCA mean velocity. However, ONSD, assessed by both US and CT, appeared enlarged, suggesting raised intracranial pressure (ICP). In a subgroup of 12 patients, increased minute ventilation was associated with a significant decrease in US-ONSD, corresponding to a drop in paCO2. At follow-up, twelve patients showed no long-term neurological sequelae, and US-ONSD was decreased in all of them. Discussion and conclusions: In this cohort, enlarged ONSD was detected during non-invasive neurological monitoring, suggesting a raised ICP, with hypercapnia playing a prominent role. Further studies are needed to explore ONSD behavior in other samples of mechanically ventilated, hypercapnic patients. [ABSTRACT FROM AUTHOR]

The diagnosis of gestational diabetes mellitus (GDM) is important to prevent maternal and neonatal complications. This study aimed to investigate the feasibility of parameters of glycaemic variability to predict neonatal complications in women with GDM. A retrospective study was conducted on pregnant women tested positive at the oral glucose tolerance test (OGTT) during 16–18 or 24–28 weeks of gestation. Glycaemic measures were extracted from patients’ glucometers and expanded to obtain parameters of glycaemic variability. Data on pregnancy outcomes were obtained from clinical folders. Descriptive group-level analysis was used to assess trends in glycaemic measures and foetal outcomes. Twelve patients were included and analysed, accounting for 111 weeks of observations. The analysis of trends in parameters of glycaemic variability showed spikes of glycaemic mean, high blood glucose index and J-index at 30–31 weeks of gestation for cases with foetal macrosomia, defined as foetal growth >90° percentile, neonatal hypoglycaemia and hyperbilirubinemia. Specific trends in parameters of glycaemic variability observed at third trimester correlate with foetal outcomes. Further research is awaited to provide evidence that monitoring of glycaemic variability trends could be more clinically informative and useful than standard glycaemic checks to manage women with GDM at delivery.

Here we propose that viruses emerging in the human population undergo an evolution that is conditioned by the rules of chaos. Our data support the notion that the initial growth rate "r" affects the chances of the virus to establish a long-lasting relationship with the new host. Indeed, an emerging virus is able to spread and adapt only when it displays an initial r falling in a range frankly associated with chaotic growth.

Although recent technological developments in the field of bionic upper limb prostheses, their rejection rate remains excessively high. The reasons are diverse (e.g. lack of functionality, control complexity, and comfortability) and most of these are reported only through self-rated questionnaires. Indeed, there is no quantitative evaluation of the extent to which a novel prosthetic solution can effectively address users’ needs compared to other technologies. This manuscript discusses the challenges and limitations of current upper limb prosthetic devices and evaluates their functionality through a standard functional assessment, the Assessment of Capacity for Myoelectric Control (ACMC). To include a good representation of technologies, the authors collect information from participants in the Cybathlon Powered Arm Prostheses Race 2016 and 2020. The article analyzes 7 hour and 41 min of video footage to evaluate the performance of different prosthetic devices in various tasks inspired by activities of daily living (ADL). The results show that commercially-available rigid hands perform well in dexterous grasping, while body-powered solutions are more reliable and convenient for competitive environments. The article also highlights the importance of wrist design and control modality for successful execution of ADL. Moreover, we discuss the limitations of the evaluation methodology and suggest improvements for future assessments. With regard to future development, this work highlights the need for research in intuitive control of multiple degrees of freedom, adaptive solutions, and the integration of sensory feedback.

Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular senescence by transcriptionally and post-transcriptionally modulating the expression of many important genes involved in senescence-associated pathways and processes. Among the different lncRNAs associated to senescence, Senescence Associated Long Non-coding RNA (SALNR) was found to be down-regulated in different cellular models of senescence. Since its release in 2015, SALNR has not been annotated in any database or public repository, and no other experimental data have been published. The SALNR sequence is located on the long arm of chromosome 10, at band 10q23.33, and it overlaps the 3' end of the HELLS gene. This investigation helped to unravel the mystery of the existence of SALNR by analyzing publicly available short- and long-read RNA sequencing data sets and RT-PCR analysis in human tissues and cell lines. Additionally, the expression of HELLS has been studied in cellular models of replicative senescence, both in silico and in vitro. Our findings, while not supporting the actual existence of SALNR as an independent transcript in the analyzed experimental models, demonstrate the expression of a predicted HELLS isoform entirely covering the SALNR genomic region. Furthermore, we observed a strong down-regulation of HELLS in senescent cells versus proliferating cells, supporting its role in the senescence and aging process.

Septoria leaf spot is one of the most widespread diseases affecting pistachio (Pistacia vera) in countries of the Mediterranean region. Septoria pistaciarum was recently confirmed as the causal agent of this disease in Italy. Currently, the detection of S. pistaciarum relies on isolation techniques. These require significant amounts of labor, and time for completion. Also, a reliable identification requires the sequencing of at least two housekeeping genes, in addition to the morphological observations. To accurately detect the presence and quantify S. pistaciarum in pistachio tissues, a molecular tool was necessary. We designed applicable primers that allow reliable amplification of the β-tubulin gene. The amplification of target DNA was highly efficient, with a 100% success rate, and the assay was able to detect as little as 100 fg/rxn of pure fungal DNA. When tested in artificial mixtures of plant and pathogen DNAs, the assay was able to detect the pathogen consistently at a limit of detection of 1 pg/rxn. The assay was also effective in identifying the pathogen in naturally infected samples, providing rapid detection in all symptomatic specimens. The resulting qPCR assay is an improved detection tool for accurate diagnosis of S. pistaciarum that can also contribute to better understand the population dynamics of the pathogen in the orchard.

ObjectiveTo explore the link between COVID-19 incidence, socio-economic covariates, and NHL incidence.DesignEcological study design.SettingSardinia, Italy.ParticipantsWe used official reports on the total cases of COVID-19 in 2020, published data on NHL incidence, and socio-economic indicators by administrative unit, covering the whole regional population.Main outcomes and measuresWe used multivariable regression analysis to explore the association between the natural logarithm (ln) of the 2020 cumulative incidence of COVID-19 and the ln-transformed NHL incidence in 1974-2003, weighing by population size and adjusting by socioeconomic deprivation and other covariates.ResultsThe cumulative incidence of COVID-19 increased in relation to past incidence of NHL (p < 0.001), socioeconomic deprivation (p = 0.006), and proportion of elderly residents (p < 0.001) and decreased with urban residency (p = 0.001). Several sensitivity analyses confirmed the finding of an association between COVID-19 and NHL.ConclusionThis ecological study found an ecological association between NHL and COVID-19. If further investigation would confirm our findings, shared susceptibility factors should be investigated among the plausible underlying mechanisms.

In industrialized countries, health care associated infections, the fourth leading cause of disease, are a major health issue. At least half of all cases of nosocomial infections are associated with medical devices. Antibacterial coatings arise as an important approach to restrict the nosocomial infection rate without side effects and the development of antibiotic resistance. Beside nosocomial infections, clot formation affects cardiovascular medical devices and central venous catheters implants. In order to reduce and prevent such infection, we develop a plasma-assisted process for the deposition of nanostructured functional coatings on flat substrates and mini catheters. Silver nanoparticles (Ag NPs) are synthesized exploiting in-flight plasma-droplet reactions and are embedded in an organic coating deposited through hexamethyldisiloxane (HMDSO) plasma assisted polymerization. Coating stability upon liquid immersion and ethylene oxide (EtO) sterilization is assessed through chemical and morphological analysis carried out by means of Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). In the perspective of future clinical application, an in vitro analysis of anti-biofilm effect has been done. Moreover, we employed a murine model of catheter-associated infection which further highlighted the performance of Ag nanostructured films in counteract biofilm formation. The anti-clot performances coupled by haemo- and cytocompatibility assays have also been performed.

Background and objectivesResolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been previously shown to attenuate vascular smooth muscle cell (VSMC) migration, a key process in the development of intimal hyperplasia. We sought to investigate the role of the cAMP/PKA pathway in mediating the effects of the aspirin-triggered epimer 17R-RvD1 (AT-RvD1) on VSMC migration.MethodsVSMCs were harvested from human saphenous veins. VSMCs were analyzed for intracellular cAMP levels and PKA activity after exposure to AT-RvD1. Platelet-derived growth factor (PDGF)-induced migration and cytoskeletal changes in VSMCs were observed through scratch, Transwell, and cell shape assays in the presence or absence of a PKA inhibitor (Rp-8-Br-cAMP). Further investigation of the pathways involved in AT-RvD1 signaling was performed by measuring Rac1 activity, vasodilator stimulated phosphoprotein (VASP) phosphorylation and paxillin translocation. Finally, we examined the role of RvD1 receptors (GPR32 and ALX/FPR2) in AT-RvD1 induced effects on VSMC migration and PKA activity.ResultsTreatment with AT-RvD1 induced a significant increase in cAMP levels and PKA activity in VSMCs at 5 minutes and 30 minutes, respectively. AT-RvD1 attenuated PDGF-induced VSMC migration and cytoskeletal rearrangements. These effects were attenuated by the PKA inhibitor Rp-8-Br-cAMP, suggesting cAMP/PKA involvement. Treatment of VSMC with AT-RvD1 inhibited PDGF-stimulated Rac1 activity, increased VASP phosphorylation, and attenuated paxillin localization to focal adhesions; these effects were negated by the addition of Rp-8-Br-cAMP. The effects of AT-RvD1 on VSMC migration and PKA activity were attenuated by blocking ALX/FPR2, suggesting an important role of this G-protein coupled receptor.ConclusionsOur results suggest that AT-RvD1 attenuates PDGF-induced VSMC migration via ALX/FPR2 and cAMP/PKA. Interference with Rac1, VASP and paxillin function appear to mediate the downstream effects of AT-RvD1 on VSMC migration.

Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs. [ABSTRACT FROM AUTHOR]

Bitter taste receptors (T2Rs) are expressed in the mammalian gastrointestinal mucosa. In the mouse colon, T2R138 is localized to enteroendocrine cells and is upregulated by long-term high fat diet that induces obesity. The aims of this study were to test whether T2R38 expression is altered in overweight/obese (OW/OB) compared to normal weight (NW) subjects and characterize the cell types expressing T2R38, the human counterpart of mouse T2R138, in human colon. Colonic mucosal biopsies were obtained during colonoscopy from 35 healthy subjects (20 OW/OB and 15 NW) and processed for quantitative RT-PCR and immunohistochemistry using antibodies to T2R38, chromogranin A (CgA), glucagon like peptide-1 (GLP-1), cholecystokinin (CCK), or peptide YY (PYY). T2R38 mRNA levels in the colonic mucosa of OW/OB were increased (> 2 fold) compared to NW subjects but did not reach statistical significance (P = 0.06). However, the number of T2R38 immunoreactive (IR) cells was significantly increased in OW/OB vs. NW subjects (P = 0.01) and was significantly correlated with BMI values (r = 0.7557; P = 0.001). In both OW/OB and NW individuals, all T2R38-IR cells contained CgA-IR supporting they are enteroendocrine. In both groups, T2R38-IR colocalized with CCK-, GLP1- or PYY-IR. The overall CgA-IR cell population was comparable in OW/OB and NW individuals. This study shows that T2R38 is expressed in distinct populations of enteroendocrine cells in the human colonic mucosa and supports T2R38 upregulation in OW/OB subjects. T2R38 might mediate host functional responses to increased energy balance and intraluminal changes occurring in obesity, which could involve peptide release from enteroendocrine cells.

BackgroundPersistent inflammation following vascular injury drives neointimal hyperplasia (NIH). Specialized lipid mediators (SPM) mediate resolution which attenuates inflammation and downstream NIH. We investigated the effects of a synthetic analogue of resolvin D1 (RvD1) on vascular cells and in a model of rat carotid angioplasty.MethodsHuman venous VSMC and endothelial cells (EC) were employed in migration, cell shape, toxicity, proliferation and p65 nuclear translocation assays. Murine RAW 264.7 cells were utilized to test the effect of pro-resolving compounds on phagocytic activity. A model of rat carotid angioplasty was used to evaluate the effects of 17R/S-benzo-RvD1 (benzo-RvD1) and 17R-RvD1 applied to the adventitia via 25% Pluronic gel. Immunostaining was utilized to examine Ki67 expression and leukocyte recruitment. Morphometric analysis was performed on arteries harvested 14 days after injury.ResultsExposure to benzo-RvD1 attenuated PDGF- stimulated VSMC migration across a range of concentrations (0.1-100 nM), similar to that observed with 17R-RvD1. Pre-treatment with either Benzo-RvD1 or 17R-RvD1 (10, 100nM) attenuated PDGF-BB-induced VSMC cytoskeletal changes to nearly baseline dimensions. Benzo-RvD1 demonstrated modest anti-proliferative activity on VSMC and EC at various concentrations, without significant cytotoxicity. Benzo-RvD1 (10nM) inhibited p65 nuclear translocation in cytokine-stimulated EC by 21% (pConclusions17R/S-benzo-RvD1 and 17R-RvD1 exhibit similar pro-resolving and anti-migratory activity in cell-based assays, and both compounds attenuated NIH following acute arterial injury in rats. Further studies of the mechanisms of resolution following vascular injury, and the translational potential of SPM analogues, are indicated.

Since their release in 2007, smartphones and their use have seemingly become a fundamental aspect of life in western society. Prior literature has suggested a link between mobile technology use and lower levels of cognitive control when people engage in a cognitively demanding task. This effect is more evident for people who report higher levels of smartphone use. The current study examined the effects of smartphones notifications on cognitive control and attention. Participants completed the Navon Letter paradigm which paired visual (frequent and rare target letters) and auditory (smartphone and control sounds) stimuli. We found that overall, participants responded slower on trials paired with smartphone notification (vs. control) sounds. They also demonstrated larger overall N2 ERP and a larger N2 oddball effect on trials paired with smartphone (vs. control) sounds, suggesting that people generally exhibited greater levels of cognitive control on the smartphone trials. In addition, people with higher smartphone addiction proneness showed lower P2 ERP on trials with the smartphone (vs. control) sounds, suggesting lower attentional engagement. These results add to the debate on the effects of smartphones on cognition. Limitations and future directions are discussed.

Over the last two decades, the incidence of gestational diabetes (GDM) has almost doubled resulting in almost 9% of pregnant women diagnosed with GDM. Occurring more frequently than GDM is impaired glucose tolerance (IGT), also known as pre-diabetes, but it has been understudied during pregnancy resulting in a lack of clinical recommendations of maternal and fetal surveillance. The purpose of this retrospective, cross-sectional study was to examine the association between microbial diversity and function of the maternal microbiome with IGT while adjusting for confounding variables. We hypothesized that reduced maternal microbial diversity and increased gene abundance for insulin resistance function will be associated with IGT as defined by a value greater than 140 mg/dL on the glucose challenge test. In the examination of microbial composition between women with IGT and those with normal glucose tolerance (NGT), we found five taxa which were significantly different. Taxa higher in participants with impaired glucose tolerance were Ruminococcacea (p = 0.01), Schaalia turicensis (p

BackgroundThe worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality.Methods and analysisSince January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care…'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice.ConclusionsThis multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics.Trial registrationThe registry was registered (ClinicalTrial.Gov Trials Register NCT04905875) on May 28,2021.

COVID-19 (Coronavirus disease 2019) hit Europe in January 2020. By March, Europe was the active centre of the pandemic. As a result, widespread "lockdown" measures were enforced across the various European countries, even if to a different extent. Such actions caused a dramatic reduction, especially in road traffic. This event can be considered the most significant experiment ever conducted in Europe to assess the impact of a massive switch-off of atmospheric pollutant sources. In this study, we focus on in situ concentration data of the main atmospheric pollutants measured in twelve European cities, characterized by different climatology, emission sources, and strengths. We propose a methodology for the fair comparison of the impact of lockdown measures considering the non-stationarity of meteorological conditions and emissions, which are progressively declining due to the adoption of stricter air quality measures. The analysis of these unmatched circumstances allowed us to estimate the impact of a nearly zero-emission urban transport scenario on air quality in 12 European cities. The clearest result, common to all the cities, is that a dramatic traffic reduction effectively reduces NO2 concentrations. In contrast, each city's PM and ozone concentrations can respond differently to the same type of emission reduction measure. From the policy point of view, these findings suggest that measures targeting urban traffic alone may not be the only effective option for improving air quality in cities.

Most proteins perform their biological function by interacting with one or more molecular partners. In this respect, characterizing local features of the molecular surface, that can potentially be involved in the interaction with other molecules, represents a step forward in the investigation of the mechanisms of recognition and binding between molecules. Predictive methods often rely on extensive samplings of molecular patches with the aim to identify hot spots on the surface. In this framework, analysis of large proteins and/or many molecular dynamics frames is often unfeasible due to the high computational cost. Thus, finding optimal ways to reduce the number of points to be sampled maintaining the biological information (including the surface shape) carried by the molecular surface is pivotal. In this perspective, we here present a new theoretical and computational algorithm with the aim of defining a set of molecular surfaces composed of points not uniformly distributed in space, in such a way as to maximize the information of the overall shape of the molecule by minimizing the number of total points. We test our procedure’s ability in recognizing hot-spots by describing the local shape properties of portions of molecular surfaces through a recently developed method based on the formalism of 2D Zernike polynomials. The results of this work show the ability of the proposed algorithm to preserve the key information of the molecular surface using a reduced number of points compared to the complete surface, where all points of the surface are used for the description. In fact, the methodology shows a significant gain of the information stored in the sampling procedure compared to uniform random sampling.

During the COVID-19 pandemic, several countries have resorted to self-adaptive mechanisms that tailor non-pharmaceutical interventions to local epidemiological and health care indicators. These mechanisms reinforce the mutual influence between containment measures and the evolution of the epidemic. To account for such interplay, we develop an epidemiological model that embeds an algorithm mimicking the self-adaptive policy mechanism effective in Italy between November 2020 and March 2022. This extension is key to tracking the historical evolution of health outcomes and restrictions in Italy. Focusing on the epidemic wave that started in mid-2021 after the diffusion of Delta, we compare the functioning of alternative mechanisms to show how the policy framework may affect the trade-off between health outcomes and the restrictiveness of mitigation measures. Mechanisms based on the reproduction number are generally highly responsive to early signs of a surging wave but entail severe restrictions. The emerging trade-off varies considerably depending on specific conditions (e.g., vaccination coverage), with less-reactive mechanisms (e.g., those based on occupancy rates) becoming more appealing in favorable contexts.

BackgroundThe coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources.AimsThe primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality.MethodsThis was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell's C-index and model calibration was assessed using a calibration plot.ResultsOut of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61-0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot.ConclusionThe predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.

Objective To explore methodological challenges when using real-world evidence (RWE) to estimate comparative-effectiveness in the context of Health Technology Assessment of direct oral anticoagulants (DOACs) in Scotland. Methods We used linkage data from the Prescribing Information System (PIS), Scottish Morbidity Records (SMR) and mortality records for newly anticoagulated patients to explore methodological challenges in the use of Propensity score (PS) matching, Inverse Probability Weighting (IPW) and covariate adjustment with PS. Model performance was assessed by standardised difference. Clinical outcomes (stroke and major bleeding) and mortality were compared for all DOACs (including apixaban, dabigatran and rivaroxaban) versus warfarin. Patients were followed for 2 years from first oral anticoagulant prescription to first clinical event or death. Censoring was applied for treatment switching or discontinuation. Results Overall, a good balance of patients’ covariates was obtained with every PS model tested. IPW was found to be the best performing method in assessing covariate balance when applied to subgroups with relatively large sample sizes (combined-DOACs versus warfarin). With the IPTW-IPCW approach, the treatment effect tends to be larger, but still in line with the treatment effect estimated using other PS methods. Covariate adjustment with PS in the outcome model performed well when applied to subgroups with smaller sample sizes (dabigatran versus warfarin), as this method does not require further reduction of sample size, and trimming or truncation of extreme weights. Conclusion The choice of adequate PS methods may vary according to the characteristics of the data. If assumptions of unobserved confounding hold, multiple approaches should be identified and tested. PS based methods can be implemented using routinely collected linked data, thus supporting Health Technology decision-making.

Focus of this study is to design an automated image processing pipeline for handling uncontrolled acquisition conditions of images acquired in the field. The pipeline has been tested on the automated identification and count of uncapped brood cells in honeybee (Apis Mellifera) comb images to reduce the workload of beekeepers during the study of the hygienic behavior of honeybee colonies. The images used to develop and test the model were acquired by beekeepers on different days and hours in summer 2020 and under uncontrolled conditions. This resulted in images differing for background noise, illumination, color, comb tilts, scaling, and comb sizes. All the available 127 images were manually cropped to approximately include the comb area. To obtain an unbiased evaluation, the cropped images were randomly split into a training image set (50 images), which was used to develop and tune the proposed model, and a test image set (77 images), which was solely used to test the model. To reduce the effects of varied illuminations or exposures, three image enhancement algorithms were tested and compared followed by the Hough Transform, which allowed identifying individual cells to be automatically counted. All the algorithm parameters were automatically chosen on the training set by grid search. When applied to the 77 test images the model obtained a correlation of 0.819 between the automated counts and the experts' counts. To provide an assessment of our model with publicly available images acquired by a different equipment and under different acquisition conditions, we randomly extracted 100 images from a comb image dataset made available by a recent literature work. Though it has been acquired under controlled exposure, the images in this new set have varied illuminations; anyhow, our pipeline obtains a correlation between automatic and manual counts equal to 0.997. In conclusion, our tests on the automatic count of uncapped honey bee comb cells acquired in the field and on images extracted from a publicly available dataset suggest that the hereby generated pipeline successfully handles varied noise artifacts, illumination, and exposure conditions, therefore allowing to generalize our method to different acquisition settings. Results further improve when the acquisition conditions are controlled.

Introduction The ReIMAGINE Consortium was conceived to develop risk-stratification models that might incorporate the full range of novel prostate cancer (PCa) diagnostics (both commercial and academic). Methods ReIMAGINE Risk is an ethics approved (19/LO/1128) multicentre, prospective, observational cohort study which will recruit 1000 treatment-naive men undergoing a multi-parametric MRI (mpMRI) due to an elevated PSA (≤20ng/ml) or abnormal prostate examination who subsequently had a suspicious mpMRI (score≥3, stage ≤T3bN0M0). Primary outcomes include the detection of ≥Gleason 7 PCa at baseline and time to clinical progression, metastasis and death. Baseline blood, urine, and biopsy cores for fresh prostate tissue samples (2 targeted and 1 non-targeted) will be biobanked for future analysis. High-resolution scanning of pathology whole-slide imaging and MRI-DICOM images will be collected. Consortium partners will be granted access to data and biobanks to develop and validate biomarkers using correlation to mpMRI, biopsy-based disease status and long-term clinical outcomes. Results Recruitment began in September 2019(n = 533). A first site opened in September 2019 (n = 296), a second in November 2019 (n = 210) and a third in December 2020 (n = 27). Acceptance to the study has been 65% and a mean of 36.5ml(SD+/-10.0), 12.9ml(SD+/-3.7) and 2.8ml(SD+/-0.7) urine, plasma and serum donated for research, respectively. There are currently 4 academic and 15 commercial partners spanning imaging (~9 radiomics, artificial intelligence/machine learning), fluidic (~3 blood-based and ~2urine-based) and tissue-based (~1) biomarkers. Conclusion The consortium will develop, or adjust, risk models for PCa, and provide a platform for evaluating the role of novel diagnostics in the era of pre-biopsy MRI and targeted biopsy.

The causes of the peculiar time trend in the incidence of non-Hodgkin's lymphoma (NHL) in most parts of the world and of its geographic distribution are still unknown. We used the data base of 1974-2003 incident cases of hematological malignancies to explore the time trend of NHL incidence in the region of Sardinia, Italy, and we used Bayesian methods to plot the probability of NHL incidence by residential unit on the regional map. In 1974-2003, 4109 NHL cases were diagnosed among resident adults in Sardinia, with an incidence rate of 13.38 x 10-5 (95% CI 12.97-13.80). NHL incidence showed an upward trend along the study period with an average annual percent change (APC) of 4.94 (95% CI -5.39-16.4), which did not vary by gender or by age-group. Cancer registry data, covering part of the region starting from 1993, suggest that the increasing trend did not persist in the subsequent years. Areas with the highest probability of an excess incidence tended to cluster in the north-eastern part of the region and in two major urban centers, with the low incidence areas located in the south, confirming previous observations. Prevalence of viral infections, environmental and occupational exposures, or socio-economic deprivation would not explain the peculiar geographic distribution we observed. These findings provide convincing arguments for extending the coverage of routine cancer registration over the whole Sardinian population, while prompting further research on the genetic and environmental determinants of NHL in the risk areas.

Purpose The aim of this study was to explore the effects of chronic low-dose-rate gamma-radiation at a multi-scale level. The specific objective was to obtain an overall view of the endothelial cell response, by integrating previously published data on different cellular endpoints and highlighting possible different mechanisms underpinning radiation-induced senescence. Materials and methods Different datasets were collected regarding experiments on human umbilical vein endothelial cells (HUVECs) which were chronically exposed to low dose rates (0, 1.4, 2.1 and 4.1 mGy/h) of gamma-rays until cell replication was arrested. Such exposed cells were analyzed for different complementary endpoints at distinct time points (up to several weeks), investigating cellular functions such as proliferation, senescence and angiogenic properties, as well as using transcriptomics and proteomics profiling. A mathematical model was proposed to describe proliferation and senescence. Results Simultaneous ceasing of cell proliferation and senescence onset as a function of time were well reproduced by the logistic growth curve, conveying shared equilibria between the two endpoints. The combination of all the different endpoints investigated highlighted a dose-dependence for prematurely induced senescence. However, the underpinning molecular mechanisms appeared to be dissimilar for the different dose rates, thus suggesting a more complex scenario. Conclusions This study was conducted integrating different datasets, focusing on their temporal dynamics, and using a systems biology approach. Results of our analysis highlight that different dose rates have different effects in inducing premature senescence, and that the total cumulative absorbed dose also plays an important role in accelerating endothelial cell senescence.

BackgroundSickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD.MethodsBP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR.ResultsDiastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice.ConclusionRelative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

Livestock European diffusion followed different human migration waves from the Fertile Crescent. In sheep, at least two diffusion waves have shaped the current breeds' biodiversity generating a complex genetic pattern composed by either primitive or fine-wool selected breeds. Among primitive breeds, aside from sharing common ancestral genomic components, they also show several traits such as the policeraty, large horns in the ram, short tail, and a moulting fleece, considered as ancestral. Although most of the primitive breeds characterized by these traits are confined on the very edge of Northern Europe, several residual populations are also scattered in the Mediterranean region. In fact, although in Italy a large number of local breeds are already extinct, others are listed as critically endangered, and among these there is the Quadricorna breed which is a four-horned sheep characterized by several ancestral traits. In this context we genotyped 47 individuals belonging to the Quadricorna sheep breed, a relict and endangered breed, from Central and Southern Italy. In doing so we used the Illumina OvineSNP50K array in order to explore its genetic diversity and to compare it with other 33 primitive traits-related, Mediterranean and Middle-East breeds, with the specific aim to reconstruct its origin. After retaining 35,680 SNPs following data filtering, the overall genomic architecture has been explored by using genetic diversity indices, Principal Component Analysis (PCA) and admixture analysis, while the genetic relationships and migration events have been inferred using a neighbor-joining tree based on Reynolds' distances and by the maximum likelihood tree as implemented in treemix. Multiple convergent evidence from all our population genetics analyses, indicated that the two Quadricorna populations differ from all the other Italian breeds, while they resulted to be very close to the Middle Eastern and primitive European breeds. In addition, the genetic diversity indices highlighted values comparable with those of most of the other analyzed breeds, despite the two populations exhibit slightly different genetic indices suggesting different levels of genomic inbreeding and drift (FIS and FROH). The admixture analysis does not suggest any signal of recent gene exchange with other Italian local breeds, highlighting a rather ancestral purity of the two populations, while on the other hand the treemix analysis seems to suggest an ancient admixture with other primitive European breeds. Finally, all these evidences seem to trace back the residual Quadricorna sheep to an early Neolithic spread, probably following a Mediterranean route and that urgent conservation actions are needed in order to keep the breed and all related cultural products alive.

Philaenus spumarius is a cosmopolitan species that has become a major threat to European agriculture being recognized as the main vector of the introduced plant pathogen Xylella fastidiosa, the agent of the "olive quick decline syndrome", a disease which is devastating olive orchards in southern Italy. Wolbachia are bacterial symbionts of many insects, frequently as reproductive parasites, sometime by establishing mutualistic relationships, able to spread within host populations. Philaenus spumarius harbors Wolbachia, but the role played by this symbiont is unknown and data on the infection prevalence within host populations are limited. Here, the Wolbachia infection rate was analyzed in relation to the geographic distribution and the genetic diversity of the Italian populations of P. spumarius. Analysis of the COI gene sequences revealed a geographically structured distribution of the three main mitochondrial lineages of P. spumarius. Wolbachia was detected in half of the populations sampled in northern Italy where most individuals belonged to the western-Mediterranean lineage. All populations sampled in southern and central Italy, where the individuals of the eastern-Mediterranean lineage were largely prevalent, were uninfected. Individuals of the north-eastern lineage were found only in populations from the Alps in the northernmost part of Italy, at high altitudes. In this area, Wolbachia infection reached the highest prevalence, with no difference between north-eastern and western-Mediterranean lineage. Analysis of molecular diversity of COI sequences suggested no significant effect of Wolbachia on population genetics of P. spumarius. Using the MLST approach, six new Wolbachia sequence types were identified. Using FISH, Wolbachia were observed within the host's reproductive tissues and salivary glands. Results obtained led us to discuss the role of Wolbachia in P. spumarius, the factors influencing the geographic distribution of the infection, and the exploitation of Wolbachia for the control of the vector insect to reduce the spread of X. fastidiosa.

Text formats are common in bioinformatics, as they allow for editing and filtering using standard tools, as well as, since text formats are often human readable, manual inspection and evaluation of the data. Bioinformatics is a rapidly evolving field, hence, new techniques, new software tools, new kinds of data often require the definition of new formats. Often new formats are not formally described in a standard or specification document. Although software libraries are available for accessing the most common formats, writing parsers for text formats, for which no library is currently available, is a very common though tedious task, utilized by many researchers in the field. This manuscript presents the open source software library and toolset TextFormats (available at https://github.com/ggonnella/textformats), which aims at simplifying the definition and parsing of text formats. Formats specifications are written in a simple data description format using an interactive wizard. Automatic generation of data examples and automatic testing of specifications allow for checking for correctness. Given the specification for a text format, TextFormats allows parsing and writing data in that format, using several programming languages (Nim, Python, C/C++) or the provided command line and graphical user interface tools. Although designed as a general purpose software, the main target application field, for the above mentioned reasons, is expected to be in bioinformatics: Thus, the specifications of several common existing bioinformatics formats are included.

BackgroundThe first Covid-19 epidemic outbreak has enormously impacted the delivery of clinical healthcare and hospital management practices in most of the hospitals around the world. In this context, it is important to assess whether the clinical management of non-Covid patients has not been compromised. Among non-Covid cases, patients with Acute Myocardial Infarction (AMI) and stroke need non-deferrable emergency care and are the natural candidates to be studied. Preliminary evidence suggests that the time from onset of symptoms to emergency department (ED) presentation has significantly increased in Covid-19 times as well as the 30-day mortality and in-hospital mortality.MethodsWe check, in a causal inference framework, the causal effect of the hospital's stress generated by Covid-19 pandemic on in-hospital mortality rates (primary end-point of the study) of AMI and stroke over several time-windows of 15-days around the implementation date of the State of Emergency restrictions for COVID-19 (March, 9th 2020) using two quasi-experimental approaches, regression-discontinuity design (RDD) and difference-in-regression-discontinuity (DRD) designs. Data are drawn from Spedali Civili of Brescia, one of the most hit provinces in Italy by Covid-19 during March and May 2020.FindingsDespite the potential adverse effects on expected mortality due to a longer time to hospitalization and staff extra-burden generated by the first wave of Covid-19, the AMI and stroke mortality rates are overall not statistically different during the first wave of Covid-19 than before the first peak. The obtained results provided by RDD models are robust also when we account for seasonality and unobserved factors with DRD models.InterpretationThe non-statistically significant impact on mortality rates for AMI and stroke patients provides evidence of the hospital ability to manage -with the implementation of a dual track organization- the simultaneous delivery of high-quality cares to both Covid and non-Covid patients.

Few studies provide an analysis of conservative two-stage revision of hip periprosthetic joint infection (PJI) and its impact on final outcome. A conservative revision is defined when soft tissues and bone quality enable the use of primary prosthetic components. Data of patients treated for chronic hip PJI who underwent two-stage revision between 2009 and 2016 and had a minimum of 2 years of follow-up were collected. Oxford Hip Score (OHS), Harris Hip Score (HHS) and radiological and microbiological data were retrieved and analysed. Clinical and functional outcome, survival, mortality, eradication, reinfection and re-revision rates within subgroups of patients with primary components and revision components are reported herein. A total of 148 patients underwent two-stage hip exchange with a mean follow-up of 55.6 ± 23.1 months and a mean age at surgery of 64.3 ± 12.7 years. Forty-four percent of patients underwent conservative revision. The mean HHS significantly improved from 40.6 ± 9.4 points to the final value of 87.8 ± 10.5 points (p = .002), and the mean OHS went from 20.3 ± 3.8 points to 40.3 ± 5. points (p< .001). Patients who were treated with primary components or isolated revision stems in the second stage had a significant reduction in surgical times (p< .001). The mortality rate for all causes of death was 6.8%, the eradication rate was 89.9%, the reinfection rate was 4.7% and the reoperation rate was 7.4% without differences between conservative and non-conservative revisions. Two-stage exchange arthroplasty for total hip arthroplasty (THA) PJI is a good strategy that provides satisfactory results, high eradication rates and no further need for revision. The conservative two-stage revision in patients with adequate bone stock represents a feasible option with good results and survival rates.

Sexually transmitted infections (STIs) have seen a considerable increase in the last years and given the health burden they may represent from both a personal and community perspective, they require surveillance and prevention programmes based on a timely and decentralized diagnosis. In this context, user-friendly rapid molecular tests may represent a good trade-off between diagnostic accuracy, accessibility and affordability. In this study we evaluated the diagnostic performance of a new real-time LAMP (Loop Mediated Isothermal Amplification) method for the rapid detection and differentiation of 7 major sexually transmissible pathogens by analysing real clinical samples (genital and extra-genital matrices) from individuals with suspected STIs. The assay showed good overall diagnostic performances in terms of sensitivity, specificity and concordance with a gold-standard PCR-based molecular method. This assay, not requiring specialised laboratory technicians or expensive instrumentation, but nonetheless capable of guaranteeing accurate results, is within the reach of outpatient settings, obstetrics, and gynaecology clinic, hence ensuring on-field access to early diagnosis. [ABSTRACT FROM AUTHOR]

Numerical body models of children are used for designing medical devices, including but not limited to optical imaging, ultrasound, CT, EEG/MEG, and MRI. These models are used in many clinical and neuroscience research applications, such as radiation safety dosimetric studies and source localization. Although several such adult models have been reported, there are few reports of full-body pediatric models, and those described have several limitations. Some, for example, are either morphed from older children or do not have detailed segmentations. Here, we introduce a 29-month-old male whole-body native numerical model, "MARTIN", that includes 28 head and 86 body tissue compartments, segmented directly from the high spatial resolution MRI and CT images. An advanced auto-segmentation tool was used for the deep-brain structures, whereas 3D Slicer was used to segment the non-brain structures and to refine the segmentation for all of the tissue compartments. Our MARTIN model was developed and validated using three separate approaches, through an iterative process, as follows. First, the calculated volumes, weights, and dimensions of selected structures were adjusted and confirmed to be within 6% of the literature values for the 2-3-year-old age-range. Second, all structural segmentations were adjusted and confirmed by two experienced, sub-specialty certified neuro-radiologists, also through an interactive process. Third, an additional validation was performed with a Bloch simulator to create synthetic MR image from our MARTIN model and compare the image contrast of the resulting synthetic image with that of the original MRI data; this resulted in a "structural resemblance" index of 0.97. Finally, we used our model to perform pilot MRI safety simulations of an Active Implantable Medical Device (AIMD) using a commercially available software platform (Sim4Life), incorporating the latest International Standards Organization guidelines. This model will be made available on the Athinoula A. Martinos Center for Biomedical Imaging website.

BackgroundDuring the COVID-19 pandemic, the number of individuals needing hospital admission has sometimes exceeded the availability of hospital beds. Since hospitalization can have detrimental effects on older individuals, preference has been given to younger patients. The aim of this study was to assess the utility of hospitalization for elderly affected by COVID-19. We hypothesized that their mortality decreases when there is greater access to hospitals.MethodsThis study examined 1902 COVID-19 patients consecutively admitted to three large hospitals in Milan, Italy. Overall mortality data for Milan from the same period was retrieved. Based on emergency department (ED) data, both peak and off-peak phases were identified. The percentage of elderly patients admitted to EDs during these two phases were compared by calculating the standardized mortality ratio (SMR) of the individuals younger than, versus older than, 80 years.ResultsThe median age of the patients hospitalized during the peak phase was lower than the median age during the off-peak phase (64 vs. 75 years, respectively; p ConclusionsGreater access to hospitals during an off-peak phase did not affect the mortality rate of COVID-19-positive elderly patients in Milan. This finding, if confirmed in other settings, should influence future decisions regarding resource management of health care organizations.

Neuropathic pain is a chronic debilitating condition caused by injury or disease of the nerves of the somatosensory system. Although several therapeutic approaches are recommended, none has emerged as an optimal treatment leaving a need for developing more effective therapies. Given the small number of approved drugs and their limited clinical efficacy, combining drugs with different mechanisms of action is frequently used to yield greater efficacy. We demonstrate that the combination of trazodone, a multifunctional drug for the treatment of major depressive disorders, and gabapentin, a GABA analogue approved for neuropathic pain relief, results in a synergistic antinociceptive effect in the mice writhing test. To explore the potential relevance of this finding in chronic neuropathic pain, pharmacodynamic interactions between low doses of trazodone (0.3 mg/kg) and gabapentin (3 mg/kg) were evaluated in the chronic constriction injury (CCI) rat model, measuring the effects of the two drugs both on evoked and spontaneous nociception and on general well being components. Two innate behaviors, burrowing and nest building, were used to assess these aspects. Besides exerting a significant antinociceptive effect on hyperalgesia and on spontaneous pain, combined inactive doses of trazodone and gabapentin restored in CCI rats innate behaviors that are strongly reduced or even abolished during persistent nociception, suggesting that the combination may have an impact also on pain components different from somatosensory perception. Our results support the development of a trazodone and gabapentin low doses combination product for optimal multimodal analgesia treatment.

Among the many aspects that characterize the COVID-19 pandemic, two seem particularly challenging to understand: i) the great geographical differences in the degree of virus contagiousness and lethality that were found in the different phases of the epidemic progression, and, ii) the potential role of the infected people's blood type in both the virus infectivity and the progression of the disease. A recent hypothesis could shed some light on both aspects. Specifically, it has been proposed that, in the subject-to-subject transfer, SARS-CoV-2 conserves on its capsid the erythrocytes' antigens of the source subject. Thus these conserved antigens can potentially cause an immune reaction in a receiving subject that has previously acquired specific antibodies for the source subject antigens. This hypothesis implies a blood type-dependent infection rate. The strong geographical dependence of the blood type distribution could be, therefore, one of the factors at the origin of the observed heterogeneity in the epidemics spread. Here, we present an epidemiological deterministic model where the infection rules based on blood types are taken into account, and we compare our model outcomes with the exiting worldwide infection progression data. We found an overall good agreement, which strengthens the hypothesis that blood types do play a role in the COVID-19 infection.