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Abstract Background The parasagittal dura, a tissue that lines the walls of the superior sagittal sinus, acts as an active site for immune-surveillance, promotes the reabsorption of cerebrospinal fluid, and facilitates the removal of metabolic waste products from the brain. Cerebrospinal fluid is important for the distribution of growth factors that signal immature neurons to proliferate and migrate. Autism spectrum disorder is characterized by altered cerebrospinal fluid dynamics. Methods In this retrospective study, we investigated potential correlations between parasagittal dura volume, brain structure volumes, and clinical severity scales in young children with autism spectrum disorder. We employed a semi-supervised two step pipeline to extract parasagittal dura volume from 3D-T2 Fluid Attenuated Inversion Recovery sequences, based on U-Net followed by manual refinement of the extracted parasagittal dura masks. Results Here we show that the parasagittal dura volume does not change with age but is significantly correlated with cerebrospinal fluid (p-value = 0.002), extra-axial cerebrospinal fluid volume (p-value = 0.0003) and severity of developmental delay (p-value = 0.024). Conclusions These findings suggest that autism spectrum disorder children with severe developmental delay may have a maldeveloped parasagittal dura that potentially perturbs cerebrospinal fluid dynamics.

Background:. Multiple sclerosis (MS) is a chronic disease that primarily affects young adults and causes disability by impairing the central nervous system. Gait impairments are common in people with MS (pwMS), and lower limb orthoses are often used to improve stability and mobility. However, compliance with orthotic devices can vary among individuals due to issues related to the appropriate prescription and lack of acceptability. Objective:. In this observational, cross-sectional study, we aimed to explore the experience of wearing a passive hip flexion device in a cohort of pwMS. Methods:. We included men and women >18 years old affected by MS (Expanded Disability Status Scale >4) who have been using a passive hip flexion device (ExoBand, Moveo srl) since 2020 for at least 15 days. The participants completed a phone survey that collected demographic, anthropometric, and clinical data, their perceptions of the device’s impact using the Psychosocial Impact of Assistive Devices (PIADS) questionnaire, and a qualitative part with an open-ended question. Results:. A total of 41 patients completed the survey. The participants experienced improvements in all 3 areas of the PIADS questionnaire since using the ExoBand (P

Abstract The development of media for cell culture is a major issue in the biopharmaceutical industry, for the production of therapeutics, immune-modulating molecules and protein antigens. Chemically defined media offer several advantages, as they are free of animal-derived components and guarantee high purity and a consistency in their composition. Microorganisms of the genus Leishmania represent a promising cellular platform for production of recombinant proteins, but their maintenance requires supplements of animal origin, such as hemin and fetal bovine serum. In the present study, three chemically defined media were assayed for culturing Leishmania tarentolae, using both a wild-type strain and a strain engineered to produce a viral antigen. Among the three media, Schneider's Drosophila Medium supplemented with Horseradish Peroxidase proved to be effective for the maintenance of L. tarentolae promastigotes, also allowing the heterologous protein production by the engineered strain. Finally, the engineered strain was maintained in culture up to the 12th week without antibiotic, revealing its capability to produce the recombinant protein in the absence of selective pressure.

Abstract Plasmodium falciparum with the histidine rich protein 2 gene (pfhrp2) deleted from its genome can escape diagnosis by HRP2-based rapid diagnostic tests (HRP2-RDTs). The World Health Organization (WHO) recommends switching to a non-HRP2 RDT for P. falciparum clinical case diagnosis when pfhrp2 deletion prevalence causes ≥ 5% of RDTs to return false negative results. Tanzania is a country of heterogenous P. falciparum transmission, with some regions approaching elimination and others at varying levels of control. In concordance with the current recommended WHO pfhrp2 deletion surveillance strategy, 100 health facilities encompassing 10 regions of Tanzania enrolled malaria-suspected patients between February and July 2021. Of 7863 persons of all ages enrolled and providing RDT result and blood sample, 3777 (48.0%) were positive by the national RDT testing for Plasmodium lactate dehydrogenase (pLDH) and/or HRP2. A second RDT testing specifically for the P. falciparum LDH (Pf-pLDH) antigen found 95 persons (2.5% of all RDT positives) were positive, though negative by the national RDT for HRP2, and were selected for pfhrp2 and pfhrp3 (pfhrp2/3) genotyping. Multiplex antigen detection by laboratory bead assay found 135/7847 (1.7%) of all blood samples positive for Plasmodium antigens but very low or no HRP2, and these were selected for genotyping as well. Of the samples selected for genotyping based on RDT or laboratory multiplex result, 158 were P. falciparum DNA positive, and 140 had sufficient DNA to be genotyped for pfhrp2/3. Most of these (125/140) were found to be pfhrp2+/pfhrp3+, with smaller numbers deleted for only pfhrp2 (n = 9) or only pfhrp3 (n = 6). No dual pfhrp2/3 deleted parasites were observed. This survey found that parasites with these gene deletions are rare in Tanzania, and estimated that 0.24% (95% confidence interval: 0.08% to 0.39%) of false-negative HRP2-RDTs for symptomatic persons were due to pfhrp2 deletions in this 2021 Tanzania survey. These data provide evidence for HRP2-based diagnostics as currently accurate for P. falciparum diagnosis in Tanzania.

Abstract Thyroid cancer is the most common endocrine carcinoma and, among its different subtypes, the papillary subtype (PTC) is the most frequent. Generally, PTCs are well differentiated, but a minor percentage of PTCs are characterized by a worse prognosis and more aggressive behavior. Phytochemicals, naturally found in plant products, represent a heterogeneous group of bioactive compounds that can interfere with cell proliferation and the regulation of the cell cycle, taking part in multiple signaling pathways that are often disrupted in tumor initiation, proliferation, and progression. In this work, we focused on 15,16-dihydrotanshinone I (DHT), a tanshinone isolated from Salvia miltiorrhiza Bunge (Danshen). We first evaluated DHT biological effect on PTC cells regarding cell viability, colony formation ability, and migration capacity. All of these parameters were downregulated by DHT treatment. We then investigated gene expression changes after DHT treatment by performing RNA-seq. The analysis revealed that DHT significantly reduced the Wnt signaling pathway, which plays a role in various diseases, including cancer. Finally, we demonstrate that DHT treatment decreases protein levels of β-catenin, a final effector of canonical Wnt signaling pathway. Overall, our data suggest a possible use of this nutraceutical as an adjuvant in the treatment of aggressive papillary thyroid carcinoma.

BackgroundDiagnosis of child and adolescent psychopathologies involves a multifaceted approach, integrating clinical observations, behavioral assessments, medical history, cognitive testing, and familial context information. Digital technologies, especially internet-based platforms for administering caregiver-rated questionnaires, are increasingly used in this field, particularly during the screening phase. The ascent of digital platforms for data collection has propelled advanced psychopathology classification methods such as supervised machine learning (ML) into the forefront of both research and clinical environments. This shift, recently called psycho-informatics, has been facilitated by gradually incorporating computational devices into clinical workflows. However, an actual integration between telemedicine and the ML approach has yet to be fulfilled. ObjectiveUnder these premises, exploring the potential of ML applications for analyzing digitally collected data may have significant implications for supporting the clinical practice of diagnosing early psychopathology. The purpose of this study was, therefore, to exploit ML models for the classification of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) using internet-based parent-reported socio-anamnestic data, aiming at obtaining accurate predictive models for new help-seeking families. MethodsIn this retrospective, single-center observational study, socio-anamnestic data were collected from 1688 children and adolescents referred for suspected neurodevelopmental conditions. The data included sociodemographic, clinical, environmental, and developmental factors, collected remotely through the first Italian internet-based screening tool for neurodevelopmental disorders, the Medea Information and Clinical Assessment On-Line (MedicalBIT). Random forest (RF), decision tree, and logistic regression models were developed and evaluated using classification accuracy, sensitivity, specificity, and importance of independent variables. ResultsThe RF model demonstrated robust accuracy, achieving 84% (95% CI 82-85; P

Abstract Effectiveness of dihydroartemisinin-piperaquine (DP) as seasonal malaria chemoprevention (SMC) was assessed in Nanyumbu and Masasi Districts. Between March and June 2021, children aged 3–59 months were enrolled in a cluster randomized study. Children in the intervention clusters received a monthly, 3-days course of DP for three consecutive months regardless of malaria infection status, and those in the control clusters received no intervention. Malaria infection was assessed at before the first-round and at 7 weeks after the third-round of DP in both arms. Malaria prevalence after the third-round of DP administration was the primary outcome. Chi-square tests and logistic regression model were used to compare proportions and adjust for explanatory variables. Before the intervention, malaria prevalence was 13.7% (161/1171) and 18.2% (212/1169) in the intervention and control clusters, respectively, p

Objective. Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis. Methods. This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate. Results. This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3). Conclusions. Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Abstract Background Although isolated fractures of the ulnar shaft are considered common and relatively benign injuries, numerous complications can arise especially in the context of suboptimal care pathways. For pediatric patients, however, there is no single indication of the surgical approach. In the context of the management of these complications, it is known that the vascularized fibular graft has numerous advantages and indications in the treatment of recurrent pseudarthrosis. However, in revision surgery the frequent occurrence of anatomical subversions requires the use of fixation means adapted to the individual patient. We present a clinical case of an adult patient suffering from post-traumatic ulnar pseudarthrosis treated with autologous vascularized fibula grafts and 3D-planned custom-made plate. Case presentation A 38-year-old Ivorian woman came to our attention with a painful nonunion of the ulnar shaft and significant dysmorphism of the left forearm, with shortening and flexion of the limb as an outcome of unspecified road trauma in childhood. No alterations of the nerve compartment were reported. As far as detectable, she had undergone autologous bone grafting and implantation of questionable synthetic means, without acute treatment. Since we evaluated the patient (2012), we have performed two debridement surgeries, associated with autologous avascular bone graft from the iliac crest and plate fixation (2012 and 2014). In both cases, rupture of the fixation media was observed. In 2021, the pseudarthrosis was treated with a vascularized fibular bone graft. The subverted radius and ulna anatomy and poor bone quality required patient-specific reconstruction of the pseudarthrosic ulna from a 3D scan and the production of custom-made plate and screws, supported by the creation of special guides for drilling and by optimizing the positioning of screws with preoperative digital models. In the postoperative period, regular follow-up visits with X-rays evaluations were performed at 1, 3 and 6 months after surgery. No inflammatory reactions or local rejection were found. The fibula graft healed at the proximal ulnar junction six months after the operation while it took eight months to heal at the distal junction. Functionally, we observed a pain reduction and a range-of-motion preservation. Conclusions The multiple failures of diaphyseal reconstruction with avascular bone grafts have forced the indication to the vascularized fibular flap. This case is a unique experience but we believe that the association between vascularized bone graft and the potential for customization through 3D planning represents a valid surgical potentiality in complex cases of post-traumatic reconstruction.

Despite a significant evolution in treatment strategies for early breast cancer (EBC) patients, up to 30% of them experience recurrence due to occult micrometastasis. The minimal residual disease (minimal RD) in EBC patients after the treatment with curative intent cannot be easily detected by clinical examination and radiological imaging, as they are both burdened by limited sensitivity. A new frontier and promising approach to address this unmet need is the study of liquid biopsy (LB). The most studied tumor-derived analytes in the peripheral blood for minimal RD monitoring are currently: i) the circulating tumor DNA (ctDNA), for the detection of somatic DNA alterations, so referred to as molecular residual disease (MRD); ii) circulating tumor cells (CTCs), for the detection of cellular residual disease (CRD).MRD detection, while reaching a high specificity, is still presenting a number of limitations. On the other hand, CRD allows a real-time disease monitoring, detecting live cells, and possess the potential to provide an enormous amount of biological information. Indeed, CTCs can provide a multi-level portrait (i.e., DNA, RNA and proteins) of the tumor, longitudinally depicting its evolving landscape, and can be used for functional (in vitro/in vivo) characterization. Moreover, CRD goes beyond the association with the risk of recurrence: predictive biomarkers for treatment response can also be evaluated. Nevertheless, CTCs are less studied in this context, because of their need to be immediately processed and their limited detection in a small fraction of patients in the early and post-surgery setting. These limitations could however be overcome by the use of newly developed technologies that enable an increased CTC detection rate and retrospective studies.Here, we review the strengths and limitations of using MRD and CRD for minimal RD detection, focusing on the methodologies available for LB analysis in this setting, and on the main clinical studies investigating MRD and CRD in EBC. Considering the limits and the advantages of both MRD and CRD, we propose the integration of ctDNA and CTCs as complementary tools for minimal RD assessment to achieve a synergistic and novel approach for minimal RD analysis.

The majority of fatal cases of SARS-CoV-2 was concentrated among older patients. We aimed at assessing risk factors contributing to mortality in this population. A retrospective study including 584 COVID-19 patients aged ≥80 years hospitalized between October 10th 2020 to May 4th 2021 at Ospedale di Circolo (Varese, Italy) and Ospedale Galmarini (Tradate, Italy) was conducted. Evaluation of risk factors associated with in-hospital mortality was the primary endpoint. 509 patients were considered. Median age was 86 [82-89] years. Almost half of the patients (n=241) suffered from ≥3 comorbidities. Overall in-hospital mortality was 39.7% (n=202). Age, chronic kidney disease (CKD), peripheral oxygen saturation at admission, and high-flow oxygen during hospital stay independently predicted in-hospital mortality. Overall mortality at 6 months was 57.8% (n=294) and increased with increasing age and number of comorbidities (P

Visual statistical Learning (SL) allows infants to extract the statistical relationships embedded in a sequence of elements. SL plays a crucial role in language and communication competencies and has been found to be impacted in Autism Spectrum Disorder (ASD). This study aims to investigate visual SL in infants at higher likelihood of developing ASD (HL-ASD) and its predictive value on autistic-related traits at 24-36 months. At 6 months of age, SL was tested using a visual habituation task in HL-ASD and neurotypical (NT) infants. All infants were habituated to a visual sequence of shapes containing statistically predictable patterns. In the test phase, infants viewed the statistically structured, familiar sequence in alternation with a novel sequence that did not contain any statistical information. HL-ASD infants were then evaluated at 24-36 months to investigate the associations between visual SL and ASD-related traits. Our results showed that NT infants were able to learn the statistical structure embedded in the visual sequences, while HL-ASD infants showed different learning patterns. A regression analysis revealed that SL ability in 6-month-old HL-ASD infants was related to social communication and interaction abilities at 24-36 months of age. These findings indicate that early differences in learning visual statistical patterns might contribute to later social communication skills.

Abstract As malaria transmission declines, the need to monitor the heterogeneity of malaria risk at finer scales becomes critical to guide community-based targeted interventions. Although routine health facility (HF) data can provide epidemiological evidence at high spatial and temporal resolution, its incomplete nature of information can result in lower administrative units without empirical data. To overcome geographic sparsity of data and its representativeness, geo-spatial models can leverage routine information to predict risk in un-represented areas as well as estimate uncertainty of predictions. Here, a Bayesian spatio-temporal model was applied on malaria test positivity rate (TPR) data for the period 2017–2019 to predict risks at the ward level, the lowest decision-making unit in mainland Tanzania. To quantify the associated uncertainty, the probability of malaria TPR exceeding programmatic threshold was estimated. Results showed a marked spatial heterogeneity in malaria TPR across wards. 17.7 million people resided in areas where malaria TPR was high (≥ 30; 90% certainty) in the North-West and South-East parts of Tanzania. Approximately 11.7 million people lived in areas where malaria TPR was very low (

Achieving malaria elimination requires considering both Plasmodium falciparum and non–P. falciparum infections. We determined prevalence and geographic distribution of 4 Plasmodium spp. by performing PCR on dried blood spots collected within 8 regions of Tanzania during 2017. Among 3,456 schoolchildren, 22% had P. falciparum, 24% had P. ovale spp., 4% had P. malariae, and 0.3% had P. vivax infections. Most (91%) schoolchildren with P. ovale infections had low parasite densities; 64% of P. ovale infections were single-species infections, and 35% of those were detected in low malaria endemic regions. P. malariae infections were predominantly (73%) co-infections with P. falciparum. P. vivax was detected mostly in northern and eastern regions. Co-infections with >1 non–P. falciparum species occurred in 43% of P. falciparum infections. A high prevalence of P. ovale infections exists among schoolchildren in Tanzania, underscoring the need for detection and treatment strategies that target non–P. falciparum species.

Botulinum toxin type-A (BoNT-A) has emerged as a key therapeutic agent for the management of spasticity. This paper presents a comprehensive bibliometric and visual analysis of research concerning BoNT-A treatment of spasticity to elucidate current trends and future directions in this research area. A search was conducted in the Web of Science database for articles focused on the use of BoNT-A in spasticity published between 2000 and 2022. We extracted various metrics, including counts of publications and contributions from different countries, institutions, authors, and journals. Analytical methods in CiteSpace were employed for the examination of co-citations, collaborations, and the co-occurrence of keywords. Our search yielded 1489 publications. Analysis revealed a consistent annual increase in research output. The United States, United Kingdom, and Italy were the leading contributors. The top institution in this research was Assistance Publique Hopitaux, Paris. The journal containing the highest number of relevant publications was Toxins. Key frequently occurring keywords were ‘stroke’, ‘cerebral palsy’, ‘adult spasticity’, and ‘upper extremity’. This study identified 12 clusters of keywords and 15 clusters of co-cited references, indicating the main focus areas and emerging themes in this field. This study comprehensively analyzed and summarized trends in BoNT-A research in the field of spasticity over the past 22 years.

The human epidermal growth factor receptor 2 (HER2) plays a central role in breast cancer (BC). Therefore, it is critical to develop a method that can capture its spatial and temporal heterogeneity. Nowadays, therapeutic decisions for BC patients relies on evaluation of HER2 status from tissue biopsies using immunohistochemistry and in situ hybridization. Nevertheless, considering the technical and logistical challenges associated with tissue biopsies, there is an unmet need for a non-invasive and accurate approach to obtain real-time assessment of HER2 status. In this context, circulating biomarkers, particularly circulating tumor cells (CTCs), emerged as promising candidates. HER2 assessment on CTCs can be performed at genomic, transcriptomic, and protein levels on both bulk CTCs and at the single-cell resolution. However, the main limitation of the literature to date is the lack of a consistent definition of HER2-positive CTCs, which poses a major challenge for both, future research and clinical applications. Several studies revealed discordance in HER2 status between the primary tumor and corresponding CTCs. For instance, HER2-positive CTCs have been detected among patients with HER2-negative BC and vice versa. As a result, researchers have evaluated the prognostic and predictive value of HER2 status in CTCs, both in the early and metastatic settings, to increase the possibility of using anti-HER2 therapy also for these patients and to dissect mechanisms of treatment resistance. This review aims to provide an overview of the methods to determine HER2 status in CTCs and to summarize the evidence and future perspective on how CTCs-HER2 assessment can be integrated into the clinical management of BC patients.

Introduction Oral cavity squamous cell carcinoma (OCSCC) is the most common malignancy in the oral cavity. Two types of mandibular resections have been described: the segmental mandibulectomy and the marginal mandibulectomy. Both may have a different impact over the quality of life, oncological prognosis, and functional or aesthetic result.

Abstract This study was designed to investigate the feasibility and the potential effects on walking performance of a short gait training with a novel impairment-specific hip assistance (iHA) through a bilateral active pelvis orthosis (APO) in patients with acquired brain injury (ABI). Fourteen subjects capable of independent gait and exhibiting mild-to-moderate gait deficits, due to an ABI, were enrolled. Subjects presenting deficit in hip flexion and/or extension were included and divided into two groups based on the presence (group A, n = 6) or absence (group B, n = 8) of knee hyperextension during stance phase of walking. Two iHA-based profiles were developed for the groups. The protocol included two overground gait training sessions using APO, and two evaluation sessions, pre and post training. Primary outcomes were pre vs. post-training walking distance and steady-state speed in the 6-min walking test. Secondary outcomes were self-selected speed, joint kinematics and kinetics, gait symmetry and forward propulsion, assessed through 3D gait analysis. Following the training, study participants significantly increased the walked distance and average steady-state speed in the 6-min walking tests, both when walking with and without the APO. The increased walked distance surpassed the minimal clinically important difference for groups A and B, (respectively, 42 and 57 m > 34 m). In group A, five out of six subjects had decreased knee hyperextension at the post-training session (on average the peak of the knee extension angle was reduced by 36%). Knee flexion during swing phase increased, by 16% and 31%, for A and B groups respectively. Two-day gait training with APO providing iHA was effective and safe in improving walking performance and knee kinematics in ABI survivors. These preliminary findings suggest that this strategy may be viable for subject-specific post-ABI gait rehabilitation.

Abstract The Delta (B.1.617.2) variant was the predominant UK circulating SARS-CoV-2 strain between May and December 2021. How Delta infection compares with previous variants is unknown. This prospective observational cohort study assessed symptomatic adults participating in the app-based COVID Symptom Study who tested positive for SARS-CoV-2 from May 26 to July 1, 2021 (Delta overwhelmingly the predominant circulating UK variant), compared (1:1, age- and sex-matched) with individuals presenting from December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the predominant variant). We assessed illness (symptoms, duration, presentation to hospital) during Alpha- and Delta-predominant timeframes; and transmission, reinfection, and vaccine effectiveness during the Delta-predominant period. 3581 individuals (aged 18 to 100 years) from each timeframe were assessed. The seven most frequent symptoms were common to both variants. Within the first 28 days of illness, some symptoms were more common with Delta versus Alpha infection (including fever, sore throat, and headache) and some vice versa (dyspnoea). Symptom burden in the first week was higher with Delta versus Alpha infection; however, the odds of any given symptom lasting ≥ 7 days was either lower or unchanged. Illness duration ≥ 28 days was lower with Delta versus Alpha infection, though unchanged in unvaccinated individuals. Hospitalisation for COVID-19 was unchanged. The Delta variant appeared more (1.49) transmissible than Alpha. Re-infections were low in all UK regions. Vaccination markedly reduced the risk of Delta infection (by 69-84%). We conclude that COVID-19 from Delta or Alpha infections is similar. The Delta variant is more transmissible than Alpha; however, current vaccines showed good efficacy against disease. This research framework can be useful for future comparisons with new emerging variants.

A strong correlation has been reported between patient-reported quality of life (QoL) and the investigator-rated Disability Assessment Scale (DAS) in patients with spasticity. The current analysis evaluates the effect of incobotulinumtoxinA on QoL-related outcomes (limb position abnormality, as well as dressing- and hygiene-related disability, measured with the DAS) in adults with upper limb spasticity, using pooled data from six studies. Separate analyses for each DAS domain were performed using data from patients with disabilities for that domain (DAS score ≥1). Results showed that a significantly greater proportion of incobotulinumtoxinA-treated compared with placebo-treated patients achieved a ≥1-point reduction from baseline in each of the DAS domains (improvement) 4 weeks after the first injection. The benefits of incobotulinumtoxinA were observed regardless of the baseline severity of DAS impairment and of the time elapsed since stroke. The effects of incobotulinumtoxinA 4 weeks after injection were maintained or enhanced over multiple injection cycles for all three DAS domains, supporting the use of repeated injection cycles to provide sustained QoL benefit. IncobotulinumtoxinA represents an important treatment option to achieve better QoL-related outcomes for patients with upper limb spasticity, irrespective of the duration of their condition.

The objective of this article is to introduce the GO-FAST Tool (developed by the Toxnet group) to clinicians working in the field of neurological rehabilitation, specifically post-stroke spasticity management. The concepts utilized in the Tool and described in this article can be broadly grouped into five topics: the principles of patient-centred goal-setting; an algorithm for setting SMART (specific, measurable, attainable, realistic, and timed) treatment goals; goal-related target muscles and botulinum toxin type A dose determinants; goal attainment follow-up, scoring, and interpretation; and the multimodal approach to spasticity management. The Tool can enhance clinical practice by providing guided assistance with goal-setting and target muscle selection for botulinum toxin type A treatment. It also provides support with the follow-up evaluation of goal attainment and calculation of treatment success. The Tool is designed to be used by clinicians with varying levels of expertise in the field of neurological rehabilitation and post-stroke spasticity management, from those who are new to the field to those with many years of experience. A case study is presented in the Results Section of the article to illustrate the utility of the Tool in setting SMART treatment goals in the management of patients with post-stroke spasticity.

This module discusses the pathophysiology of spasticity and the lesions underlying the condition. It considers the clinical presentation of spasticity and outlines the relevant clinical history that should be documented. The positive and negative signs of spasticity are explained. Clinical presentations of spasticity are discussed, and an illustrated table of spastic limb postures details how the muscles involved in each individual's condition may be identified. The main systems for assessing the severity of the condition, the Ashworth Scale, the modified Ashworth scale, and the Tardieu Scale, are explained. The likelihood of spasticity developing following a stroke and the probable long-term outcomes are considered. The value of involving patients in their own treatment regimens, by defining and setting goals, using the SMARTER system is explained, and the need to continually assess and refine treatment with time as the condition progresses is also discussed.

IntroductionCare for head and neck cancers is complex in particular for the rare ones. Knowledge is limited and histological heterogeneity adds complexity to the rarity. There is a wide consensus that to support clinical research on rare cancer, clinical registries should be developed within networks specializing in rare cancers. In the EU, a unique opportunity is provided by the European Reference Networks (ERN). The ERN EURACAN is dedicated to rare adults solid cancers, here we present the protocol of the EURACAN registry on rare head and neck cancers (ClinicalTrials.gov Identifier: NCT05483374).Study designRegistry-based cohort study including only people with rare head and neck cancers.Objectivesto help describe the natural history of rare head and neck cancers;to evaluate factors that influence prognosis;to assess treatment effectiveness;to measure indicators of quality of care.MethodsSettings and participants It is an hospital based registry established in hospitals with expertise in head and neck cancers. Only adult patients with epithelial tumours of nasopharynx; nasal cavity and paranasal sinuses; salivary gland cancer in large and small salivary glands; and middle ear will be included in the registry. This registry won't select a sample of patients. Each patient in the facility who meets the above mentioned inclusion criteria will be followed prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for the patient follow-up. Variables Data will be collected on patient characteristics (eg. patient demographics, lifestyle, medical history, health status); exposure data (eg. disease, procedures, treatments of interest) and outcomes (e.g. survival, progression, progression-free survival, etc.). In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will be also collected. Statistical methods The data analyses will include descriptive statistics showing patterns of patients' and cancers' variables and indicators describing the quality of care. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause specific mortality will be used to determine independent predictors of overall survival, recurrence etc. Variables to include in the multivariable regression model will be selected based on the results of univariable analysis. The role of confounding or effect modifiers will be evaluated using stratified analysis or sensitivity analysis. To assess treatment effectiveness, multivariable models with propensity score adjustment and progression-free survival will be performed. Adequate statistical (eg. marginal structural model) methods will be used if time-varying treatments/confounders and confounding by indication (selective prescribing) will be present.ResultsThe registry initiated recruiting in May 2022. The estimated completion date is December 2030 upon agreement on the achievement of all the registry objectives. As of October 2022, the registry is recruiting. There will be a risk of limited representativeness due to the hospital-based nature of the registry and to the fact that hospital contributing to the registry are expert centres for these rare cancers. Clinical Follow-up could also be an issue but active search of the life status of the patients will be guaranteed.

Abstract Background Although Osteogenesis Imperfecta (OI) affects the connective tissue causing extremely brittle bones with consequent skeletal deformities, it is important to go beyond bones. Indeed, the quality of life in OI does not only depend on bones status, as OI might affect also other important functions. We have therefore implemented a multidisciplinary study to assess lung function, breathing pattern, sleep quality and nutritional status in 27 adult OI type III and IV patients (median age: 34.6 years; 19 women; 14 type III). Results According to nocturnal oxygen desaturation, two groups were identified: 13 patients with (OI_OSA, incidence: 48.2%) and 14 without (no_OSA) obstructive sleep apnea. The former was characterized by higher spinal and ribcage deformity, by more restrictive lung function, by paradoxical thoracic breathing in supine position, by rapid and shallow breathing, by higher body mass index, by longer neck and waist circumferences; by higher abdominal volume and by greater percentage of body fat mass, particularly localized in the trunk. The best predictor of OI_OSA was the negative value of the supine ribcage contribution to tidal volume, followed by the ratio between the neck and the waist circumferences with body height and the supine thoraco-abdominal volumes phase shift angle. Conclusions The pathophysiology of OI ensued a dangerous vicious circle, in which breathing, sleep and nutritional status are tightly linked, and they might all end up in negatively affecting the quality of life. The vicious circle is fed by some intrinsic characteristics of the disease (thoracic, cranial and mandibular deformities) and some bad daily habits of the patients (i.e. physical inactivity and low dietary quality). The former impacts on restricting the respiratory function, the latter makes Olers more prone to experience overweight or obesity. The main consequence is a high incidence of obstructive sleep apnea, which remains an underdiagnosed disorder in individuals with severe OI who are obese, with a neck to height ratio over than 31.6%, and characterized by paradoxical breathing in supine position. A multidisciplinary approach, including evaluations of breathing, sleep and nutrition, is required to better manage the disease and fulfil the maximizing well-being of OI patients.

BackgroundThe rapid extent of digital innovation for the collection of data has transformed the way in which health professionals collect, share, and analyze health information for better clinical decision-making and health care. In the last decade, there has been an increased interest in telemedicine by mental health agencies; the gap between the need for care and both diagnosis and treatment is wide, and digital technology could play an important role in filling this gap. However, there are limited data on the effectiveness of the clinical process and cost-effectiveness of most telemedicine applications. ObjectiveThis study examined the implementation of the first Italian online, web-based, comprehensive screening tool and described the screening and diagnostic process through the interactive web platform in a child psychopathology clinic. This is a feasibility study that aims to present the design and implementation of the best practices to improve patient experiences and clinical outcomes. Moreover, the paper evaluates the platform with qualitative and quantitative measures. MethodsWe planned, designed, and implemented a web-based system to collect, store, and manage clinical data. The platform was developed by a multidisciplinary team composed of researchers, clinicians, and informatics professionals through different steps. First, we defined the clinical information to be collected. A number of measures were chosen, tapping several clinical risk areas such as neurodevelopmental disorders and emotional and behavioral problems. The web application architecture and process were then designed. The three phases of process design are described in detail: design of the input interface, processing design, and design of the output interface. Finally, the system has been implemented and evaluated. Based on indicators recommended by the National Quality Forum and the Italian National Guidelines, we evaluated the quality of the system and used quantitative measures that were replicable and comparable over time. ResultsWe present the implemented architecture and features of Medea Information and Clinical Assessment On-Line (MedicalBIT), and we provide performance measures for the data collected between October 2018 and June 2021. The measured concepts pertain to four domains: access to care, financial impact/cost, experience, and effectiveness. ConclusionsIn this study, we present the successful implementation of an innovative digital tool. The findings of this study show that the implemented web-based platform appears to be an efficient, cost-effective, and feasible way to improve digital care in the field of child psychiatry.

By blocking the release of neurotransmitters, botulinum toxin A (BoNT-A) is an effective treatment for muscle over-activity and pain in stroke patients. BoNT-A has also been reported to increase passive range of motion (p-ROM), the decrease of which is mainly due to muscle shortening (i.e., muscle contracture). Although the mechanism of action of BoNT-A on p-ROM is far from understood, pain relief may be hypothesized to play a role. To test this hypothesis, a retrospective investigation of p-ROM and pain was conducted in post-stroke patients treated with BoNT-A for upper limb hypertonia. Among 70 stroke patients enrolled in the study, muscle tone (Modified Ashworth Scale), pathological postures, p-ROM, and pain during p-ROM assessment (Numeric Rating Scale, NRS) were investigated in elbow flexors (48 patients) and in finger flexors (64 patients), just before and 3–6 weeks after BoNT-A treatment. Before BoNT-A treatment, pathological postures of elbow flexion were found in all patients but one. A decreased elbow p-ROM was found in 18 patients (38%). Patients with decreased p-ROM had higher pain-NRS scores (5.08 ± 1.96, with a pain score ≥8 in 11% of cases) than patients with normal p-ROM (0.57 ± 1.36) (p < 0.001). Similarly, pathological postures of finger flexion were found in all patients but two. A decreased finger p-ROM was found in 14 patients (22%). Pain was more intense in the 14 patients with decreased p-ROM (8.43 ± 1.74, with a pain score ≥ 8 in 86% of cases) than in the 50 patients with normal p-ROM (0.98 ± 1.89) (p < 0.001). After BoNT-A treatment, muscle tone, pathological postures, and pain decreased in both elbow and finger flexors. In contrast, p-ROM increased only in finger flexors. The study discusses that pain plays a pivotal role in the increase in p-ROM observed after BoNT-A treatment.

Abstract After a stroke event, most survivors suffer from arm paresis, poor motor control and other disabilities that make activities of daily living difficult, severely affecting quality of life and personal independence. This randomized controlled trial aimed at evaluating the efficacy of a music-based sonification approach on upper limbs motor functions, quality of life and pain perceived during rehabilitation. The study involved 65 subacute stroke individuals during inpatient rehabilitation allocated into 2 groups which underwent usual care dayweek) respectively of standard upper extremity motor rehabilitation or upper extremity treatment with sonification techniques. The Fugl-Meyer Upper Extremity Scale, Box and Block Test and the Modified Ashworth Scale were used to perform motor assessment and the McGill Quality of Life-it and the Numerical Pain Rating Scale to assess quality of life and pain. The assessment was performed at baseline, after 2 weeks, at the end of treatment and at follow-up (1 month after the end of treatment). Total scores of the Fugl-Meyer Upper Extremity Scale (primary outcome measure) and hand and wrist sub scores, manual dexterity scores of the affected and unaffected limb in the Box and Block Test, pain scores of the Numerical Pain Rating Scale (secondary outcomes measures) significantly improved in the sonification group compared to the standard of care group (time*group interaction

Abstract We tested whether pregnant and non-pregnant women differ in COVID-19 symptom profile and severity, and we extended previous investigations on hospitalized pregnant women to those who did not require hospitalization. Two female community-based cohorts (18–44 years) provided longitudinal (smartphone application, N = 1,170,315, n = 79 pregnant tested positive) and cross-sectional (web-based survey, N = 1,344,966, n = 134 pregnant tested positive) data, prospectively collected through self-participatory citizen surveillance in UK, Sweden and USA. Pregnant and non-pregnant were compared for frequencies of events, including SARS-CoV-2 testing, symptoms and hospitalization rates. Multivariable regression was used to investigate symptoms severity and comorbidity effects. Pregnant and non-pregnant women positive for SARS-CoV-2 infection were not different in syndromic severity, except for gastrointestinal symptoms. Pregnant were more likely to have received testing, despite reporting fewer symptoms. Pre-existing lung disease was most closely associated with syndromic severity in pregnant hospitalized. Heart and kidney diseases and diabetes increased risk. The most frequent symptoms among non-hospitalized women were anosmia [63% pregnant, 92% non-pregnant] and headache [72%, 62%]. Cardiopulmonary symptoms, including persistent cough [80%] and chest pain [73%], were more frequent among pregnant who were hospitalized. Consistent with observations in non-pregnant populations, lung disease and diabetes were associated with increased risk of more severe SARS-CoV-2 infection during pregnancy.

Italy has been one of the first-hit and most affected countries worldwide by the coronavirus disease 2019 (COVID-19) outbreak, and Lombardy accounts for almost half of all Italian cases. Vulnerable population is the one suffering the most from the current epidemic, without guaranteed access to basic needs. This aspect becomes critical for people experiencing disability, either due or not to COVID-19. To face the pandemic, all the regional health system services, rehabilitation ones included, were forced to radically adapt their operating paradigm and even sometimes to leave their intrinsic mission. The Italian Society of Physical and Rehabilitation Medicine (SIMFER) since the beginning of the outbreak was profoundly involved in the clinical and organizational response to COVID-19. The Lombardy regional group cooperated strictly and continuously with the national group to coordinate rehabilitation processes region wide. The paper presents a brief report of our field experience describing the phases faced since the beginning of the pandemic and suggesting the organizational strategies that could be useful in rehabilitation services for both inpatients and outpatients. Springing from literature and the experience of the Lombardy section of SIMFER, this paper should help clinicians to respond to the need of the disabled patient facing the new COVID-19 outbreak.

BackgroundScreening for latent tuberculosis infection is recommended in patients with rheumatoid arthritis (RA) starting Janus kinase inhibitors (Jaki). Interferon (IFN)-gamma release assays (IGRAs) are increasingly used for this purpose. Jaki tend to decrease the levels of IFNs, questioning the reliability of IGRAs during treatment with these drugs.ObjectivesTo compare the performance of QuantiFERON-TB Gold Plus (QFT-P) and QFT Gold In-tube (QFT-GIT) in RA patients treated with Jaki.MethodsRA patients underwent QFT-P and QFT-GIT at baseline (T0), and after 3 (T3) and 12 months (T12) of treatment with Jaki. The agreement between the two tests was calculated. The agreement between IGRAs and tuberculin skin test (TST) or chest radiography at baseline was also determined. The variability of QTF-P results was longitudinally assessed.ResultsTwenty-nine RA patients (F/M 23/6; median age/IQR 63/15.5 years; median disease duration/IQR 174/216 months) were enrolled. A perfect agreement was found between QFT-P and QFT-GIT at all times (κ = 1). At T0, no agreement was recorded between IGRAs and TST (κ = -0.08) and between TST and chest radiography (κ = -0.07), a low agreement was found between QFT-P and chest radiography (κ = 0.17). A variation of 33.3% in the results of QFT-P was recorded at T3 vs T0, of 29.4% at T12 vs T0, and of 11.8% at T12 vs T3. The median levels of IFN-γ produced by lymphocytes in response to the mitogen of QFT-P decreased after 3 months followed by an increase after 12 months (not significant). No change in the median number of circulating lymphocytes was documented. Glucocorticoids intake was associated with a higher probability of negative or indeterminate IGRA results at T0 (pConclusionA response to IGRAs is detectable during treatment with Jaki. However, fluctuations in the results of IGRAs have been observed in the absence of correlation with clinical outcomes, thus challenging their interpretation.

BackgroundMalnutrition and malaria are common co-morbidities in low-income countries, especially among under-fives children. But the malnutrition situation in Masasi and Nanyumbu districts, its interaction with malaria infection and the influence of socioeconomic factors are not well understood.MethodsChildren aged between 3-59 months in Masasi and Nanyumbu were screened for nutritional status and malaria infection in the community. Nutritional status was determined using age and anthropometric parameters. Z-scores (weight for age (WAZ), height for age (HAZ) and weight for height (WHZ)) were calculated based on the World Health Organisation (WHO) growth reference curves. Malaria infection was determined using malaria rapid diagnostic test and microscopy. Hemoglobin concentration was assessed using HemoCue spectrophotometer, and anemia was classified as hemoglobin concentration < 11.0g/dL. Structured questionnaire was used to collect socio- demographic information electronically.ResultsA total of 2242 children, 1539 (68.6%) from Masasi and 1169 (52.1%) females were involved in the study. The mean z-scores (WAZ = -0.60 and HAZ = -1.56) were lower than the WHO reference population. The overall prevalence of malnutrition was 49%, and it was significantly higher in Nanyumbu (52.5%) than in Masasi (47.3%), (x2 = 5.045, p = 0.025). Prevalence of malnutrition was higher in boys (53.0%) than in girls (45.0%) (x2 = 13.9, p < 0.001). Stunting was the most prevalent component of undernutrition; it was slightly prevalent in Nanyumbu (46.5%) compared to Masasi (42.0%), (x2 = 3.624, p = 0.057) and in boys (48.2%) than in girls (39.1%), x2 = 17.44, pConclusionUndernutrition was highly prevalent in the study population and was influenced sex, age, anaemia and malaria infection. More emphasis is needed to address the malnutrition problem especially stunting in Masasi and Nanyumbu districts.

Tree ring features are affected by environmental factors and therefore are the basis for dendrochronological studies to reconstruct past environmental conditions. Oak wood often provides the data for these studies because of the durability of oak heartwood and hence the availability of samples spanning long time periods of the distant past. Wood formation is regulated in part by epigenetic mechanisms such as DNA methylation. Studies of the methylation state of DNA preserved in oak heartwood thus could identify epigenetic tree ring features informing on past environmental conditions. In this study, we aimed to establish protocols for the extraction of DNA, the high-throughput sequencing of whole-genome DNA libraries (WGS) and the profiling of DNA methylation by whole-genome bisulfite sequencing (WGBS) for oak (Quercus robur) heartwood drill cores taken from the trunks of living standing trees spanning the AD 1776-2014 time period. Heartwood contains little DNA, and large amounts of phenolic compounds known to hinder the preparation of high-throughput sequencing libraries. Whole-genome and DNA methylome library preparation and sequencing consistently failed for oak heartwood samples more than 100 and 50 years of age, respectively. DNA fragmentation increased with sample age and was exacerbated by the additional bisulfite treatment step during methylome library preparation. Relative coverage of the non-repetitive portion of the oak genome was sparse. These results suggest that quantitative methylome studies of oak hardwood will likely be limited to relatively recent samples and will require a high sequencing depth to achieve sufficient genome coverage.

BackgroundMalaria and anemia remain major public health challenges in Tanzania. Household socioeconomic factors are known to influence these conditions. However, it is not clear how these factors influence malaria transmission and anemia in Masasi and Nanyumbu Districts. This study presents findings on malaria and anemia situation in under-five children and its influencing socioeconomic factors in Masasi and Nanyumbu Districts, surveyed as part of an ongoing seasonal malaria chemoprevention operational study.MethodsA community-based cross-sectional survey was conducted between August and September 2020. Finger-prick blood samples collected from children aged 3-59 months were used to test for malaria infection using malaria rapid diagnostic test (mRDT), thick smears for determination of asexual and sexual parasitemia, and thin smear for parasite speciation. Hemoglobin concentration was measured using a HemoCue spectrophotometer. A structured questionnaire was used to collect household socioeconomic information from parents/caregivers of screened children. The prevalence of malaria was the primary outcome. Chi-square tests, t-tests, and logistic regression models were used appropriately.ResultsOverall mRDT-based malaria prevalence was 15.9% (373/2340), and was significantly higher in Nanyumbu (23.7% (167/705) than Masasi District (12.6% (206/1635), pConclusionPrevalence of malaria and anemia was high and was strongly associated with household socioeconomic factors. Improving household socioeconomic status is expected to reduce the prevalence of the conditions in the area.

The Performance of the Upper Limb (PUL) module is an externally-assessed clinical scale, initially designed for the Duchenne muscular dystrophy population. It provides an upper extremity functional score suitable for both weaker ambulatory and non-ambulatory phases up to the severely impaired patients. It is capable of characterizing overall progression and severity of disease and of tracking the stereotypical proximal-to-distal progressive loss of upper limb function in muscular dystrophy. Since the PUL module has been validated only with Duchenne patients, its use also for Becker and Limb-Girdle muscular dystrophy patients has been here evaluated, to verify its reliability and extend its use. In particular, two different assessors performed this scale on 32 dystrophic subjects in two consecutive days. The results showed that the PUL module has high reliability, both absolute and relative, based on the calculation of Pearson's r (0.9942), Intraclass Correlation Coefficient (0.9943), Standard Error of Measurement (1.36), Minimum Detectable Change (3.77), and Coefficient of Variation (3%). The Minimum Detectable Change, in particular, can be used in clinical trials to perform a comprehensive longitudinal evaluation of the effects of interventions with the lapse of time. According to this analysis, an intervention is effective if the difference in the PUL score between subsequent evaluation points is equal or higher than 4 points; otherwise, the observed effect is not relevant. Inter-rater reliability with ten different assessors was evaluated, and it has been demonstrated that deviation from the mean is lower than calculated Minimum Detectable Change. The present work provides evidence that the PUL module is a reliable and valid instrument for measuring upper limb ability in people with different forms of muscular dystrophy. Therefore, the PUL module might be extended to other pathologies and reliably used in multicenter settings.

IntroductionThe decision-making process for malaria control and elimination strategies has become more challenging. Interventions need to be targeted at council level to allow for changing malaria epidemiology and an increase in the number of possible interventions. Models of malaria dynamics can support this process by simulating potential impacts of multiple interventions in different settings and determining appropriate packages of interventions for meeting specific expected targets.MethodsThe OpenMalaria model of malaria dynamics was calibrated for all 184 councils in mainland Tanzania using data from malaria indicator surveys, school parasitaemia surveys, entomological surveillance, and vector control deployment data. The simulations were run for different transmission intensities per region and five interventions, currently or potentially included in the National Malaria Strategic Plan, individually and in combination. The simulated prevalences were fitted to council specific prevalences derived from geostatistical models to obtain council specific predictions of the prevalence and number of cases between 2017 and 2020. The predictions were used to evaluate in silico the feasibility of the national target of reaching a prevalence of below 1% by 2020, and to suggest alternative intervention stratifications for the country.ResultsThe historical prevalence trend was fitted for each council with an agreement of 87% in 2016 (95%CI: 0.84-0.90) and an agreement of 90% for the historical trend (2003-2016) (95%CI: 0.87-0.93) The current national malaria strategy was expected to reduce the malaria prevalence between 2016 and 2020 on average by 23.8% (95% CI: 19.7%-27.9%) if current case management levels were maintained, and by 52.1% (95% CI: 48.8%-55.3%) if the case management were improved. Insecticide treated nets and case management were the most cost-effective interventions, expected to reduce the prevalence by 25.0% (95% CI: 19.7%-30.2) and to avert 37 million cases between 2017 and 2020. Mass drug administration was included in most councils in the stratification selected for meeting the national target at minimal costs, expected to reduce the prevalence by 77.5% (95%CI: 70.5%-84.5%) and to avert 102 million cases, with almost twice higher costs than those of the current national strategy. In summary, the model suggested that current interventions are not sufficient to reach the national aim of a prevalence of less than 1% by 2020 and a revised strategic plan needs to consider additional, more effective interventions, especially in high transmission areas and that the targets need to be revisited.ConclusionThe methodology reported here is based on intensive interactions with the NMCP and provides a helpful tool for assessing the feasibility of country specific targets and for determining which intervention stratifications at sub-national level will have most impact. This country-led application could support strategic planning of malaria control in many other malaria endemic countries.

The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments. Herein, we describe the screening of a proprietary compound collection against Klebsiella pneumoniae OXA-48, leading to the identification of several chemotypes, like the 4-ideneamino-4H-1,2,4-triazole (SC_2) and pyrazolo[3,4-b]pyridine (SC_7) cores as potential inhibitors. Importantly, the most potent representative of the latter series (ID2, AC50 = 0.99 μM) inhibited OXA-48 via a reversible and competitive mechanism of action, as demonstrated by biochemical and X-ray studies; furthermore, it slightly improved imipenem’s activity in Escherichia coli ATCC BAA-2523 β-lactam resistant strain. Also, ID2 showed good solubility and no sign of toxicity up to the highest tested concentration, resulting in a promising starting point for further optimization programs toward novel and effective non-β-lactam BLIs.

Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs’ interactions and to evaluate patient’s metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS® technology and Mitra® devices, consisting of a sampling technique for the collection of fixed-volume capillary blood, was developed. These new devices provide a new home-sampling technique for whole blood that has been spread out to simplify sample collection from finger-pricks. This review is aimed to compare published articles concerning the application of VAMS® in epilepsy and to identify the strengths and improvement points for the TDM of antiseizure medications. VAMS® allowed a minimally invasive blood sampling even in the absence of trained personnel. Good stability data have indicated that storage and delivery can be facilitated only for specific ASMs. Trueness and precision parameters have been evaluated, and the hematocrit (HCT) effect was minimized.

Hexarelin, a synthetic hexapeptide, exerts cyto-protective effects at the mitochondrial level in cardiac and skeletal muscles, both in vitro and in vivo, may also have important neuroprotective bioactivities. This study examined the inhibitory effects of hexarelin on hydrogen peroxide (H2O2)-induced apoptosis in Neuro-2A cells. Neuro-2A cells were treated for 24 h with various concentrations of H2O2 or with the combination of H2O2 and hexarelin following which cell viability and nitrite (NO2−) release were measured. Cell morphology was also documented throughout and changes arising were quantified using Image J skeleton and fractal analysis procedures. Apoptotic responses were evaluated by Real-Time PCR (caspase-3, caspase-7, Bax, and Bcl-2 mRNA levels) and Western Blot (cleaved caspase-3, cleaved caspase-7, MAPK, and Akt). Our results indicate that hexarelin effectively antagonized H2O2-induced damage to Neuro-2A cells thereby (i) improving cell viability, (ii) reducing NO2− release and (iii) restoring normal morphologies. Hexarelin treatment also reduced mRNA levels of caspase-3 and its activation, and modulated mRNA levels of the BCL-2 family. Moreover, hexarelin inhibited MAPKs phosphorylation and increased p-Akt protein expression. In conclusion, our results demonstrate neuroprotective and anti-apoptotic effects of hexarelin, suggesting that new analogues could be developed for their neuroprotective effects.

There is extensive literature supporting the efficacy of botulinum toxin (BoNT-A) for the treatment of post-stroke spasticity, however, there remain gaps in the routine management of patients with post-stroke spasticity. A panel of 21 Italian experts was selected to participate in this web-based survey Delphi process to provide guidance that can support clinicians in the decision-making process. There was a broad consensus among physicians that BoNT-A intervention should be administered as soon as the spasticity interferes with the patients’ clinical condition. Patients monitoring is needed over time, a follow-up of 4–6 weeks is considered necessary. Furthermore, physicians agreed that treatment should be offered irrespective of the duration of the spasticity. The Delphi consensus also stressed the importance of patient-centered goals in order to satisfy the clinical needs of the patient regardless of time of onset or duration of spasticity. The findings arising from this Delphi process provide insights into the unmet needs in managing post-stroke spasticity from the clinician’s perspective and provides guidance for physicians for the utilization of BoNT-A for the treatment of post-stroke spasticity in daily practice.

Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and ‘easy to use’ oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis.

BACKGROUND:Huntington disease (HD) is a devastating inherited neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms without any cure to slow down or stop the progress of the disease. The BACHD rat model for HD carrying the human full-length mutant huntingtin protein (mHTT) with 97 polyQ repeats has been recently established as a promising model which reproduces several HD-like features. While motor and cognitive functions have been characterized in BACHD rats, little is known about their social phenotype. OBJECTIVE:This study focuses especially on social behavior since evidence for social disturbances exists in human patients. Our objective was to compare social behavior in BACHD and wild-type (WT) rats at different ages, using two different measures of sociability. METHODS:Animals were tested longitudinally at the age of 2, 4 and 8 months in the social interaction test to examine different parameters of sociability. A separate cohort of 7 month old rats was tested in the three chamber social test to measure both sociability and social novelty. Gene expression analyses in 8 months old animals were performed by real time qRT-PCR to evaluate a potential involvement of D1 and D2 dopaminergic receptors and the contribution of Brain-derived neurotrophic factor (BDNF) to the observed behavioral alterations. RESULTS:In the social interaction test, BACHD rats showed age-dependent changes in behaviour when they were-re introduced to their cagemate after a 24 hours-period of individual housing. The time spent on nape attacks increased with aging. Furthermore, a significant higher level of pinning at 2 months of age was shown in the BACHD rats compared to wild-types, followed by a reduction at 4 and 8 months. On the other hand, BACHD rats exhibited a decreased active social behaviour compared to wild-types, reflected by genotype-effects on approaching, following and social nose contact. In the three chamber social test, BACHD rats seemed to show a mild deficit in preference for social novelty, but no changes in social interest. Molecular analyses revealed that BACHD animals exposed to the social interaction test displayed decreased mRNA levels of the total form of BDNF in ventral striatum and unaltered striatal expression of D1 and D2 dopamine receptors. CONCLUSIONS:Taken together, these results indicate deficits in several parameters representative of sociability. Altered BDNF expression in the ventral striatum may contribute to the deficits in sociability in 8 months old BACHD rats. These data support the validity of the BACHD rat model in mimicking features of certain social deficits that could be relevant to symptoms in patients.