The effects of stimulating the cerebellum on social sequences: A tDCS-fMRI pilot study

Research on the involvement of the cerebellum in social behavior and its relationship with social mentalizing has just begun. Social mentalizing is the ability to attribute mental states such as desires, intentions, and beliefs to others. This ability involves the use of social action sequences which are believed to be stored in the cerebellum. In order to better understand the neurobiology of social mentalizing, we applied cerebellar transcranial direct current stimulation (tDCS) on 23 healthy participants in the MRI scanner, immediately followed by measuring their brain activity during a task that required to generate the correct sequence of social actions involving false (i.e., outdated) and true beliefs, social routines and non-social (control) events. The results revealed that stimulation decreased task performance along with decreased brain activation in mentalizing areas, including the temporoparietal junction and the precuneus. This decrease was strongest for true belief sequences compared to the other sequences. These findings support the functional impact of the cerebellum on the mentalizing network and belief mentalizing, contributing to the understanding of the role of the cerebellum in social sequences. (AU)

The retrospective study of the metabolic patterns of BCG-vaccination in type-2 diabetic individuals in COVID-19 infection.

Background: The cross-protective nature of Bacillus Calmette-Guerin (BCG) vaccine against SARS-CoV-2 virus was previously suggested, however its effect in COVID-19 patients with type 2 diabetes (T2D) and the underlying metabolic pathways has not been addressed. This study aims to investigate the difference in the metabolomic patterns of type 2 diabetic patients with BCG vaccination showing different severity levels of COVID-19 infection. Methods: Sixty-seven COVID-19 patients were categorized into diabetic and non-diabetic individuals who had been previously vaccinated or not with BCG vaccination. Targeted metabolomics were performed from serum samples from all patients using tandem mass spectrometry. Statistical analysis included multivariate and univariate models. Results: Data suggested that while BCG vaccination may provide protection for individuals who do not have diabetes, it appears to be linked to more severe COVID-19 symptoms in T2D patients (p = 0.02). Comparing the metabolic signature of BCG vaccinated T2D individuals to non-vaccinated counterparts revealed that amino acid (sarcosine), cholesterol esters (CE 20:0, 20:1, 22:2), carboxylic acid (Aconitic acid) were enriched in BCG vaccinated T2D patients, whereas spermidine, glycosylceramides (Hex3Cer(d18:1_22:0), Hex2Cer(d18:1/22:0), HexCer(d18:1/26:1), Hex2Cer(d18:1/24:0), HexCer(d18:1/22:0) were higher in BCG vaccinated non- T2D patients. Furthermore, data indicated a decrease in sarcosine synthesis from glycine and choline and increase in spermidine synthesis in the BCG vaccinated cohort in T2D and non-T2D groups, respectively. Conclusion: This pilot study suggests increased severity of COVID-19 in BCG vaccinated T2D patients, which was marked by decreased sarcosine synthesis, perhaps via lower sarcosine-mediated removal of viral antigens.

Arterial pulsation modulates the optical attenuation coefficient of skin.

Photoplethysmographic (PPG) signals arise from the modulation of light reflectivity on the skin due to changes of physiological origin. Imaging plethysmography (iPPG) is a video-based PPG method that can remotely monitor vital signs in a non-invasive manner. iPPG signals result from skin reflectivity modulation. The origin of such reflectivity modulation is still a subject of debate. Here, we have used optical coherence tomography (OCT) imaging to find whether iPPG signals may result from skin optical properties being directly or indirectly modulated by arterial transmural pressure propagation. The light intensity across the tissue was modeled through a simple exponential decay (Beer-Lambert law) to analyze in vivo the modulation of the optical attenuation coefficient of the skin by arterial pulsation. The OCT transversal images were acquired from a forearm of three subjects in a pilot study. The results show that the optical attenuation coefficient of skin changes at the same frequency as the arterial pulsation due to transmural pressure propagation (local ballistographic effect), but we cannot discard the contribution of global ballistographic effects.

A Novel 3D Volumetric Method of Analyzing Gingival Positional and Dimensional Alterations During Orthodontic Therapy: A Pilot Study.

The aim of the present study was to develop a 3D digital image-analysis method to quantitatively assess gingival changes after clear-aligner orthodontic therapy. Using teeth as fixed reference points, 3D image analysis tools have been used to quantify mucosal level changes after specific therapies. This technology has not been applied to orthodontic therapy, primarily because orthodontic tooth movement precludes using teeth as fixed reference points. Rather than superimposing the pre- and posttherapy volumes for the entire dentition, the methodology presented herein superimposed the pre- and post-therapy volumes for individual teeth. The lingual tooth surfaces, which remained unaltered, were used as fixed references. Intraoral scans taken before and after clear-aligner orthodontic therapy were imported for comparison. Volumes were created for each 3D image and were superimposed in a 3D image-analysis software that allowed quantitative measurements. The results demonstrated this technique's ability to measure very small changes in the apicocoronal position of the gingival zenith, as well as alterations of gingival margin thickness, following clear-aligner orthodontic therapy. The present 3D image-analysis method offers a useful tool for investigating the periodontal dimensional and positional changes that accompany orthodontic therapy.

Modified-dropless protocol (nil intraocular) for micro-incision vitrectomy surgery (MIVS): a retrospective pilot study.

BACKGROUND: Perioperative infection and inflammation prophylaxis after ocular surgery has evolved over the years along with improvements in surgical equipment and a growing interest in alternatives to the standard topical eye drops. The purpose of this study is to evaluate the outcomes of a novel, modified-dropless protocol for 23-gauge (23-G), 25-gauge (25-G) and 27-gauge (27-G) micro-incision vitrectomy surgery (MIVS) that omits any intraocular injections of antibiotics or steroids. METHODS: This Institutional Review Board-approved, single-surgeon retrospective study reviewed MIVS post-surgical outcomes in patients who received a modified-dropless protocol from February 2020 to March 2021. A total of 158 charts were reviewed, of which 150 eyes met the eligibility criteria. After each case, patients were administered a 0.5 cc subconjunctival injection of a 1:1 Cefazolin (50 mg/cc):Dexamethasone (10 mg/cc) in the inferior fornix and 0.5 cc of posterior Sub-Tenon's Kenalog (STK). No intravitreal injections were administered, and no pre- or postoperative antibiotic or steroid eye drops were prescribed. For patients allergic to penicillin, separate subconjunctival injections of 0.25 cc each of Vancomycin (10 mg/cc) and Dexamethasone (10 mg/cc) were administered. The primary safety parameter was postoperative cases of endophthalmitis. Secondary endpoints consisted of Best-Corrected Distance Visual Acuity (BCVA), intraocular pressure (IOP), and postoperative complications (retinal detachments, inflammation, need for additional surgery) within three months of surgery. Statistical analysis was performed using chi-square (χ²) tests for categorical values, and a Student's t-test to compare continuous outcomes. RESULTS: The majority of surgeries (96%) were performed with the 27G MIVS platform. There were no cases of postoperative endophthalmitis. Mean logMAR BCVA improved from 0.71 (± 0.67) to 0.61 (± 0.60) post-operatively (p = 0.02). Excluding patients who had silicone oil tamponade, postoperative BCVA improved from 0.67 (± 0.66) to 0.54 (± 0.55) (p = 0.003). Mean IOP increased from 14.6 (± 3.8) to 15.3 (± 4.1) (p = 0.05). Ten patients required further medication therapy for an increase in IOP, one had inflammatory signs, and 14 required a second surgical intervention mostly due to recurrences of initial surgical indication. CONCLUSION: A modified-dropless postoperative protocol involving subconjunctival and posterior sub-Tenon's injections only may be a safe and convenient alternative to topical eye drops for patients undergoing MIVS, but additional and larger studies are needed.

A pilot clinical study of complex rhegmatogenous retinal detachment treatment via foldable capsular buckle scleral buckling.

BACKGROUND: To evaluate the feasibility of and identify problems in treating complex rhegmatogenous retinal detachment using foldable capsular buckle scleral buckling. METHODS: This prospective clinical study enrolled five patients with complex rhegmatogenous retinal detachment treated with foldable capsular buckle scleral buckling at the 988th Hospital of People's Liberation Army Joint Logistic Force, China. During the 24-week follow-up period, the patients underwent measurements of their best-corrected visual acuity, slit-lamp examination, indirect ophthalmoscopy, and visual field testing. Additionally, B-ultrasound and fundus photography of the patients' retinal reattachments helped evaluate the treatment's post-surgery efficacy. We determined the safety of foldable capsular buckle scleral buckling based on infection, eye pain, diplopia, elevated intraocular pressure, and other postoperative severe complications. RESULTS: All five patients' complex rhegmatogenous retinal detachments were successfully treated and evaluated via B-ultrasound and fundus photography after surgery. Visual acuity was enhanced in four patients 24 weeks after surgery, while the remaining patients developed diplopia after surgery. No other complications were observed. CONCLUSION: This pilot study preliminarily determined that foldable capsular buckle scleral buckling is feasible for efficient and safe treatment of complex rhegmatogenous retinal detachment. These results support this surgery as a potential and novel alternative to current extraocular procedures for treating complex rhegmatogenous retinal detachment. TRIAL REGISTRATION: The prospective observational clinical study protocol was approved by the Institutional Review Board and Ethics Committee and registered at the clinical research center in the 988th Hospital of People's Liberation Army Joint Logistic Force, China (9,882,019,000).

Implementation of a referral pathway for cancer survivors to access allied health services in the community.

BACKGROUND: The growing demands for multidisciplinary cancer survivorship care require new approaches to address the needs of people living after a cancer diagnosis. Good Life-Cancer Survivorship is a self-management support survivorship program delivered by community allied health (AH) services for people diagnosed with cancer. A pilot study established the benefits of Good Life-Cancer Survivorship to help survivors manage their health and wellbeing in the community health setting. This study expanded the program to four community health services and evaluated the implementation outcomes of the referral pathway to the survivorship program. METHODS: Eligible cancer survivors attending hospital oncology services were referred to the survivorship program. Data was collected between 19/02/2021-22/02/2022 and included allied health service utilisation, consumer surveys, and interviews to understand consumer experience with the referral pathway. Interviews and focus groups with hospital and community health professionals explored factors influencing the referral uptake. Implementation outcomes included Adoption, Acceptability, Appropriateness, Feasibility, and Sustainability. RESULTS: Of 35 eligible survivors (mean age 65.5 years, SD = 11.0; 56% women), 31 (89%) accepted the referral. Most survivors had two (n = 14/31; 45%) or more (n = 11/31; 35%) allied health needs. Of 162 AH appointments (median appointment per survivor = 4; range = 1-15; IQR:5), 142/162 (88%) were scheduled within the study period and 126/142 (89%) were attended. Consumers' interviews (n = 5) discussed the referral pathway; continuation of survivorship care in community health settings; opportunities for improvement of the survivorship program. Interviews with community health professionals (n = 5) highlighted the impact of the survivorship program; cancer survivorship care in community health; sustainability of the survivorship program. Interviews (n = 3) and focus groups (n = 7) with hospital health professionals emphasised the importance of a trusted referral process; a holistic and complementary model of care; a person-driven process; the need for promoting the survivorship program. All evaluations favourably upheld the five implementation outcomes. CONCLUSIONS: The referral pathway provided access to a survivorship program that supported survivors in self-management strategies through tailored community allied health services. The referral pathway was well adopted and demonstrated acceptability, appropriateness, and feasibility. This innovative care model supports cancer survivorship care delivery in community health settings, with clinicians recommending sustaining the referral pathway.

Accessibility to and awareness of rheumatology care provided by a nurse - a pilot study.

INTRODUCTION: Good medical care depends both on the access to specialists and awareness of patients and healthcare professionals. AIM: The purpose of this study was to assess the accessibility to rheumatology outpatient care and the awareness of patients with inflammatory joint diseases with regard to the types of sources and preferences of sources for obtaining information related to their disease and treatment, as well as to establish the extent to which this information is useful to patients. MATERIALS AND METHODS: A pilot, cross-sectional, single center, anonymous study was conducted among adult patients with inflammatory joint diseases who were monitored in an outpatient rheumatology room at St George Diagnostic and Consultative Center in Plovdiv. A total of 56 patients were monitored. The questionnaire contained 56 questions, divided into 5 main groups: 1. questions about the disease, 2. questions about the sociodemographic profile of the patients, 3. questions about accessibility to specialized healthcare, 4. questions about the role of the nurse in the training of patients with inflammatory joint disease, and 5. questions evaluating the attitude to the monitoring medical team. The data were analyzed with IBM SPSS V.26, at a statistical significance level of p<0.05 for all analyses. RESULTS: Women predominated among the patients under observation (37, 66%), as well as patients in the age group of 50-79 years (46, 82%). Twenty-four (42.9%) were the patients attending the consulting room twice a year. On-the-spot booking in the consulting room was preferred mainly among patients who lived within 50 km (3/16, 19%), while the rest of the patients preferred booking appointments by phone. Forty-five (80%) patients of the total number of patients used subcutaneous biological agents. Among them, the patients whose first application was performed by a nurse in a rheumatology room predominated (44 patients, 96%). All respondents (56, 100%) indicated that they had received self-injection training from a healthcare professional. CONCLUSION: Patients with inflammatory joint diseases need information to help them manage issues related to their disease and treatment, as well as cope with their physical and psychological needs. Our study shows that patients most commonly use a combination of information sources - they get information from a doctor or from a healthcare professional, i.e. a nurse. We highlighted in the study the crucial role of nurses in improving the access of patients to specialized rheumatology care and satisfying patients' information needs.

[Analysis of the quality of preventive examinations of children (according to the survey of dentists)]. / Analiz kachestva provedeniya profilakticheskikh osmotrov detei (po dannym anketirovaniya vrachei-stomatologov).

OBJECTIVE: To improve the methodology for conducting preventive examinations of children by a dentist by identifying and preventing the risks of achieving their qualitative results. MATERIAL AND METHODS: A test version of the questionnaire was created, which was tested in a pilot study to assess validity and correction. A survey of 100 general dentists in Smolensk, Kaluga, Kaliningrad, Tula, who had previously participated in preventive dental examinations of children, was conducted. Questions were asked regarding the problems of organizing inspections, training, proposals for improving inspections. A comparative analysis of the risks of reducing the quality of examinations for each of the regions was carried out, proposals were made to improve the organization and conduct of medical examinations of children. RESULTS: As a result of the survey, a significant similarity of opinions of dentists in four cities of the Russian Federation on the problems and risks of annual preventive examinations of children was established. Among the weaknesses of the process, one should highlight the lack of time to examine the child; lack of specialized premises and a nurse; the absence of a unified form of a dental preventive examination card. This reduces the quality of diagnostics and continuity of medical care. Self-assessment by general practice dentists of their training in relation to diagnostics in children demonstrated a low level of knowledge of the issues of bite pathology, oral mucosa, and age periods of the dentoalveolar system. The lack of medical knowledge of more than 70% of doctors involved in preventive examinations of children is a key risk that requires immediate corrective action. CONCLUSION: The results of this study are the basis for the recommendation of advanced training of dentists at least once every three years on the subject of preventive examinations of children. The process of dental medical examination of the child population needs to be corrected at the legislative and executive levels.

Implementing Home-Based Clinical Research for Caregivers and Persons with Stroke: Lessons Learned.

Conducting research in the home environment presents challenges related to setting, study participants, methods, and researchers. Researchers should be aware of potential challenges to ensure rigor and improve planning for future studies. This paper describes difficulties experienced and lessons learned when conducting a two-group, randomized pilot study (n = 32) of a web-based intervention (Carepartner and Constraint-Induced Therapy [CARE-CITE]) designed to foster positive carepartner engagement in home-based activities to improve upper extremity function in persons with stroke. Challenges and issues included: 1) recruitment and referral, 2) data collection in the home setting, 3) participants' understanding of the rationale for adhering to constraint-induced movement therapy principles (wearing mitt on the less-affected limb), 4) tracking adherence of upper extremity practice time, 5) participant-driven goal setting, 6) potentially unsafe participant practice activities, 7) home visit safety, 8) encouraging versus controlling-using autonomy support, 9) participant needs beyond study scope, and 10) ethical safeguards for addressing depressive symptoms. Researchers can incorporate suggested strategies to support methodological rigor and facilitate interventions engaging carepartners in the rehabilitation process when planning for research in the home environment.

Accuracy of age estimation using root dentin translucency in Peruvian adults. A pilot study.

INTRODUCTION: Age estimation is an important forensic resource in human identification. Amongst the different methods of dental age estimation, root dentin transparency (RDT) is considered a reliable parameter, as well as an indicator of chronological age at time of death in human adult remains. The aim of this study was to estimate the age of individuals using the Bang and Ramm method and to derive a new formula suitable for age estimation in the Peruvian population by assessing the length and percentage length of RDT. MATERIALS AND METHODS: The sample consisted of 248 teeth collected from 124 deceased individuals, between the ages of 30 and 70 years. RDT length was digitally measured from sectioned and photographed teeth. Linear and quadratic regressions were made to derive Peruvian formulae and the new formulae were applied to another group of samples (n=30). RESULTS: Data showed a significant correlation (p<0.01) between chronological age and translucency length (Pearson´s correlation=0.775) and percentage length (Pearson´s correlation=0.778). Linear and quadratic regressions for obtaining Peruvian formulae showed that quadratic equations expressed greater determination coefficients. Comparisons between estimated age using Peruvian formulae showed that dental age from percentage of length of RDT a higher percentage of estimates with errors <± 05 and <± 10 years. The accuracy of the new Peruvian formula using the percentage of length of RDT (MAE=7.83) can be considered acceptable. CONCLUSION: As shown in the results, age estimation using the Peruvian formula derived from the percentage of length of RDT has proven to be more accurate than estimates using the Bang and Ramm method. Thus, it could be used in age estimation for Peruvian individuals, as it is the most accurate methods and provides a larger number of acceptable estimates.

Psycho-Cognitive Profile and NGF and BDNF Levels in Tears and Serum: A Pilot Study in Patients with Graves' Disease.

Nerve Growth Factor (NGF) and Brain derived Neurotrophic Factor (BDNF) mature/precursor imbalance in tears and serum is suggested as a risk factor and symptomatology aggravation in ophthalmology and neuropsychiatric disturbances. Cognitive and mood alterations are reported by patients with Graves' Orbitopathy (GO), indicating neurotrophin alterations might be involved. To address this question, the expression levels of NGF and BDNF and their precursors in serum and tears of GO patients were analyzed and correlated with the ophthalmological and psycho-cognitive symptoms. Hamilton Rating Scale for Anxiety (HAM-A) and Depression (HAM-D), Temperament and Character Inventory (TCI), and Cambridge Neuropsychological Test Automated Battery (CANTAB) test were used as a score. NGF and BDNF levels were measured using ELISA and Western Blot and statistically analyzed for psychiatric/ocular variable trend association. GO patients show memorization time and level of distraction increase, together with high irritability and impulsiveness. HAM-A and CANTAB variables association, and some TCI dimensions are also found. NGF and BDNF expression correlates with ophthalmological symptoms only in tears, while mature/precursor NGF and BDNF correlate with the specific psycho-cognitive variables both in tears and serum. Our study is the first to show that changes in NGF and BDNF processing in tears and serum might profile ocular and cognitive alterations in patients.

Blood-Based Proteomic Profiling Identifies Potential Biomarker Candidates and Pathogenic Pathways in Dementia.

Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic studies have emerged as a promising approach for identifying the protein biomarkers associated with dementia. This pilot study aimed to investigate the plasma proteome profile and identify a panel of various protein biomarkers for dementia. We used a high-throughput proximity extension immunoassay to quantify 1090 proteins in 122 participants (22 with dementia, 64 with mild cognitive impairment (MCI), and 36 controls with normal cognitive function). Limma-based differential expression analysis reported the dysregulation of 61 proteins in the plasma of those with dementia compared with controls, and machine learning algorithms identified 17 stable diagnostic biomarkers that differentiated individuals with AUC = 0.98 ± 0.02. There was also the dysregulation of 153 plasma proteins in individuals with dementia compared with those with MCI, and machine learning algorithms identified 8 biomarkers that classified dementia from MCI with an AUC of 0.87 ± 0.07. Moreover, multiple proteins selected in both diagnostic panels such as NEFL, IL17D, WNT9A, and PGF were negatively correlated with cognitive performance, with a correlation coefficient (r2) ≤ -0.47. Gene Ontology (GO) and pathway analysis of dementia-associated proteins implicated immune response, vascular injury, and extracellular matrix organization pathways in dementia pathogenesis. In conclusion, the combination of high-throughput proteomics and machine learning enabled us to identify a blood-based protein signature capable of potentially differentiating dementia from MCI and cognitively normal controls. Further research is required to validate these biomarkers and investigate the potential underlying mechanisms for the development of dementia.

Reference Values on Children's Hair for 28 Elements (Heavy Metals and Essential Elements) Based on a Pilot Study in a Representative Non-Contaminated Local Area.

Studies have been published, and laboratories offer services of measuring elements in hair as biomarkers of environmental exposure and/or control of essential elements (trace or macro). These reported values can have only sense if compared with adopted reference values. In this work, we propose provisional reference values based on a pilot child population. The concentrations of 28 elements were measured in children's hair samples. An observational, descriptive, cross-sectional study was conducted in a typical child population in the Mediterranean region void of excessive pollution problems to analyze 419 hair samples of children aged 3-12 years. Children were selected by a simple random method from eight primary education schools in different municipal districts, which included urban, rural and industrial areas. Samples of around 100 mg were washed and acid digested by an optimized procedure. All measures were performed using ICP-MS with Sc, Y and Re as internal standards. The statistical analysis was performed by two approaches: (a) considering all the data and (b) without outliers (second-order atypical data) to compare them with other published studies. The distribution curves in all the elements studied were asymmetric and did not fit the theoretical normality distributions. Therefore, the analysis based on percentiles was more appropriate. In most elements, only slight differences were observed with sex or age, which did not justify proposing separate reference ranges. From the results of this study, provisional reference values are proposed following two criteria: (a) simple application of the table of percentiles built by removing outlier values and (b) values after a detailed analysis case-by-case, considering other data as the distribution profile and other published data of each element. Although the pilot sample was from a limited area, it was carefully selected to be representative of a general non-contaminated population. With this limitation, the proposed reference values might be useful for researchers and physicians until a wider geographical study is available for a large number of elements.

Electrical Bioimpedance Analysis for Evaluating the Effect of Pelotherapy on the Human Skin: Methodology and Experiments.

BACKGROUND: Pelotherapy is the traditional procedure of applying curative muds on the skin's surface-shown to have a positive effect on the human body and cure illnesses. The effect of pelotherapy is complex, functioning through several mechanisms, and depends on the skin's functional condition. The current research objective was to develop a methodology and electrodes to assess the passage of the chemical and biologically active compounds of curative mud through human skin by performing electrical bioimpedance (EBI) analysis. METHODS: The methodology included local area mud pack and simultaneous tap water compress application on the forearms with the comparison to the measurements of the dry skin. A custom-designed small-area gold-plated electrode on a rigid printed circuit board, in a tetrapolar configuration, was designed. A pilot study experiment with ten volunteers was performed. RESULTS: Our results indicated the presence of an effect of pelotherapy, manifested by the varying electrical properties of the skin. Distinguishable difference in the measured real part of impedance (R) emerged, showing a very strong correlation between the dry and tap-water-treated skin (r = 0.941), while a poor correlation between the dry and mud-pack-treated skin (r = 0.166) appeared. The findings emerged exclusively in the frequency interval of 10 kHz …1 MHz and only for R. CONCLUSIONS: EBI provides a promising tool for monitoring the variations in the electrical properties of the skin, including the skin barrier. We foresee developing smart devices for promoting the exploitation of spa therapies.

A new method for investigating bioequivalence of inhaled formulations: A pilot study on salbutamol.

Purpose: An efficient, cost-effective and non-invasive test is required to overcome the challenges faced in the process of bioequivalence (BE) studies of various orally inhaled drug formulations. Two different types of pressurized meter dose inhalers (MDI-1 and MDI-2) were used in this study to test the practical applicability of a previously proposed hypothesis on the BE of inhaled salbutamol formulations. Methods: Salbutamol concentration profiles of the exhaled breath condensate (EBC) samples collected from volunteers receiving two inhaled formulations were compared employing BE criteria. In addition, the aerodynamic particle size distribution of the inhalers was determined by employing next generation impactor. Salbutamol concentrations in the samples were determined using liquid and gas chromatographic methods. Results: The MDI-1 inhaler induced slightly higher EBC concentrations of salbutamol when compared with MDI-2. The geometric MDI-2/MDI-1 mean ratios (confidence intervals) were 0.937 (0.721-1.22) for maximum concentration and 0.841 (0.592-1.20) for area under the EBC-time profile, indicating a lack of BE between the two formulations. In agreement with the in vivo data, the in vitro data indicated that the fine particle dose (FPD) of MDI-1 was slightly higher than that for the MDI-2 formulation. However, the FPD differences between the two formulations were not statistically significant. Conclusion: EBC data of the present work may be considered as a reliable source for assessment of the BE studies of orally inhaled drug formulations. However, more detailed investigations employing larger sample sizes and more formulations are required to provide more evidence for the proposed method of BE assay.

Examining the neural mechanisms of rTMS: a naturalistic pilot study of acute and serial effects in pharmacoresistant depression.

Introduction: Previous studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course. Methods: A total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR). Results: We found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820, p = 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37, p = 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093, p = 0.017) and IDS-SR (t (14) = 2.5278, p = 0.024) and progressed along the treatment course. Discussion: Our findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response.

Analysis of Clinical Laboratory Detecting Challenging Variants from Exome Sequencing Using Simulated Patient-Parent Trio Sample: Pilot Study for Neurodevelopmental Disorder de Novo Variants.

To date, there has been no systematic analysis for the clinical laboratory in detecting technically challenging variants using the trio-based exome sequencing (ES) approach. Here, we present an interlaboratory pilot proficiency testing study that used synthetic patient-parent specimens to assess the detection of challenging variants with de novo dominant inheritance modes for neurodevelopmental disorders using various trio-based ES. In total, 27 clinical laboratories that performed diagnostic exome analyses participated in the survey. One of the 26 challenging variants was identified by all laboratories, whereas all 26 variants were identified by only nine laboratories. The lack of identification of mosaic variants was often due to the bioinformatics analysis that excluded the variant. For missing intended heterozygous variants, probable root causes were related to the technical bioinformatics pipeline and variant interpretation and reporting. For each missing variant, there may be more than one probable reason from the different laboratories. There was considerable variation in interlaboratory performance for detecting challenging variants using trio-based ES. This finding may have important implications for the design and validation of tests for different variant types in clinical laboratories, especially for technically challenging variants, and necessary workflow modification can potentially improve trio-based ES performance.

Transplantation for metastatic liver disease.

The liver is a common site of metastases from many cancers, particularly those originating in the gastrointestinal tract. Liver transplantation is an uncommonly used but promising and at times controversial treatment option for neuroendocrine and colorectal liver metastases. Transplantation with meticulous patient selection has been associated with excellent long-term outcomes in individuals with neuroendocrine liver metastases, but questions remain regarding the role of transplantation in those who could also be eligible for hepatectomy, the role of neoadjuvant/adjuvant treatments in minimising recurrence, and the optimal timing of the procedure. A prospective pilot study of liver transplantation for unresectable colorectal liver metastases that reported a 5-year overall survival rate of 60% reinvigorated interest in this area following initially dismal outcomes. This has been followed by larger studies, and prospective trials are ongoing to quantify the potential benefits of liver transplantation over palliative chemotherapy. This review provides a critical summary of currently available knowledge on liver transplantation for neuroendocrine and colorectal liver metastases, and highlights avenues for further study to address gaps in the evidence base.

Peracetic acid as a disinfectant for wastewater reuse - Regulation (EU) 2020/741 application on a pilot-scale.

Water scarcity affects already a large part of the world's population. To overcome this situation, water management is needed, and wastewater reuse must be implemented and included as a new approach. To achieve that objective water quality must comply with the parameters established in the Regulation (EU) 2020/741 of the European Parliament and the Council of the European Union and new treatment solutions have to be developed. The main goal of this pilot study was to evaluate the peracetic acid (PAA) disinfection efficiency in a real wastewater treatment plant (WWTP) in order to accomplish the wastewater reuse objective. To this end, six disinfection conditions were studied, three PAA doses (5, 10, and 15) and three contact times (5, 10, and 15) based on the commonly used disinfection operational conditions in real WWTP. Comparing the Total Suspended Solids (TSS), turbidity, Biological Oxygen Demand (BOD5) and Escherichia coli content, after and before the disinfection step, was possible to conclude that PAA ensures the Regulation (EU) 2020/741 requirements and that the disinfected effluent can be reused for several uses. All the conditions in which the PAA dose was 15 mg/L and the condition with 10 mg/L of PAA with a contact time of 15 min were the most promising, presenting the second highest water quality class achieved. The results of this study illustrate the potential of PAA as an alternative disinfectant for wastewater treatment and, bring it closer to the water reuse objective by presenting several possibilities for water uses.