Action sequence learning, habits, and automaticity in obsessive-compulsive disorder.

This study investigates the goal/habit imbalance theory of compulsion in obsessive-compulsive disorder (OCD), which postulates enhanced habit formation, increased automaticity, and impaired goal/habit arbitration. It directly tests these hypotheses using newly developed behavioral tasks. First, OCD patients and healthy participants were trained daily for a month using a smartphone app to perform chunked action sequences. Despite similar procedural learning and attainment of habitual performance (measured by an objective automaticity criterion) by both groups, OCD patients self-reported higher subjective habitual tendencies via a recently developed questionnaire. Subsequently, in a re-evaluation task assessing choices between established automatic and novel goal-directed actions, both groups were sensitive to re-evaluation based on monetary feedback. However, OCD patients, especially those with higher compulsive symptoms and habitual tendencies, showed a clear preference for trained/habitual sequences when choices were based on physical effort, possibly due to their higher attributed intrinsic value. These patients also used the habit-training app more extensively and reported symptom relief post-study. The tendency to attribute higher intrinsic value to familiar actions may be a potential mechanism leading to compulsions and an important addition to the goal/habit imbalance hypothesis in OCD. We also highlight the potential of smartphone app training as a habit reversal therapeutic tool.

Non-invasive surveillance of shared pathogens in the Eurasian brown bear (Ursus arctos) human interface.

Multi-host communities are perfect scenarios for the emergence and spread of pathogens, threatening the recovery of endangered, isolated, or inbred populations, such as the brown bear (Ursus arctos) in northwestern Spain. The population recovery in recent years has forced bears to occupy highly anthropized areas, increasing their interaction with human and domestic animals, with potential consequences for global health. During 2022-2023 a survey of parasites, bacteria and viruses shared between wildlife, domestic animals and humans was performed in this population using non-invasive surveillance, i.e., bear fecal samples (n = 73) and sponge-based sampling of trees (n = 42; 14 rubbed trees and 28 control trees). Pathogen detection rates were defined as the percentage of qPCR or culture-positive samples. Generalized linear models were fitted to assess their relationship with environmental variables including dispersion of the human population, and percentage of agricultural and periurban habitats in a 6 km-buffer around each sample. Canine Adenovirus type 1 (45.2%), Giardia spp. (15.1%), Salmonella spp. (12.3%), and extended-spectrum-beta-lactamases (ESBL) Escherichia coli (1.4%) were identified in fecal samples. In contrast, only five sponges from three rubbed and two control trees resulted positive to E. coli (14.3%). The results suggest that several pathogens are common in the Cantabrian brown bear population and that anthropization of the territory modulates their prevalence and richness. The effective design of management programs for bear conservation will require a one-health approach, in which genetic analysis of non-invasive samples can be key tools for the sanitary surveillance at the wildlife-livestock-human interface.

¿Cómo mejoramos la participación comunitaria en salud? Análisis de las acciones propuestas tras la aplicación de una herramienta de evaluación / How to improve community engagement in health: Analysis of proposed actions following the implementation of a community engagement assessment tool

Objetivo Analizar las líneas de acción propuestas por los proyectos de promoción de la salud participantes en el proyecto de investigación EvaluAGPS, y su relación con las puntuaciones obtenidas con EvalGuía, una herramienta para evaluar la participación comunitaria basada en la evidencia. Diseño Estudio multicéntrico cuali-cuantitativo. Emplazamiento Proyectos de atención primaria o de red intersectorial de atención primaria y municipalidades de 5 comunidades autónomas en España. Participantes Personas que trabajan en 10 proyectos de promoción de la salud, seleccionados con muestreo intencional según criterios de inclusión (proyectos con un mínimo de participación comunitaria centrados en la salud comunitaria). Método Se recogieron los datos mediante cuestionarios (herramienta EvalGuía) y talleres participativos. Los datos cuantitativos se analizaron con estadística descriptiva, los datos cualitativos se analizaron utilizando el análisis de matriz. Resultados Tras pasar la herramienta EvalGuía, las puntuaciones más bajas estaban en la evaluación de resultados, conocimiento de leyes relacionadas con participación comunitaria, diversidad en el grupo motor, medidas de conciliación, recursos financieros y devolución de resultados. Las líneas de acción planteadas eran heterogéneas y no siempre coinciden con las priorizadas. Las líneas priorizadas giraban en torno a la organización del proyecto y a la comunicación. Conclusiones La herramienta EvalGuía puede ser útil para diseñar planes de acción en proyectos de promoción de la salud. La implementación de medidas en 12 meses para aumentar la diversidad del grupo motor, incorporar medidas de conciliación o mejorar la evaluación es difícil. Se requiere más tiempo para implementar este tipo de medidas. (AU)

Objective To analyse the lines of action identified in the health promotion projects participating in the EvaluA GPS research, and their relationship with the scores assigned in EvalGuia, a tool for evaluating evidence-based community participation. Design Qualitative-quantitative multicentre study. Setting Primary care or intersectoral network of primary care and municipalities in five autonomous communities in Spain. Participants Participants of 10 health promotion projects, selected with convenience sampling, following inclusion criteria (projects with a minimum of community engagement and centred on community health). Method Data were collected through questionnaires (EvalGuía tool) and participatory workshops. Quantitative data were analysed with descriptive statistics, qualitative data were analysed using matrix analysis. Results After implementing the EvalGuide tool, the lowest scores were assigned in outcome evaluation, knowledge of policies related to community participation, diversity in the core working group, inclusivity policies, financial resources and diffusion of results. The lines of action proposed were heterogeneous and did not always match with those prioritised as lower score. The prioritised lines revolved around project organisation and communication. Conclusions The EvalGuide tool can be helpful to design action plans in Health Promotion projects. The implementation of measures in 12 months to increase the diversity of the core working group, to incorporate work–life balance measures or to improve evaluation is difficult. More time is needed to implement such measures. (AU)

Soluble urokinase plasminogen activator receptor is associated with kidney disease and its progression in sickle cell anemia.

Not available.

DLPNO-CCSD(T) and DFT study of the acetate-assisted C-H activation of benzaldimine at [RuCl2(p-cymene)]2: the relevance of ligand exchange processes at ruthenium(II) complexes in polar protic media.

To gain mechanistic insights into the acetate-assisted cyclometallations of arylimines promoted by [RuCl2(p-cymene)]2 in polar protic media, DFT geometry optimizations (with M06 and ωB97X-D3 functionals and the cc-pVDZ-PP[Ru] basis set) followed by DLPNO-CCSD(T)/CBS energy evaluations were performed using benzaldimine as a model substrate and methanol as the solvent (with CPCM or SMD models). The calculation results show that coordination of the imine to an acetate ruthenium precursor is followed by anion (chloride or acetate) dissociation as the rate-determining step of the process. H-Bonding of two explicit MeOH to the anion reduces the calculated activation energy to ca. 23 kcal mol-1, in good agreement with the experimental half-life at room temperature. Subsequent AMLA/CMD C-H activation of the intermediate cationic complexes is a faster, reversible process. Alternative reaction pathways involving neutral diacetate ruthenium complexes offer AMLA/CMD transition state structures of lower energy but are precluded due to higher energy barriers for the initial ligand exchange processes at ruthenium. Solvent assistance accelerates the final chloride/acetate exchange processes on the cycloruthenate intermediates, particularly when compression in the condensed phase is taken into consideration. The performance of six DFT functionals (with the aug-pVTZ-PP[Ru] basis set) was assessed using the DLPNO-CCSD(T)/CBS reference energies. Neutral diacetate ruthenium complexes were incorrectly predicted as being kinetically relevant when using hybrid DFT methods (PBE0-D3(BJ), M06-2X or ωB97M-V). Good agreement between the calculated barrier heights and our benchmark energy results was obtained by using double-hybrid DFT methods. PWPB95 with D3(BJ) or D4 dispersion energy corrections was found to be the most accurate (ΔG≠ MUE of ca. 1 kcal mol-1). This study may aid our understanding of and help with further experimental investigations of synthetically useful carboxylate-assisted C-H bond functionalizations involving (N,C)-cyclometallated (p-cymene)Ru(II) intermediate complexes in sustainable polar protic solvents.

Bullous Lung Disease due to Pulmonary Tuberculosis: A Rare Case Complicated With Tension Pneumothorax and Bronchopleural Fistula.

Bullous lung disease caused by tuberculosis is rare, and complications have a poor prognosis with uncertain pathophysiologic mechanisms. We describe a 29-year-old male patient who was admitted to the emergency department due to bilateral tension pneumothorax, which was complicated by bronchopleural fistula. This was managed with the placement of chest tubes, continuity of anti-TB drug treatment, and Heimlich valve placement.

Prevalence of kidney health genetic variants in adults with sickle cell nephropathy.

The pathophysiology and genetic risk for sickle cell disease (SCD)-related chronic kidney disease (CKD) are not well understood. In 70 adults with SCD-related CKD and without APOL1 inherited in a high-risk pattern, 24 (34%) had pathogenic variants in candidate genes using KidneySeq™. A moderate impact INF2 variant was observed in 20 (29%) patients and those with 3 versus 0-2 pathogenic or moderate impact glomerular genetic variants had higher albuminuria and lower estimated glomerular filtration rate (adjusted p ≤ 0.015). Using a panel of preselected genes implicated in kidney health, we observed several variants in people with sickle cell nephropathy.

Typology and characterization of the agricultural productive units in the NE Amazonian region of Ecuador.

Objective: Many studies have observed different characteristics among productive systems in the rural territories of Latin America. Therefore, understanding and characterizing them while they function plays an essential role in determining their relationship between development and environment. A study has been conducted in the Orellana province of NE Ecuador to determine their typology and then classify them according to the variables that describe their main traits or attributes using cluster analysis (CA). Materials and Methods: A survey was structured to investigate physical, productive, environmental, as well as socioeconomic character variables, which were subsequently applied to a random sample of the 5,963 agricultural productive units (APUs) through face-to-face contact with producers during an in situ visit to their farms. Result: The CA allowed us to identify three typologies of APUs in the Orellana Province. The first has been Type 1, which is denominated as the most conventional (40%), while Type 2 uses more efficient natural resources but represents an amount of only 9.4%. In contrast, type 3 (50.6%) depends on a significant part of local or national development programs. Conclusion: All groups indicated some peculiarities in common, as there were marked differences in the use and distribution of land as well as production methods among them. Consequently, this pioneering study allowed us to identify different production methods. Therefore, we encourage local and national governments to establish policies for natural resource conservation in such high-diversity zones.

A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study.

Inherited hearing impairment is a remarkably heterogeneous monogenic condition, involving hundreds of genes, most of them with very small (< 1%) epidemiological contributions. The exception is GJB2, the gene encoding connexin-26 and underlying DFNB1, which is the most frequent type of autosomal recessive non-syndromic hearing impairment (ARNSHI) in most populations (up to 40% of ARNSHI cases). DFNB1 is caused by different types of pathogenic variants in GJB2, but also by large deletions that keep the gene intact but remove an upstream regulatory element that is essential for its expression. Such large deletions, found in most populations, behave as complete loss-of-function variants, usually associated with a profound hearing impairment. By using CRISPR-Cas9 genetic edition, we have generated a murine model (Dfnb1em274) that reproduces the most frequent of those deletions, del(GJB6-D13S1830). Dfnb1em274 homozygous mice are viable, bypassing the embryonic lethality of the Gjb2 knockout, and present a phenotype of profound hearing loss (> 90 dB SPL) that correlates with specific structural abnormalities in the cochlea. We show that Gjb2 expression is nearly abolished and its protein product, Cx26, is nearly absent all throughout the cochlea, unlike previous conditional knockouts in which Gjb2 ablation was not obtained in all cell types. The Dfnb1em274 model recapitulates the clinical presentation of patients harbouring the del(GJB6-D13S1830) variant and thus it is a valuable tool to study the pathological mechanisms of DFNB1 and to assay therapies for this most frequent type of human ARNSHI.

CLI: A new protocol for the isolation of Lactic Acid Bacteria from complex plant samples.

Lactic Acid Bacteria (LAB) are predominantly probiotic microorganisms and the most are Generally Recognized As Safe (GRAS). LAB inhabit in the human gut ecosystem and are largely found in fermented foods and silage. In the last decades, LAB have also has been found in plant microbiota as a new class of microbes with probiotic activity to plants. For this reason, today the scientific interest in the study and isolation of LAB for agronomic application has increased. However, isolation protocols from complex samples such as plant tissues are scarce and inefficient. In this study, we developed a new protocol (CLI, Complex samples LAB Isolation) which yields purified LAB from plants. The sensitivity of CLI protocol was sufficient to isolate representative microorganisms of LAB genera (i.e. Leuconostoc, Lactococcus and Enterococcus). CLI protocol consists on five steps: i) sample preparation and pre-incubation in 1% sterile peptone at 30 °C for 24-48 h; ii) Sample homogenization in vortex by 10 min; iii) sample serial dilution in quarter-strength Ringer solution, iv) incubation in MRS agar plates with 0.2% of sorbic acid, with 1% of CaCO3, O2 < 15%, at pH 5.8 and 37 °C for 48 h.; v) Selection of single colonies with LAB morphology and CaCO3-solubilization halo. Our scientific contribution is that CLI protocol could be used for several complex samples and represents a useful method for further studies involving native LAB.

Low-dose ionizing γ-radiation elicits the extrusion of neutrophil extracellular traps.

PURPOSE: Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. EXPERIMENTAL DESIGN: NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. RESULTS: Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. CONCLUSIONS: NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity from a Phase I Study of Simlukafusp Alfa (FAP-IL2v) in Advanced/Metastatic Solid Tumors.

PURPOSE: Simlukafusp alfa (FAP-IL2v), a tumor-targeted immunocytokine, comprising an interleukin-2 variant moiety with abolished CD25 binding fused to human immunoglobulin G1, is directed against fibroblast activation protein-α. This phase I, open-label, multicenter, dose-escalation and extension study (NCT02627274) evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of FAP-IL2v in patients with advanced/metastatic solid tumors. METHODS: Participants received FAP-IL2v intravenously once weekly. Dose escalation started at 5 mg; flat dosing (≤25 mg) and intra-participant up-titration regimens (15/20 mg, 20/25 mg, 20/20/35 mg, 20/35/35 mg) were evaluated. Primary objectives were dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended expansion dose, and pharmacokinetics. RESULTS: Sixty-one participants were enrolled. DLTs included fatigue (flat dose 20 mg: n = 1), asthenia (25 mg: n = 1), drug-induced liver injury (up-titration regimen 20/25 mg: n = 1), transaminase increase (20/25 mg: n = 1), and pneumonia (20/35/35 mg: n = 1). Up-titration regimen 15/20 mg was the MTD and was selected as the recommended expansion dose. Increases in peripheral blood absolute immune cell counts were seen for all tested doses (natural killer cells, 13-fold; CD4+ T cells [including Tregs], 2-fold; CD8+ T cells, 3.5-fold), but without any percentage change in Tregs. Clinical activity was observed from 5 mg (objective response rate, 5.1% [n = 3]; disease control rate, 27.1% [n = 16]). Responses were durable (n = 3; 2.8 [censored], 6.3, and 43.4 months). CONCLUSIONS: FAP-IL2v had a manageable safety profile and showed initial signs of antitumor activity in advanced/metastatic solid tumors.

Misperception of body verticality in neurological disorders: A systematic review and meta-analysis.

INTRODUCTION: The internal representation of verticality could be disturbed when a lesion in the central nervous system (CNS) affects the centers where information from the vestibular, visual, and/or somatosensory systems, increasing the risk of falling. OBJECTIVE: The aim was to evaluate the vestibular and somatosensory contribution to the verticality pattern in patients with stroke and other neurological disorders. METHODS: A literature search was performed in PubMed, Scopus, Web of Science, and CINAHL databases. Cross-sectional, case-control, and cohort studies comparing body verticality in patients with stroke or CNS diseases (CNSD) versus healthy controls were selected. Subjective postural vertical (SPV) in roll and pitch planes was used as the primary variable. RESULTS: Ten studies reporting data from 390 subjects were included. The overall effect for CNSD patients showed a misperception of body verticality in roll (standardized mean difference [SMD] = 1.05; 95% confidence interval [CI] .84-1.25) and pitch planes (SMD = 1.03; 95% CI .51-1.55). In subgroup analyses, a high effect was observed in the perception of SPV both in roll and pitch planes in stroke (p = .002) and other CNSD (p < .001). CONCLUSION: These findings suggest a potential misperception of SPV in patients with stroke and other neurological disturbances. Patients with CNSD could present an alteration of vestibular and somatosensory contribution to verticality construction, particularly stroke patients with pusher syndrome (PS), followed by those with PS combined with hemineglect.

Dynamic Workflow Proposal for Continuous Frameless Electromagnetic Neuronavigation in Rigid Neuroendoscopy.

BACKGROUND: Ventriculoscopic neuronavigation has been described in several articles. However, there are different ventriculoscopes and navigation systems. Due to these different combinations, it is difficult to find detailed neuronavigation protocols. We describe, step-by-step, a simple method to navigate both the trajectory until reaching the ventricular system, as well as the intraventricular work. METHODS: We use a rigid ventriculoscope (LOTTA, KarlStorz) with an electromagnetic stylet (S8-StealthSystem, Medtronic). The protocol is based on a modified or 3-dimensionally printed trocar for navigating the extraventricular step and on a modified pediatric nasogastric tube for the intraventricular navigation. RESULTS: This protocol can be set up in less than 10 minutes. The extraventricular part is navigated by introducing the electromagnetic stylet inside the modified or 3-dimensionally printed trocar. Intraventricular navigation is done by combining a modified pediatric nasogastric tube with the electromagnetic stylet inside the endoscope's working channel. The most critical point is to obtain a blunt-bloodless ventriculostomy while achieving perfect alignment of all targeted structures via pure straight trajectories. CONCLUSIONS: This protocol is easy-to-set-up, avoids head rigid-fixation and bulky optical-based attachments to the ventriculoscope, and allows continuous navigation of both parts of the surgery. Since we have implemented this protocol, we have noticed a significant enhancement in both simple and complex ventriculoscopic procedures because the surgery is dramatically simplified.

Estrogen Receptor Expression in DICER1-related Lesions is Associated With the Presence of Cystic Components.

DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving kidney, lung, and female reproductive system. Over 70% of sarcomas in DICER1 tumor predisposition syndrome occur in females. Notably, pediatric cystic nephroma (pCN), a classic DICER1 tumor predisposition syndrome lesion, shows estrogen receptor (ER) expression in stromal cells. There are also renal, hepatic, and pancreatic lesions unassociated with DICER1 tumor predisposition syndrome that have an adult female predominance and are characterized/defined by ER-positive stromal cells. Except for pCN, the expression of ER in DICER1-associated lesions remains uninvestigated. In the present study, ER expression was assessed by immunohistochemistry in 89 cases of DICER1-related lesions and 44 lesions lacking DICER1 pathogenic variants. Expression was seen in stromal cells in pCN and pleuropulmonary blastoma (PPB) types I and Ir, whereas anaplastic sarcoma of kidney and PPB types II and III were typically negative, as were other solid tumors of non-Müllerian origin. ER expression was unrelated to the sex or age of the patient. Expression of ER showed an inverse relationship to preferentially expressed antigen in melanoma (PRAME) expression; as lesions progressed from cystic to solid (pCN/anaplastic sarcoma of kidney, and PPB types I to III), ER expression was lost and (PRAME) expression increased. Thus, in DICER1 tumor predisposition syndrome, there is no evidence that non-Müllerian tumors are hormonally driven and antiestrogen therapy is not predicted to be beneficial. Lesions not associated with DICER1 pathogenic variants also showed ER-positive stromal cells, including cystic pulmonary airway malformations, cystic renal dysplasia, and simple renal cysts in adult kidneys. ER expression in stromal cells is not a feature of DICER1 perturbation but rather is related to the presence of cystic components.

Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.