Opportunistic genetic screening increases the diagnostic yield and is medically valuable for care of patients and their relatives with hereditary cancer.

BACKGROUND: Multigene panel testing by next-generation sequencing (MGP-NGS) enables the detection of germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes beyond those associated with a certain cancer phenotype. Opportunistic genetic screening based on MGP-NGS in patients with suspicion of hereditary cancer reveals these incidental findings (IFs). METHODS: MGP-NGS was performed in patients who fulfilled the clinical criteria to undergo genetic testing according to the Catalan Health Service guidelines. Variants were classified following the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and the Cancer Variant Interpretation Group UK guidelines. RESULTS: IFs were identified in 10 (1.22%) of the 817 patients who underwent MGP-NGS. The mean age at cancer diagnosis was 49.4±9.5 years. Three IFs (30.0%) were detected in PMS2, two (20.0%) in ATM and TP53 and one (10.0%) in MSH6, NTHL1 and VHL. Seven (70.0%) IFs were single-nucleotide substitutions, two (20.0%) were deletions and one (10.0%) was a duplication. Three (30.0) IFs were located in intronic regions, three (30.3%) were nonsense, two (20.0%) were frameshift and two (20.0%) were missense variations. Six (60.0%) IFs were classified as PVs and four (40.0%) as LPVs. CONCLUSIONS: Opportunistic genetic screening increased the diagnostic yield by 1.22% in our cohort. Most of the identified IFs were present in clinically actionable genes (n=7; 70.0%), providing these families with an opportunity to join cancer early detection programmes, as well as secondary cancer prevention. IFs might facilitate the diagnosis of asymptomatic individuals and the early management of cancer once it develops.

Variation of Plasma Damage-Associated Molecular Patterns in Patients with Advanced Solid Tumors after Standard of Care Systemic Treatment.

BACKGROUND: Immunogenic cell death (ICD) is known for releasing damage-associated molecular patterns (DAMPs) from tumor cells. We aimed to find ICD signals by assessing the variation of plasmatic DAMPs (HMGB1, S100A8) before-after standard of care (SoC) systemic treatment in patients with advanced solid tumors. METHODS: Patients scheduled to start a new line of systemic treatment were included. Plasmatic concentrations of HMGB1 and S100A8 were measured (ng/mL) before and after three months of treatment. RESULTS: Fifty-two patients were included. Forty-four patients (85%) had metastases, and 8 (15%) were treated for stage III tumors. The most frequent tumor sites were colorectal (35%) and lung (25%). Forty-two patients (81%) received this treatment in the first-line setting. Thirty-six patients (69%) were treated chemotherapy (CT) alone, ten (19%) CT plus targeted therapy, two (3.8%) carboplatin-pemetrexed-pembrolizumab, three (5.8%) pembrolizumab alone and one (1.9%) cetuximab alone. Median plasmatic concentration of S100A8 was significantly higher before than after treatment in the whole population (3.78 vs. 2.91 ng/mL; p = 0.011) and more markedly in the subgroups of patients who experienced RECIST-assessed tumor response (5.70 vs. 2.63 ng/mL; p = 0.002). Median plasmatic concentration of HMGB1was not significantly different before and after treatment (10.23 vs. 11.85 ng/mL; p = 0.382) and did not differ depending on tumor response. Median PFS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (8.0 vs. 10.6 months; p = 0.29) after treatment. Median PFS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (12 vs. 4.7 months; p < 0.001). Median OS was not significantly different between patients whose plasma HMBG1 concentration decreased or increased (13.1 vs. 14.7 months; p = 0.46) after treatment. Median OS was significantly longer in those patients in whom the plasma concentration of S100A8 decreased after treatment (16.7 vs. 9.0 months; p < 0.001). CONCLUSIONS: Signals of ICD were not observed. S100A8 behaves as an inflammatory marker with decreased concentration after treatment, mostly in RECIST-responders. PFS and OS were significantly prolonged in those patients who experienced a decrease of S100A8 compared with those patients who experienced increase of plasma S100A8 at three months.

Elevated plasma levels of epithelial and endothelial cell markers in COVID-19 survivors with reduced lung diffusing capacity six months after hospital discharge.

BACKGROUND: Some COVID-19 survivors present lung function abnormalities during follow-up, particularly reduced carbon monoxide lung diffusing capacity (DLCO). To investigate risk factors and underlying pathophysiology, we compared the clinical characteristics and levels of circulating pulmonary epithelial and endothelial markers in COVID-19 survivors with normal or reduced DLCO 6 months after discharge. METHODS: Prospective, observational study. Clinical characteristics during hospitalization, and spirometry, DLCO and plasma levels of epithelial (surfactant protein (SP) A (SP-A), SP-D, Club cell secretory protein-16 (CC16) and secretory leukocyte protease inhibitor (SLPI)), and endothelial (soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and Angiopoietin-2) 6 months after hospital discharge were determined in 215 COVID-19 survivors. RESULTS: DLCO was < 80% ref. in 125 (58%) of patients, who were older, more frequently smokers, had hypertension, suffered more severe COVID-19 during hospitalization and refer persistent dyspnoea 6 months after discharge. Multivariate regression analysis showed that age ≥ 60 years and severity score of the acute episode ≥ 6 were independent risk factors of reduced DLCO 6 months after discharge. Levels of epithelial (SP-A, SP-D and SLPI) and endothelial (sICAM-1 and angiopoietin-2) markers were higher in patients with reduced DLCO, particularly in those with DLCO ≤ 50% ref. Circulating SP-A levels were associated with the occurrence of acute respiratory distress syndrome (ARDS), organizing pneumonia and pulmonary embolisms during hospitalization. CONCLUSIONS: Reduced DLCO is common in COVID-19 survivors 6 months after hospital discharge, especially in those older than 60 years with very severe acute disease. In these individuals, elevated levels of epithelial and endothelial markers suggest persistent lung damage.

Once-daily 1 g ceftriaxone optimizes exposure in patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration.

PURPOSE: Ceftriaxone total and unbound pharmacokinetics (PK) can be altered in critically ill patients with septic shock and hypoalbuminemia receiving continuous veno-venous hemodiafiltration (CVVHDF). The objective of this study was to determine the dosing strategy of ceftriaxone that maximizes the probability of maintaining the concentration above the MIC of the susceptible bacteria (≤2 mg/L by the EUCAST) for a 100% of the dosing interval (100% ƒuT>MIC). METHODS: In a prospective PK study in the intensive care units of two tertiary Spanish hospitals, six timed blood samples were collected per patient; for each sample, ceftriaxone total and unbound concentrations were measured using a liquid chromatography coupled to tandem mass spectrometry method. Population PK analysis and Monte-Carlo simulations were performed using NONMEMv.7.3®. RESULTS: We enrolled 8 critically ill patients that met the inclusion criteria (47 blood samples). Median age (range) was 70 years (47-85), weight 72.5 kg (40-95), albumin concentration 24.2 g/L (22-34), APACHE II score at admission 26 (17-36), and SOFA score on the day of study 12 (9-15). The unbound fraction (ƒu) of ceftriaxone was 44%, and total CL was 1.27 L/h, 25-30% higher than the CL reported in septic critically ill patients not receiving renal replacement therapies, and dependent on albumin concentration and weight. Despite this increment in ƒu and CL, Monte-Carlo simulations showed that a dose of 1 g once-daily ceftriaxone is sufficient to achieve a 100% ƒuT>MIC for MICs ≤2 mg/L for any range of weight and albumin concentration. CONCLUSION: Once-daily 1 g ceftriaxone provides optimal exposure in critically ill patients with septic shock and hypoalbuminemia receiving CVVHDF.

Role of respiratory intermediate care units during the SARS-CoV-2 pandemic.

RATIONALE: The SARS-CoV2 pandemic increased exponentially the need for both Intensive (ICU) and Intermediate Care Units (RICU). The latter are of particular importance because they can play a dual role in critical and post-critical care of COVID-19 patients. Here, we describe the setup of 2 new RICUs in our institution to face the SARS-CoV-2 pandemic and discuss the clinical characteristics and outcomes of the patients attended. METHODS: Retrospective analysis of the characteristics and outcomes of COVID-19 patients admitted to 2 new RICUs built specifically in our institution to face the first wave of the SARS-CoV-2 pandemic, from April 1 until May 30, 2020. RESULTS: During this period, 106 COVID-19 patients were admitted to these 2 RICUs, 65 of them (61%) transferred from an ICU (step-down) and 41 (39%) from the ward or emergency room (step-up). Most of them (72%) were male and mean age was 66 ± 12 years. 31% of them required support with oxygen therapy via high-flow nasal cannula (HFNC) and 14% non-invasive ventilation (NIV). 42 of the 65 patients stepping down (65%) had a previous tracheostomy performed and most of them (74%) were successfully decannulated during their stay in the RICU. Length of stay was 7 [4-11] days. 90-day mortality was 19% being significantly higher in stepping up patients than in those transferred from the ICU (25 vs. 10% respectively; p < 0.001). CONCLUSIONS: RICUs are a valuable hospital resource to respond to the challenges of the SARS-CoV-2 pandemic both to treat deteriorating and recovering COVID-19 patients.

Intervention to reduce perceived loneliness in community-dwelling older people.

AIM: We evaluated the reduction in perceived loneliness and depression and the increase in social support and quality of life in community-dwelling lonely people aged >65 years included in a community intervention compared with nonlonely controls from the same urban area. DESIGN: Randomised clinical trial without blind evaluation. LOCATION: Urban area of Barcelona. PARTICIPANTS: Community dwellers aged >65 years with loneliness identified by the primary care team. INTERVENTIONS: The primary care team together with community agents (municipal social services, community civil and religious associations) carried out 18 sessions developing activities including educational workshops, mindfulness, yoga, walking and visits to urban gardens. RESULTS: We included 55 patients (87% female, mean age 80.6 ± 6.86 years) of whom 82% had moderate and 18% severe loneliness. Six months postintervention, 48.3% of the intervention group did not feel lonely compared with 26.9% of controls (p = 0.001). Social support (DUKE-UNC-11) increased from 33.5 ± 9.3 to 41.4 ± 6.6, and mental health (SF-12) from 36 ± 610.4 to 48 ± 11.1 and depressive symptoms (Yesavage test) decreased from 9.2 ± 3.6 to 5.2 ± 5.0 in the intervention but not the control group. CONCLUSIONS: The intervention mainly reached people with moderate loneliness and significantly improved the perception of loneliness, depressive symptoms, social support and the mental health component of the quality of life. The intervention may be more suitable for people with moderate loneliness, but these types of activities may be difficult to accept by people with severe loneliness not related to the barriers to socialisation generated by ageing.

[Profiles of loneliness and social isolation in urban population]. / Perfiles de soledad y aislamiento social en población urbana.

OBJECTIVE: To assess the prevalence of loneliness and social isolation in a population over 65 cared by a urban primary health team and to identify its main characteristics. DESIGN: Cross-sectional descriptive study by a telephone survey. SETTING: Basic health area of Barcelona. PARTICIPANTS: Random sample of assigned population of 65 or more years old. MAIN MEASUREMENTS: UCLA Loneliness Scale and Lubben Social Network Scale. RESULTS: 278 persons were interviewed (61,36% response rate), 172 women and 106 men, with an average age of 76,7 ± 7,9 years. A higher proportion of factors related to loneliness were identified in non-respondents. Loneliness was closely correlated to social r = 0,736. Moderate loneliness, with a prevalence of 16,54%, was associated to walking difficulties (OR 3,09, 95%, IC 1,03-9,29), cognitive impairment (OR 3,97, 95% IC 1,19-13,27) and architectural barriers (OR 5.29, 95% IC 2.12-13,23), although severe loneliness, with a prevalence of 18,71% was only associated to living together with less people (OR 0.61, 95% IC 0.40-0.93). Social isolation, with a prevalence of 38,85% was associated to aging (OR 1,06, 95% IC 1,02-1,10) and to the belief of having health problems (OR 4,35, 95% IC 1,11-16,99). CONCLUSIONS: Loneliness and social isolation are of high prevalence. The telephone survey underestimates its prevalence. There are 2profiles of loneliness, one with moderate associated to the socialisation difficulties related to aging and another severe not related to health or to barriers that only can be identified by surveys or clinical interview. Interventions must be targeted to each of these profiles.

Transient Cell-intrinsic Activity Regulates the Migration and Laminar Positioning of Cortical Projection Neurons.

Neocortical microcircuits are built during development and require the coordinated assembly of excitatory glutamatergic projection neurons (PNs) into functional networks. Neuronal migration is an essential step in this process. In addition to cell-intrinsic mechanisms, external cues including neurotransmitters regulate cortical neuron migration, suggesting that early activity could influence this process. Here, we aimed to investigate the role of cell-intrinsic activity in migrating PNs in vivo using a designer receptor exclusively activated by a designer drug (DREADD) chemogenetic approach. In utero electroporation was used to specifically express the human M3 muscarinic cholinergic Gq-coupled receptor (hM3Dq) in PNs and calcium activity, migratory dynamics, gene expression, and laminar positioning of PNs were assessed following embryonic DREADD activation. We found that transient embryonic DREADD activation induced premature branching and transcriptional changes in migrating PNs leading to a persistent laminar mispositioning of superficial layer PNs into deep cortical layers without affecting expression of layer-specific molecular identity markers. In addition, live imaging approaches indicated that embryonic DREADD activation increased calcium transients in migrating PNs and altered their migratory dynamics by increasing their pausing time. Taken together, these results support the idea that increased cell-intrinsic activity during migration acts as a stop signal for migrating cortical PNs.

Randomized trial to reduce emergency visits or hospital admissions using telephone coaching to complex patients.

Background: Comorbidity remains a matter of international interest, given growing prevalence of chronic conditions. Objective: To evaluate the impact that adding a telephone coaching intervention by a family physician to usual care has on reducing resource consumption and improving health status, caregiver burden and quality of life among complex chronic patients (CCP) compared with usual care. Methods: A randomized controlled trial was conducted on a random sample of CCP from three primary care teams in Barcelona. Patients were randomly allocated into intervention or control groups. Evaluations were conducted at baseline and after six-month follow-up. Intervention patients were phoned twice a month by a family physician. Both groups received usual care. Primary endpoint was change in total number of urgent visits per patient. Secondary endpoints were changes in health and mental status, quality of life and caregiver burden. Results: Hundred and sixty-one CCP were included. During follow-up, 9 patients died and 2 were lost. At baseline, patients' characteristics and resource consumption were similar for both groups. After six months, urgent visits per patient decreased in intervention (1.27 baseline versus 0.89 follow-up, P = 0.091) and control (1.06 baseline versus 0.86 follow-up, P = 0.422) groups, mean difference 0.18 [confidence interval (CI) 95% -0.48 to 0.84]. Intervention patients improved in the physical component of the SF-12 questionnaire, while worsening in control patients, mean difference 4.71 (CI 95% -9.03 to -0.41). Differences were not found in the rest of the endpoints. Conclusion: The intervention did not reduce urgent visits among CCP neither improved patient's health.

Self-perception of leadership styles and behaviour in primary health care.

BACKGROUND: The concept of leadership has been studied in various disciplines and from different theoretical approaches. It is a dynamic concept that evolves over time. There are few studies in our field on managers' self-perception of their leadership style. There are no pure styles, but one or another style is generally favoured to a greater or lesser degree. In the primary health care (PHC) setting, managers' leadership style is defined as a set of attitudes, behaviours, beliefs and values. The objectives of this study were to describe and learn about the self-perception of behaviours and leadership styles among PHC managers; to determine the influence of the leadership style on job satisfaction, efficiency, and willingness to work in a team; and to determine the relationship between transformational and transactional styles according age, gender, profession, type of manager years of management experience, and the type of organization. METHODS: To describe leadership styles as perceived by PHC managers, a cross sectional study was performed using an 82 items-self-administered Multifactor Leadership Questionnaire (MLQ). This questionnaire measures leadership styles, attitudes and behaviour of managers. The items are grouped into three first order variables (transformational, transactional and laissez-faire) and ten second order variables (which discriminate leader behaviours). Additionally, the questionnaire evaluates organizational consequences such as extra-effort, efficiency and satisfaction. RESULTS: One hundred forty responses from 258 managers of 133 PHC teams in the Barcelona Health Area (response rate: 54.26 %). Most participants were nurses (61.4 %), average age was 49 years and the gender predominantly female (75 %). Globally, managers assessed themselves as equally transactional and transformational leaders (average: 3.30 points). Grouped by profession, nurses (28.57 % of participants) showed a higher transactional leadership style, over transformational leadership style, compared to physicians (3.38 points, p < 0.003). Considering gender, men obtained the lowest results in transactional style (p < 0.015). Both transactional and transformational styles correlate with efficiency and job satisfaction (r = 0.724 and r = 0.710, respectively). CONCLUSIONS: PHC managers' self-perception of their leadership style was transactional, focused on the maintenance of the status quo, although there was a trend in some scores towards the transformational style, mainly among nurse managers. Both styles correlate with satisfaction and willingness to strive to work better.

[Social isolation and loneliness: What can we do as Primary Care teams?] / Aislamiento social y soledad: ¿qué podemos hacer los equipos de atención primaria?

Loneliness and social isolation are emerging health conditions in the elderly population, in particular widows, high frequency users of health services and those with chronic problems and depression. Loneliness is the subjective feeling of having less affection and closeness than that desired in the intimate or relational field. Social isolation is an objective situation of having minimal contact with other people. Its contribution to increased morbidity and mortality is comparable to other well known risk factors that we deal with daily as Primary Care teams. Strategies to identify these problems in our patients and to perform scientific evidence based studies at individual and community level in cooperation with other community resources and interventions are discussed. The Primary Care team must promote the autonomy of these patients, facilitating their sociability, and act on their social maladaptive thoughts that hinder their social integration.

PSMA PET/CT SUVmax as a prognostic biomarker in patients with metachronous metastatic hormone-sensitive prostate cancer (mHSPC).

BACKGROUND: Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy. MATERIAL AND METHODS: Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68 Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons. RESULTS: A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered. CONCLUSIONS: PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies.

A Descriptive Study of 103 Primary Cutaneous B-Cell Lymphomas: Clinical and Pathological Characteristics and Treatment from the Spanish Lymphoma Oncology Group (GOTEL).

Primary cutaneous B-cell lymphomas (PCBCLs) are B-cell lymphomas that can occur in the skin without evidence of extracutaneous involvement. The 2005 WHO/EORTC classification of cutaneous lymphomas and its 2018 update have distinguished three main categories based on clinicopathological, immunohistochemical, and genetic characteristics: primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle centre lymphoma (PCFCL), and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT). PCMZL and PCFCL are clinically indolent, while PCDLBCL-LT is an aggressive lymphoma. Due to its low incidence and lack of prospective studies, it is difficult to establish a standard treatment for each subgroup. The objective of our study was to describe the clinical and pathological characteristics of 103 patients with cutaneous B-cell lymphoma from 12 centres belonging to the Spanish Lymphoma Oncology Group. The median age was 53 years (40-65). According to skin extension, 62% had single-site lymphoma, 17% had regional lymphoma, and 20% had multifocal lymphoma. Histology: 66% had PCMZL, 26% had PCFCL, and 8% had PCDLBCL-LT. Twenty-three percent of the patients were treated exclusively with surgery, 26% with radiotherapy only, 21% with surgery plus radiotherapy, 10% with polychemotherapy, and 5% with rituximab monotherapy. Overall, 96% of patients achieved a complete response, and 44% subsequently relapsed, most of them relapsing either locally or regionally. The 10-year OS was 94.5% for the entire cohort, 98% for the PCMZL cohort, 95% for the PCFCL cohort, and 85.7% for the PCDLBCL-LT cohort. Our data are comparable to those of other published series, except for the high frequency of PCMZL. The expected heterogeneity in therapeutic management has been observed.

Predictors of mortality among elderly dependent home care patients.

BACKGROUND: The purpose of this study is to identify which variables--among those commonly available and used in the primary care setting--best predict mortality in a cohort of elderly dependent patients living at home (EDPLH) that were included in a home care program provided by Primary Care Teams (PCT). Additionally, we explored the risk of death among a sub-group of these patients that were admitted to hospital the year before they entered the home care program. METHODS: A one-year longitudinal cohort study of a sample of EDPLH patients included in a home care programme provided by 72 PCTs. Variables collected from each individual patient included health and social status, carer's characteristics, carer's burden of care, health and social services received. RESULTS: 1,001 patients completed the study (91.5%), 226 were admitted to hospital the year before inclusion. 290 (28.9%) died during the one-year follow-up period. In the logistic regression analysis women show a lower risk of death [OR= 0.67 (0.50-0.91)]. The risk of death increases with comorbidity [Charlson index OR= 1.14 (1,06-1.23)], the number of previous hospital admissions [OR= 1,16 (1.03-1.33)], and with the degree of pressure ulcers [ulcers degree 1-2 OR = 2.94 (1.92-4.52); ulcers degree 3-4 OR = 4.45 (1.90-10.92)]. The logistic predictive model of mortality for patients previously admitted to hospital identified male sex, comorbidity, degree of pressure ulcers, and having received home care rehabilitation as independent variables that predict death. CONCLUSIONS: Comorbidity, hospital admissions and pressure ulcers predict mortality in the following year in EDPLH patients. The subgroup of patients that entered home care programs with a previous record of hospital admission and a high score in our predictive model might be considered as candidates for palliative care.