Self-determined motivational health coaching ('SAMI') during outpatient treatment to promote physical activity of people with serious mental illness: a pilot controlled trial.

BACKGROUND: Brief motivational coaching, integrated into health care; seems promising to address physical inactivity of people with serious mental illness (SMI). AIMS: To test the impact of a self-determined health coaching approach (the "SAMI" intervention) during outpatient mental health treatment on moderate-to-vigorous physical activity (MVPA) of people with SMI. METHODS: Adults (mean age = 41.9, SD = 10.9) with an ICD-10 diagnosis of mental illness were semi-randomized to the SAMI-intervention group (IG) or control group (CG). The IG received 30 minutes of health coaching based on the self-determination theory (SDT). MVPA and sedentary time (ST) were measured with the International Physical Activity Questionnaire - short form (IPAQ-SF) and symptoms of mental illness with the Brief Symptom Inventory (BSI-18), each at baseline and follow-up (3-4 months). Differences in primary (MVPA) and secondary (ST, BSI-18) outcomes were evaluated using negative binomial regressions and general linear models. RESULTS: In the IG (n = 30), MVPA increased from 278 (interquartile range [IQR] = 175-551) to 435 (IQR = 161-675) min/week compared to a decrease from 250 (IQR = 180-518) to 155 (IQR = 0-383) min/week in the CG (n = 26; adjusted relative difference at follow-up: Incidence Rate Ratio [IRR] = 2.14, 95% CI: 1.17-3.93, p = 0.014). There were no statistically significant differences in ST and BSI-18. CONCLUSIONS: Brief self-determined health coaching during outpatient treatment could increase post-treatment MVPA in people with SMI, potentially up to a clinically relevant level. However, great uncertainty (for all outcomes) weakens the assessment of clinical relevance.

Environmental risk factors analysis in paediatric oral health: a cross-sectional study.

AIM: The aim of the present study was to evaluate the association between environmental risk factors [adherence to the Mediterranean diet (MD), eating habits, hygiene habits, body mass index (BMI)] with the presence of caries in a university-based cohort of paediatric patients. MATERIALS: A total of 118 paediatric patients were included in the study. In addition to the evaluation of clinical (vitality test, percussion test) and radiographic (X-ray bitewing, OPT) parameters, patients' lifestyle was investigated through validated questionnaries. Data regarding decayed, missing, filled teeth index were recorded for both permanent (DMFT) and deciduous teeth (dmft). Logistic/linear regression models (crude estimates) and multiple regression models (logistic/linear) adjusted for confounding factors were built to evaluate the association between lifestyle habits and caries. The results were reported as Odds Ratio (OR - con 95% CI) for logistic regression models and Mean Difference (MD - con 95% CI) for linear models. CONCLUSION: The present study confirmed the role of nutritional habits in caries development in the paediatric population, especially for deciduous dentition. Further clinical studies are needed to improve the quality of administered questionnaires and evaluate the cause/effect relationship between environmental risk factors and caries.

The Impact of Oxidative Stress on Pregnancy. The Neglected Role of Alcohol Misuse.

Abstract: Oxygen is essential for human life. However, it could cause damaging effects on biological systems causing oxidative stress. Oxidative stress defined as "an alteration in the pro-oxidant-antioxidant balance in favor of the former that leads to potential damage" is characterized by the release of Reactive Oxygen Species (ROS). Oxidative stress is now recognized to play a central role in the pathophysiology of many different disorders, including complications of pregnancy such as placental pathology, PreEclampsia (PE), Intrauterine Growth Restriction (IUGR), gestational diabetes, and miscarriage. This narrative review aims to summarize pieces of evidence about the role of oxidative stress in the pathophysiology of the main obstetric complications with par-ticular interest in the neglected role of alcohol abuse.

Single-Cell RNA Sequencing for the Detection of Clonotypic V(D)J Rearrangements in Multiple Myeloma.

Multiple myeloma (MM) has a highly heterogeneous genetic background, which complicates its molecular tracking over time. Nevertheless, each MM patient's malignant plasma cells (PCs) share unique V(D)J rearranged sequences at immunoglobulin loci, which represent ideal disease biomarkers. Because the tumor-specific V(D)J sequence is highly expressed in bulk RNA in MM patients, we wondered whether it can be identified by single-cell RNA sequencing (scRNA-seq). To this end we analyzed CD138+ cells purified from bone marrow aspirates of 19 samples with PC dyscrasias by both a standard method based on bulk DNA and by an implementation of the standard 10x Genomics protocol to detect expressed V(D)J sequences. A dominant clonotype was easily identified in each sample, accounting on average for 83.65% of V(D)J-rearranged cells. Compared with standard methods, scRNA-seq analysis proved highly concordant and even more effective in identifying clonal productive rearrangements, by-passing limitations related to the misannealing of consensus primers in hypermutated regions. We next validated its accuracy to track 5 clonal cells with absolute sensitivity in a virtual sample containing 3180 polyclonal cells. This shows that single-cell V(D)J analysis may be used to find rare clonal cells, laying the foundations for functional single-cell dissection of minimal residual disease.

Triple careers of athletes: exploring the challenges of planning a pregnancy among female elite athletes using semi-structured interviews.

BACKGROUND: The challenging factors that elite athletes perceive for combining their sportive career with planning a pregnancy and motherhood need to be identified in order to develop supportive measures. Therefore, this phenomenological qualitative study aimed to explore challenges associated with planning a pregnancy among female, non-pregnant elite athletes. METHODS: Semi-structured skype-interviews were performed among female elite athletes (athletes competing on national or international level) aged 28 years or older. Using Mayring's qualitative content analysis approach, anchor examples served to identify potential challenges of planning a pregnancy which were categorized independently by two researchers. RESULTS: Interviews of 16 elite athletes (mean age 30.7 years) entered analysis. Eleven challenges of planning a pregnancy were identified, categorized into organizational / environmental, financial, personal, and physical factors. CONCLUSIONS: With regard to financial challenges, we propose mandatory maternity leave and continuation of the contracts and salary. Furthermore, mentoring programs may help to provide support and advice to new generations of female elite athletes and help to reduce concerns regarding the wish of becoming pregnant during a sportive career. In order to reduce physical concerns regarding pregnancy and exercise, we see a need for scientific studies investigating the association of sport discipline specific characteristics on sportive performance and the mother´s, fetus' and child´s health. Finally, the results of the current study may be used in future quantitative studies to test specific hypotheses.

Functional Impact of Genomic Complexity on the Transcriptome of Multiple Myeloma.

PURPOSE: Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments. EXPERIMENTAL DESIGN: We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an in silico drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the Celligner algorithm. RESULTS: Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our in silico DSS showed that not only t(11;14) but also chr(1q)gain/amps and CYLD inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax. CONCLUSIONS: The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.

COVID-19 induces proatherogenic alterations in moderate to severe non-comorbid patients: A single-center observational study.

Patients with COVID-19 can be asymptomatic or present mild to severe symptoms, leading to respiratory and cardiovascular complications and death. Type 2 diabetes mellitus (T2DM) and obesity are considered risk factors for COVID-19 poor prognosis. In parallel, COVID-19 severe patients exhibit dyslipidemia and alterations in neutrophil to lymphocyte ratio (NLR) associated with disease severity and mortality. To investigate whether such alterations are caused by the infection or results from preexisting comorbidities, this work analyzed dyslipidemia and the hemogram profile of COVID-19 patients according to the severity and compared with patients without T2DM or obesity comorbidities. Dyslipidemia, with a marked decrease in HDL levels, and increased NLR accompanied the disease severity, even in non-T2DM and non-obese patients, indicating that COVID-19 causes the observed alterations. Because decreased hemoglobin is involved in COVID-19 severity, and hemoglobin concentration is associated with metabolic diseases, the erythrogram of patients was also evaluated. We verified a drop in hemoglobin and erythrocyte number in severe patients, independently of T2DM and obesity, which may explain in part the need for artificial ventilation in severe cases. Thus, the control of such parameters (especially HDL levels, NLR, and hemoglobin concentration) could be a good strategy to prevent COVID-19 complications and death.

Genomics of Smoldering Multiple Myeloma: Time for Clinical Translation of Findings?

Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is reflected in a markedly variable progression risk among patients. Recently proposed risk stratification models mainly rely on indirect markers of disease burden and are unable to identify cases in whom clonal PCs have already undergone the "malignant switch" but major clonal expansion has not occurred yet. In the last years, the application of next-generation sequencing (NGS) techniques has led to profound advances in the understanding of the molecular bases of SMM progression, and in all likelihood, it will contribute to the needed improvement of SMM prognostication. In this Review, we describe the recent advances in characterizing the genomic landscape of SMM and intrinsic determinants of its progression, highlighting their implications in terms of understanding of tumor evolution and prognostication. We also review the main studies investigating the role of the microenvironment in this early disease stage. Finally, we mention the results of the first randomized clinical trials and discuss the potential clinical translability of the genomic insights.

ROBO1 Promotes Homing, Dissemination, and Survival of Multiple Myeloma within the Bone Marrow Microenvironment.

The bone marrow (BM) microenvironment actively promotes multiple myeloma (MM) pathogenesis and therapies targeting both cancer cells and the niche are highly effective. We were interested in identifying novel signaling pathways supporting MM-BM crosstalk. Mutations in the transmembrane receptor Roundabout 1 (ROBO1) were recently identified in MM patients, however their functional consequences are uncertain. Through protein structure-function studies, we discovered that ROBO1 is necessary for MM adhesion to BM stromal and endothelial cells and ROBO1 knock out (KO) compromises BM homing and engraftment in a disseminated mouse model. ROBO1 KO significantly decreases MM proliferation in vitro and intra- and extramedullary tumor growth, in vivo. Mechanistically, ROBO1 C-terminus is cleaved in a ligand-independent fashion and is sufficient to promote MM proliferation. Viceversa, mutants lacking the cytoplasmic domain, including the human-derived G674* truncation, act dominantly negative. Interactomic and RNA sequencing studies suggest ROBO1 may be involved in RNA processing, supporting further studies.

Pattern of the Heart Rate Performance Curve in Subjects with Beta-Blocker Treatment and Healthy Controls.

(1): Heart rate performance curve (HRPC) in incremental exercise was shown to be not uniform, causing false intensity estimation applying percentages of maximal heart rate (HRmax). HRPC variations are mediated by ß-adrenergic receptor sensitivity. The aim was to study age and sex dependent differences in HRPC patterns in adults with ß-blocker treatment (BB) and healthy controls (C). (2): A total of 535 (102 female) BB individuals were matched 1:1 for age and sex (male 59 ± 11 yrs, female 61 ± 11 yrs) in C. From the maximum incremental cycle ergometer exercise a first and second heart rate (HR) threshold (Th1 and Th2) was determined. Based on the degree of the deflection (kHR), HRPCs were categorized as regular (downward deflection (kHR > 0.1)) and non-regular (upward deflection (kHR < 0.1), linear time course). (3): Logistic regression analysis revealed a higher odds ratio to present a non-regular curve in BB compared to C (females showed three times higher odds). The odds for non-regular HRPC in BB versus C decreased with older age (OR interaction = 0.97, CI = 0.94-0.99). Maximal and submaximal performance and HR variables were significantly lower in BB (p < 0.05). %HRmax was significantly lower in BB versus C at Th2 (male: 77.2 ± 7.3% vs. 80.8 ± 5.0%; female: 79.2 ± 5.1% vs. 84.0 ± 4.3%). %Pmax at Th2 was similar in BB and C. (4): The HRPC pattern in incremental cycle ergometer exercise is different in individuals receiving ß-blocker treatment compared to healthy individuals. The effects were also dependent on age and sex. Relative HR values at Th2 varied substantially depending on treatment. Thus, the percentage of Pmax seems to be a stable and independent indicator for exercise intensity prescription.

Monitoring Sleep Changes via a Smartphone App in Bipolar Disorder: Practical Issues and Validation of a Potential Diagnostic Tool.

Background: Sleep disturbances are common early warning signs of an episode of bipolar disorder, and early recognition can favorably impact the illness course. Symptom monitoring via a smartphone app is an inexpensive and feasible method to detect an early indication of changes such as sleep. The study aims were (1) to assess the acceptance of apps and (2) to validate sleeping times measured by the smartphone app UP!. Methods:UP! was used by 22 individuals with bipolar disorder and 23 controls. Participants recorded their time of falling asleep and waking-up using UP! for 3 weeks. Results were compared to a validated accelerometer and the Pittsburgh Sleep Quality Index. Additionally, participants were interviewed regarding early warning signs and their feedback for apps as monitoring tools in bipolar disorder (NCT03275714). Results: With UP!, our study did not find strong reservations concerning data protection or continual smartphone usage. Correlation analysis demonstrates UP! to be a valid tool for measuring falling asleep and waking-up times. Discussion: Individuals with bipolar disorder assessed the measurement of sleep disturbances as an early warning sign with a smartphone as positive. The detection of early signs could change an individual's behavior and strengthen self-management. The study showed that UP! can be used to measure changes in sleep durations accurately. Further investigation of smartphone apps' impact to measure other early signs could significantly contribute to clinical treatment and research in the future through objective, continuous, and individual data collection.

Drastic Reductions in Mental Well-Being Observed Globally During the COVID-19 Pandemic: Results From the ASAP Survey.

Most countries affected by the COVID-19 pandemic have repeatedly restricted public life to control the contagion. However, the health impact of confinement measures is hitherto unclear. We performed a multinational survey investigating changes in mental and physical well-being (MWB/PWB) during the first wave of the pandemic. A total of 14,975 individuals from 14 countries provided valid responses. Compared to pre-restrictions, MWB, as measured by the WHO-5 questionnaire, decreased considerably during restrictions (68.1 ± 16.9 to 51.9 ± 21.0 points). Whereas 14.2% of the participants met the cutoff for depression screening pre-restrictions, this share tripled to 45.2% during restrictions. Factors associated with clinically relevant decreases in MWB were female sex (odds ratio/OR = 1.20, 95% CI: 1.11-1.29), high physical activity levels pre-restrictions (OR = 1.29, 95% CI 1.16-1.42), decreased vigorous physical activity during restrictions (OR = 1.14, 95% CI: 1.05-1.23), and working (partially) outside the home vs. working remotely (OR = 1.29, 95% CI: 1.16-1.44/OR = 1.35, 95% CI: 1.23-1.47). Reductions, although smaller, were also seen for PWB. Scores in the SF-36 bodily pain subscale decreased from 85.8 ± 18.7% pre-restrictions to 81.3 ± 21.9% during restrictions. Clinically relevant decrements of PWB were associated with female sex (OR = 1.62, 95% CI: 1.50-1.75), high levels of public life restrictions (OR = 1.26, 95% CI: 1.18-1.36), and young age (OR = 1.10, 95% CI: 1.03-1.19). Study findings suggest lockdowns instituted during the COVID-19 pandemic may have had substantial adverse public health effects. The development of interventions mitigating losses in MWB and PWB is, thus, paramount when preparing for forthcoming waves of COVID-19 or future public life restrictions.

Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma.

B cell maturation antigen (BCMA) is a target for various immunotherapies and a biomarker for tumor load in multiple myeloma (MM). We report a case of irreversible BCMA loss in a patient with MM who was enrolled in the KarMMa trial ( NCT03361748 ) and progressed after anti-BCMA CAR T cell therapy. We identified selection of a clone with homozygous deletion of TNFRSF17 (BCMA) as the underlying mechanism of immune escape. Furthermore, we found heterozygous TNFRSF17 loss or monosomy 16 in 37 out of 168 patients with MM, including 28 out of 33 patients with hyperhaploid MM who had not been previously treated with BCMA-targeting therapies, suggesting that heterozygous TNFRSF17 deletion at baseline could theoretically be a risk factor for BCMA loss after immunotherapy.

Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores angiogenic homeostasis and suppresses tumor progression.

Interactions of malignant multiple myeloma (MM) plasma cells (MM-cells) with the microenvironment control MM-cell growth, survival, drug-resistance and dissemination. As in MM microvascular density increases in the bone marrow (BM), we investigated whether BM MM endothelial cells (MMECs) control disease progression via the junctional adhesion molecule A (JAM-A). Membrane and cytoplasmic JAM-A levels were upregulated in MMECs in 111 newly diagnosed (NDMM) and 201 relapsed-refractory (RRMM) patients compared to monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Elevated membrane expression of JAM-A on MMECs predicted poor clinical outcome. Mechanistically, addition of recombinant JAM-A to MMECs increased angiogenesis whereas its inhibition impaired angiogenesis and MM growth in 2D and 3D in vitro cell culture and chorioallantoic membrane-assays. To corroborate these findings, we treated MM bearing mice with JAM-A blocking mAb and demonstrated impaired MM progression corresponding to decreased MM-related vascularity. These findings support JAM-A as an important mediator of MM progression through facilitating MM-associated angiogenesis. Collectively, elevated JAM-A expression on bone marrow endothelial cells is an independent prognostic factor for patient survival in both NDMM and RRMM. Blocking JAM-A restricts angiogenesis in vitro, in embrio and in vivo and represents a suitable druggable molecule to halt neoangiogenesis and MM progression.

A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity.

The knowledge of cancer origin and the subsequent tracking of disease evolution represent unmet needs that will soon be within clinical reach. This will provide the opportunity to improve patient's stratification and to personalize treatments based on cancer biology along its life history. In this review, we focus on the molecular pathogenesis of multiple myeloma (MM), a hematologic malignancy with a well-known multi-stage disease course, where such approach can sooner translate into a clinical benefit. We describe novel insights into modes and timing of disease initiation. We dissect the biology of the preclinical and pre-malignant phases, elucidating how knowledge of the genomics of the disease and the composition of the microenvironment allow stratification of patients based on risk of disease progression. Then, we explore cell-intrinsic and cell-extrinsic drivers of MM evolution to symptomatic disease. Finally, we discuss how this may relate to the development of refractory disease after treatment. By integrating an evolutionary view of myeloma biology with the recent acquisitions on its clonal heterogeneity, we envision a way to drive the clinical management of the disease based on its detailed biological features more than surrogates of disease burden.

Current Evidence of Measurement Properties of Physical Activity Questionnaires for Older Adults: An Updated Systematic Review.

BACKGROUND: Questionnaires provide valuable information about physical activity (PA) behaviors in older adults. Until now, no firm recommendations for the most qualified questionnaires for older adults have been provided. OBJECTIVES: This review is an update of a previous systematic review, published in 2010, and aims to summarize, appraise and compare the measurement properties of all available self-administered questionnaires assessing PA in older adults. METHODS: We included the articles evaluated in the previous review and conducted a new search in PubMed, Embase, and SPORTDiscus from September 2008 to December 2019, using the following inclusion criteria (1) the purpose of the study was to evaluate at least one measurement property (reliability, measurement error, hypothesis testing for construct validity, responsiveness) of a self-administered questionnaire; (2) the questionnaire intended to measure PA; (3) the questionnaire covered at least one domain of PA; (4) the study was performed in the general, healthy population of older adults; (5) the mean age of the study population was > 55 years; and (6) the article was published in English. Based on the Quality Assessment of Physical Activity Questionnaires (QAPAQ) checklist, we evaluated the quality and results of the studies. The content validity of all included questionnaires was also evaluated using the reviewers' rating. The quality of the body of evidence was evaluated for the overall construct of each questionnaire (e.g., total PA), moderate-to-vigorous physical activity (MVPA) and walking using a modified Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: In total, 56 articles on 40 different questionnaires (14 from the previous review and 26 from the update) were included. Reliability was assessed for 22, measurement error for four and hypotheses testing for construct validity for 38 different questionnaires. Evidence for responsiveness was available for one questionnaire. For many questionnaires, only one measurement property was assessed in only a single study. Sufficient content validity was considered for 22 questionnaires. All questionnaires displayed large measurement errors. Only versions of two questionnaires showed both sufficient reliability and hypotheses testing for construct validity, namely the Physical Activity Scale for the Elderly (PASE; English version, Turkish version) for the assessment of total PA, and the Physical Activity and Sedentary Behavior Questionnaire (PASB-Q; English version) for the assessment of MVPA. The quality of evidence for these results ranged from very low to high. CONCLUSIONS: Until more high-quality evidence is available, we recommend the PASE for measuring total PA and the PASB-Q for measuring MVPA in older adults. However, they are not equally qualified among different languages. Future studies on the most promising questionnaires should cover all relevant measurement properties. We recommend using and improving existing PA questionnaires-instead of developing new ones-and considering the strengths and weaknesses of each PA measurement instrument for a particular purpose.

HPLC-MS/MS measurement of lidocaine in rat skin and plasma. Application to study the release from medicated plaster.

A simple, sensitive HPLC-MS/MS method was developed and validated for the determination of lidocaine in skin and plasma of rats. The methods were established and validated assessing lower limit of quantitation (LLOQ), linearity, intra and inter-day precision and accuracy, selectivity, recovery and matrix effect. Chromatography was done on a Gemini column embedded with C18 stationary phase (50 mm × 2.0 mm, 5 µm particle size), using a gradient with mobile phases consisting of 0.1% HCOOH in bidistilled water and 0.1% HCOOH in acetonitrile. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring, using target ions m/z 235.10 for lidocaine and m/z 245.10 for lidocaine-d10, used as internal standard. RESULTS: The linearity of the method was in the ranges of lidocaine concentrations 10.0-200.0 ng/mL for skin homogenate (accuracy 94.1-105.5%; R2 ≥ 0.998) and 0.025-2 ng/mL for plasma (accuracy 96.2-104.8%; R2 ≥ 0.996). The intra- and inter-day precision and accuracy determined on three quality control samples (20, 75 and 170 ng/mL for skin and 0.075, 0.4 and 1.5 ng/mL for plasma) were ≤4.2% and 103.8-108.2% for skin and ≤12.4% and 95.5-101.4% for plasma. The LLOQ was 10 ng/mL in skin homogenate and 0.025 ng/mL in plasma. The applicability of the method was demonstrated by measuring lidocaine in skin and plasma after exposure to medicated patches containing 5% lidocaine.