What do we know about the role of menopause in cardiovascular autonomic regulation in hypertensive women?

OBJECTIVE: We investigated the systemic arterial hypertension effects on cardiovascular autonomic modulation and baroreflex sensitivity (BRS) in women with or without preserved ovarian function. METHODS: A total of 120 women were allocated into two groups: middle-aged premenopausal women (42 ± 3 y old; n = 60) and postmenopausal women (57 ± 4 y old; n = 60). Each group was also divided into two smaller groups (n = 30): normotensive and hypertensive. We evaluated hemodynamic and anthropometric parameters, cardiorespiratory fitness, BRS, heart rate variability (HRV), and blood pressure variability. The effects of hypertension and menopause were assessed using a two-way analysis of variance. Post hoc comparisons were performed using the Student-Newman-Keuls test. RESULTS: Comparing premenopausal groups, women with systemic arterial hypertension showed lower BRS (9.1 ± 4.4 vs 13.4 ± 4.2 ms/mm Hg, P < 0.001 ) and HRV total variance (1,451 ± 955 vs 2,483 ± 1,959 ms 2 , P = 0.005) values than normotensive; however, the vagal predominance still remained. On the other hand, both postmenopausal groups showed an expressive reduction in BRS (8.3 ± 4.2 vs 11.3 ± 4.8 ms/mm Hg, P < 0.001) and HRV characterized by sympathetic modulation predominance (low-frequency oscillations; 56% ± 17 vs 44% ± 17, P < 0.001), in addition to a significant increase in blood pressure variability variance (28.4 ± 14.9 vs 22.4 ± 12.5 mm Hg 2 , P = 0.015) compared with premenopausal groups. Comparing both postmenopausal groups, the hypertensive group had significantly lower values ​​of HRV total variance (635 ± 449 vs 2,053 ± 1,720 ms 2 , P < 0.001) and BRS (5.3 ± 2.8 vs 11.3 ± 3.2 ms/mm Hg) than the normotensive. CONCLUSIONS: Hypertensive middle-aged premenopausal women present HRV autonomic modulation impairment, but they still maintain a vagal predominance. After menopause, even normotensive women show sympathetic autonomic predominance, which may also be associated with aging. Furthermore, postmenopausal women with hypertension present even worse cardiac autonomic modulation.

Characterization of an Autoinducing Peptide Signal Reveals Highly Efficacious Synthetic Inhibitors and Activators of Quorum Sensing and Biofilm Formation in Listeria monocytogenes.

Bacteria can use chemical signals to assess their local population density in a process called quorum sensing (QS). Many of these bacteria are common pathogens, including Gram-positive bacteria that utilize agr QS systems regulated by macrocyclic autoinducing peptide (AIP) signals. Listeria monocytogenes, an important foodborne pathogen, uses an agr system to regulate a variety of virulence factors and biofilm formation, yet little is known about the specific roles of agr in Listeria infection and its persistence in various environments. Herein, we report synthetic peptide tools that will enable the study of QS in Listeria. We identified a 6-mer AIP signal in L. monocytogenes supernatants and selected it as a scaffold around which a collection of non-native AIP mimics was designed and synthesized. These peptides were evaluated in cell-based agr reporter assays to generate structure-activity relationships for AIP-based agonism and antagonism in L. monocytogenes. We discovered synthetic agonists with increased potency relative to native AIP and a synthetic antagonist capable of reducing agr activity to basal levels. Notably, the latter peptide was able to reduce biofilm formation by over 90%, a first for a synthetic QS modulator in wild-type L. monocytogenes. The lead agr agonist and antagonist in L. monocytogenes were also capable of antagonizing agr signaling in the related pathogen Staphylococcus aureus, further extending their utility and suggesting different mechanisms of agr activation in these two pathogens. This study represents an important first step in the application of chemical methods to modulate QS and concomitant virulence outcomes in L. monocytogenes.

Assessing frailty at the centers for dementia and cognitive decline in Italy: potential implications for improving care of older people living with dementia.

INTRODUCTION: Frailty is strongly associated with the clinical course of cognitive impairment and dementia, thus arguing for the need of its assessment in individuals affected by cognitive deficits. This study aimed to retrospectively evaluate frailty in patients aged 65 years and older referred to two Centers for Cognitive Decline and Dementia (CCDDs). METHODS: A total of 1256 patients consecutively referred for a first visit to two CCDDs in Lombardy (Italy) between January 2021 to July 2022 were included. All patients were evaluated by an expert physician in diagnosis and care of dementia according to a standardized clinical protocol. Frailty was assessed using a 24-items Frailty Index (FI) based on routinely collected health records, excluding cognitive decline or dementia, and categorized as mild, moderate, and severe. RESULTS: Overall, 40% of patients were affected by mild frailty and 25% of the sample has moderate to severe frailty. The prevalence and severity of frailty increased with decreasing Mini Mental State Examination (MMSE) score and advancing age. Frailty was also detected in 60% of patients with mild cognitive impairment. CONCLUSION: Frailty is common in patients referring to CCDDs for cognitive deficits. Its systematic assessment using a FI generated with readily available medical information could help develop appropriate models of assistance and guide personalization of care.

Cardiovascular autonomic modulation differences between moderate-intensity continuous and high-intensity interval aerobic training in women with PCOS: A randomized trial.

Background: Moderate-intensity continuous training (MICT) is strongly recommended for polycystic ovarian syndrome (PCOS) treatment. However, recent studies have suggested that high-intensity interval training (HIIT) would promote great benefits for cardiac autonomic control. Therefore, we investigated whether the benefits of HIIT related to cardiovascular autonomic control were greater than those of MICT in women with PCOS. Methods: Women with PCOS were randomly allocated through a blind draw into three groups: control, MICT, and HIIT. The control group did not undergo exercise, whereas those in the MICT and HIIT groups underwent 16 weeks of aerobic physical training. All groups were evaluated before and after the 16 weeks of intervention in the following aspects: quantification of serum lipids, testosterone, fasting insulin and blood glucose; physical fitness through cardiopulmonary testing; analysis of heart rate variability (HRV) by linear (time domain and frequency domain) and non-linear (symbolic analysis) methods, analysis of blood pressure variability (BPV) and spontaneous baroreflex sensitivity (BRS). Results: The final analysis, each group comprised 25 individuals. All groups had similar baseline parameters. After 16 weeks, intragroup comparison showed that the MICT and HIIT groups had a reduction in baseline heart rate (P < 0.001; P < 0.001, respectively) and testosterone levels P < 0.037; P < 0.012, respectively) associated with an increase in VO2peak (MICT, P < 0.001; HIIT, P < 0.001). The MICT (P < 0.36) and HIIT (P < 0.17) groups also showed an increase in cardiac vagal modulation, however only observed in the non-linear analysis. The intergroup comparison showed no differences between the MICT and HIIT groups in any of the hormonal, metabolic and autonomic parameters evaluated, including testosterone, peak oxygen uptake (VO2peak), HRV, BPV and BRS. Conclusion: HIIT and MICT showed similar results for the different parameters evaluated. This suggests that both training protocols can be recommended for the treatment of PCOS. Brazilian Clinical Trials Registry (RBR-78qtwy).

Integrative physiological study of adaptations induced by aerobic physical training in hypertensive hearts.

Aerobic physical training reduces arterial pressure in patients with hypertension owing to integrative systemic adaptations. One of the key factors is the decrease in cardiac sympathetic influence. Thus, we hypothesized that among other causes, cardiac sympathetic influence reduction might be associated with intrinsic cardiac adaptations that provide greater efficiency. Therefore, 14 spontaneously hypertensive rats (SHR group) and 14 normotensive Wistar Kyoto rats (WKY group) were used in this study. Half of the rats in each group were trained to swim for 12 weeks. All animals underwent the following experimental protocols: double blockade of cardiac autonomic receptors with atropine and propranolol; echocardiography; and analysis of coronary bed reactivity and left ventricle contractility using the Langendorff technique. The untrained SHR group had a higher sympathetic tone, cardiac hypertrophy, and reduced ejection fraction compared with the untrained WKY group. In addition, reduced coronary bed reactivity due to increased flow, and less ventricular contractile response to dobutamine and salbutamol administration were observed. The trained SHR group showed fewer differences in echocardiographic parameters as the untrained SHR group. However, the trained SHR group showed a reduction in the cardiac sympathetic influence, greater coronary bed reactivity, and increased left intraventricular pressure. In conclusion, aerobic physical training seems to reduce cardiac sympathetic influence and increase contractile strength in SHR rats, besides the minimal effects on cardiac morphology. This reduction suggests intrinsic cardiac adaptations resulting in beneficial adjustments of coronary bed reactivity associated with greater left ventricular contraction.

Inflammatory exposure drives long-lived impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.

Factores determinantes de la limitación física funcional en pacientes revascularizados por síndrome coronario agudo / Determining factors with regard to physical functional impairment in revascularized patients with acute coronary syndrome

Introducción: La capacidad física funcional se asocia de manera indirecta con la mortalidad, y frecuentemente se ve comprometida después de un evento cardiovascular, de ahí la importancia de considerar sus factores pronósticos durante el tratamiento en los pacientes cardiópatas. Objetivo: Identificar los factores pronósticos de la limitación física funcional en pacientes revascularizados por Síndrome Coronario Agudo (SCA). Material y método: Se realizó un análisis retrospectivo de 29 historias clínicas tomadas de pacientes sometidos a una prueba de esfuerzo (Protocolo Bruce o Bruce modificado) posterior a una revascularización miocárdica durante los meses de enero a diciembre del 2019. Para el análisis estadístico se realizó una regresión logística univariada y multivariada (odds ratio-OR), así como un análisis de regresión linear simple entre las variables de interés. Resultados: los pacientes analizados tenían una media de edad de 60 ± 9,2 años, y el 76% fueron hombres. La presencia de hipertensión arterial sistémica (HAS), menores valores de Frecuencia Cardíaca (FC) máxima (ß = 0,112; CI: 0,074, 0,149; p <0,001), altos valores de Presión Arterial Sistólica (PAS) (ß = - 0,083; CI 95%: -0,152, -0,014; p <0,020), y un mayor número de factores de riesgo (ß = - 1,580; CI 95%: -2,456-0,868; p <0,001), son considerados predictores de limitación física funcional (<7 METs). Conclusión: La presencia de HAS, un mayor número de factores de riesgo, así como altos niveles de PAS máxima y menores valores de FC máxima alcanzadas durante la prueba de esfuerzo, mostraron ser factores pronósticos de la limitación funcional en sujetos revascularizados por SCA.(AU)

Introduction: Functional physical capacity is indirectly associated with mortality, and may be compromised after a cardiovascular event, hence the importance of considering its prognostic factors during treatment in heart disease patients. Aim: To identify the prognostic factors of functional physical limitation in patients with myocardial revascularization for acute coronary syndrome. Material and method: A retrospective analysis was carried out of 29 medical records taken from patients submitted to a stress test (Bruce, modified Bruce) after myocardial revascularization during the months of January to December 2019. For the statistical analysis, a univariate and multivariate logistic regression (Odds Ratio-OR) was performed, as well as a simple linear regression analysis between the variables of interest. Results: the analyzed patients had a mean age of 60 ± 9,2 years, and 76% were men. The presence of systemic arterial hypertension (SAH), lower values of Maximum Heart Rate (HR) (ß = 0,112; CI: 0,074, 0,149; p <0.001), high values of Systolic Arterial Pressure (SBP) (ß = - 0,083; CI 95%: -0,152, -0,014; p <0.020), and a greater number of risk factors (ß = - 1,580; CI 95%: -2,456-0,868; p <0.001), are considered predictors of functional limitation (<7 METs). Conclusion: The presence of SAH, a greater number of risk factors, as well as high maximum SBP levels and lower maximum HR values reached during the stress test, were shown to be prognostic factors of functional limitation in subjects revascularized for ACS.(AU)

Feasibility and preliminary efficacy of perioperative interventions in patients undergoing coronary artery bypass grafting: the randomized controlled I-COPE trial.

OBJECTIVES: Patients undergoing coronary artery bypass graft (CABG) surgery are exposed to multiple treatment-related stressors, which can impact coping and health-related quality of life (HRQoL). The objective of this trial was to analyse the feasibility and preliminary efficacy of a multi-component intervention that combines psychological support and reduction of hospital-specific stressors on HRQoL, length of hospital and intensive care unit stay, self-efficacy, and plasma interleukin (IL)-6 and -8 levels in CABG patients. METHODS: This three-arm, randomized controlled, single-centre pilot trial assessed the Intervention for CABG to Optimize Patient Experience in 88 patients undergoing elective CABG. Standard medical care (SMC, n = 29) was compared with 2 intervention groups: (i) psychological interventions to optimize treatment expectations (IA group, n = 30) and (ii) multi-component intervention (IB group, n = 29) with psychological interventions plus an additional treatment package (light therapy, noise reduction, music, and if desired, 360° images delivered via virtual reality). RESULTS: The implementation of psychological interventions in routine medical treatment was feasible (91.5% of participants completed all intervention sessions). Both interventions were associated with significantly shorter hospital stay compared to SMC (IA/IB 9.8/9.3 days vs SMC 12.5 days). Self-efficacy expectations at post-surgery were significantly higher compared to SMC both in the IA group (P = 0.011) and marginally in the IB group (P = 0.051). However, there were no treatment effects of the interventions on HRQoL and plasma levels of IL-6 or IL-8 after CABG. CONCLUSIONS: A perioperative multi-component intervention may lead to shorter hospital stay and higher self-efficacy after CABG. Further studies are needed to determine its impact on HRQoL and inflammation. CLINICAL TRIAL REGISTRATION NUMBER: Ethical approval (# 21/2/18) for the study was obtained from the Research Ethics Committee of the University of Göttingen Medical Center, and the trial was registered in the German Clinical Trials Register (DRKS00015309, https://www.drks.de/drks_web/setLocale_EN.do).

Base editing sensor libraries for high-throughput engineering and functional analysis of cancer-associated single nucleotide variants.

Base editing can be applied to characterize single nucleotide variants of unknown function, yet defining effective combinations of single guide RNAs (sgRNAs) and base editors remains challenging. Here, we describe modular base-editing-activity 'sensors' that link sgRNAs and cognate target sites in cis and use them to systematically measure the editing efficiency and precision of thousands of sgRNAs paired with functionally distinct base editors. By quantifying sensor editing across >200,000 editor-sgRNA combinations, we provide a comprehensive resource of sgRNAs for introducing and interrogating cancer-associated single nucleotide variants in multiple model systems. We demonstrate that sensor-validated tools streamline production of in vivo cancer models and that integrating sensor modules in pooled sgRNA libraries can aid interpretation of high-throughput base editing screens. Using this approach, we identify several previously uncharacterized mutant TP53 alleles as drivers of cancer cell proliferation and in vivo tumor development. We anticipate that the framework described here will facilitate the functional interrogation of cancer variants in cell and animal models.

Cortisol Awakening Reaction and Anxiety in Depressed Coronary Artery Disease Patients.

Disturbances of HPA axis functioning as represented by cortisol awakening reaction (CAR) belong to the mediating pathways linking psychosocial distress and cardiovascular risk. Both depression and anxiety have been confirmed as independent risk factors for coronary artery disease (CAD). However, data on anxiety and cortisol output in CAD patients are scarce. Based on previous data, we hypothesized that anxiety would be associated with higher cortisol output and a more pronounced morning increase in moderately depressed CAD patients. 77 patients (60 y, 79% male) underwent saliva sampling (+0, +30, +45, +60 min after awakening, midday and late-night sample). Anxiety was measured using the Hospital Anxiety and Depression Scale (HADS) and patients were grouped into anxious versus non anxious subjects based upon the recommended score (≥11). A repeated measures ANOVA yielded a significant time and quadratic time effect referring to the typical CAR. Anxious patients showed a significantly steeper 30 min increase, higher AUCi, lower waking and late-night cortisol levels. The steeper cortisol increase in the anxious group is in line with previous data and may be interpreted as a biological substrate of affect regulation. The lower basal and late-night levels coupled with greater AUCi mirror a more dynamic reactivity pattern compared to depressed subjects without anxiety.

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.

Synthesis and Characterization of a Novel Biocompatible Alloy, Ti-Nb-Zr-Ta-Sn.

Many current-generation biomedical implants are fabricated from the Ti-6Al-4V alloy because it has many attractive properties, such as low density and biocompatibility. However, the elastic modulus of this alloy is much larger than that of the surrounding bone, leading to bone resorption and, eventually, implant failure. In the present study, we synthesized and performed a detailed analysis of a novel low elastic modulus Ti-based alloy (Ti-28Nb-5Zr-2Ta-2Sn (TNZTS alloy)) using a variety of methods, including scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and tensile test. Additionally, the in vitro biocompatibility of the TNZTS alloy was evaluated using SCP-1, SaOs-2, and THP-1 cell lines and primary human osteoblasts. Compared to Ti-6Al-4V, the elastic modulus of TNZTS alloy was significantly lower, while measures of its in vitro biocompatibility are comparable. O2 plasma treatment of the surface of the alloy significantly increased its hydrophilicity and, hence, its in vitro biocompatibility. TNZTS alloy specimens did not induce the release of cytokines by macrophages, indicating that such scaffolds would not trigger inflammatory responses. The present results suggest that the TNZTS alloy may have potential as an alternative to Ti-6Al-4V.

Effects of chronic cholinergic stimulation associated with aerobic physical training on cardiac morphofunctional and autonomic parameters in spontaneously hypertensive rats.

We investigated hemodynamic, cardiac morphofunctional, and cardiovascular autonomic adaptations in spontaneously hypertensive rats (SHRs) after aerobic physical training associated with chronic cholinergic stimulation. Fifty-four SHRs were divided into two groups: trained and untrained. Each group was further subdivided into three smaller groups: vehicle, treated with pyridostigmine bromide at 5 mg/kg/day, and treated with pyridostigmine bromide at 15 mg/kg/day. The following protocols were assessed: echocardiography, autonomic double pharmacological blockade, heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS). Physical training and pyridostigmine bromide reduced BP and HR and increased vagal participation in cardiac autonomic tonic balance. The associated responses were then potentialized. Treatment with pyridostigmine bromide increased HRV oscillation of both low frequency (LF: 0.2-0.75 Hz) and high frequency (HF: 0.75-3 Hz). However, the association with physical training attenuated HF oscillations. Additionally, treatment with pyridostigmine bromide also increased LF oscillations of BPV. Both treatment groups promoted morphofunctional adaptations, and associated increased ejection volume, ejection fraction, cardiac output, and cardiac index. In conclusion, the association of pyridostigmine bromide and physical training promoted greater benefits in hemodynamic parameters and increased vagal influence on cardiac autonomic tonic balance. Nonetheless, treatment with pyridostigmine bromide alone seems to negatively affect BPV and the association of treatment negatively influences HRV.

Study of heart rate recovery and cardiovascular autonomic modulation in healthy participants after submaximal exercise.

Heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity (BRS) provide important information on cardiovascular autonomic control. However, little is known about the reorganization of HRV, BPV, and BRS after aerobic exercise. While there is a positive relationship between heart rate (HR) recovery rate and cardiorespiratory fitness, it is unclear whether there is a relationship between cardiorespiratory fitness and reorganization of cardiovascular autonomic modulation during recovery. Thus, this study aimed to investigate whether cardiorespiratory fitness influences the cardiovascular autonomic modulation recovery, after a cardiopulmonary exercise test. Sixty men were assigned into groups according to their cardiorespiratory fitness: low cardiorespiratory fitness (LCF = VO2: 22-38 mL kg-1 min-1), moderate (MCF = VO2: 38-48 mL kg-1 min-1), and high (HCF = VO2 > 48 mL kg-1 min-1). HRV (linear and non-linear analysis) and BPV (spectral analysis), and BRS (sequence method) were performed before and after a cardiopulmonary exercise test. The groups with higher cardiorespiratory fitness had lower baseline HR values and HR recovery time after the cardiopulmonary exercise test. On comparing rest and recovery periods, the spectral analysis of HRV showed a decrease in low-frequency (LF) oscillations in absolute units and high frequency (HF) in absolute and normalized units. It also showed increases in LF oscillations of blood pressure. Nonlinear analysis showed a reduction in approximate entropy (ApEn) and in Poincare Plot parameters (SD1 and SD2), accompanied by increases in detrended fluctuation analysis (DFA) parameters α1 and α2. However, we did not find differences in cardiovascular autonomic modulation parameters and BRS in relation to cardiorespiratory fitness neither before nor after the cardiopulmonary test. We concluded that cardiorespiratory fitness does not affect cardiovascular autonomic modulations after cardiopulmonary exercise test, unlike HR recovery.

Important differences between hypertensive middle-aged women and men in cardiovascular autonomic control-a critical appraisal.

BACKGROUND: Normotensive premenopausal women show a vagal predominance of cardiac autonomic modulation, whereas age-matched men show a predominance of sympathetic modulation. However, some women develop systemic arterial hypertension (SAH) even with preserved ovarian function. Our hypothesis is that these women may have cardiovascular autonomic parameters similar to those of hypertensive men, even when subjected to pharmacological treatment. We aimed to investigate cardiovascular autonomic control and baroreflex sensitivity (BRS) in hypertensive premenopausal women and age-matched men. METHODS: One hundred volunteers between 18 and 45 years of age were assigned to two groups (50 participants each): a hypertensive group including patients with a history of SAH for at least 6 months (25 men and 25 women), who were under treatment with monotherapy (losartan, 25-50 mg/kg); and a normotensive group (25 men and 25 women). Anthropometric, hemodynamic, metabolic, and autonomic cardiovascular assessments were performed focusing on BRS, autonomic modulation of heart rate variability (HRV), and blood pressure variability (BPV). RESULTS: On HRV analysis, women showed higher values of high-frequency (HF) oscillations in absolute and normalized units, lower values ​of low-frequency (LF) in normalized units, and lower LF/HF ratio, as compared with men. When the normotensive and hypertensive groups were compared, hypertensive groups showed lower values ​of total variance and of LF and HF bands in absolute units. On BRS, hypertensive groups showed lower values than the normotensive group. CONCLUSION: Regardless of blood pressure control through pharmacological treatment, hypertensive patients continued to have reduced HRV compared to normotensive, and hypertensive men had more autonomic impairment than hypertensive premenopausal women.

Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial.

BACKGROUND: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. METHODS: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525. FINDINGS: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths. INTERPRETATION: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment. FUNDING: Karyopharm Therapeutics.

Perception of the 2020 SARS-CoV-2 pandemic among medical professionals in Germany: results from a nationwide online survey.

Background: The COVID-19 pandemic represents an unprecedented global challenge and implicates a wide range of burden on medical professionals. Here, we evaluated the perception of the COVID-19 pandemic among medical professionals in Germany. Methods: A total of n = 2827 medical professionals participated in an online survey between 27 March and 11 April. Results: While most participants stated that Germany was well prepared and rated the measures taken by their employer as positive, subgroup analyses revealed decisive differences. The preventive measures were rated significantly worse by nurses compared to doctors (p < 0.001) and by participants from ambulatory healthcare centres compared to participants from maximum-care hospitals (p < 0.001). Importantly, shortage of protective medical equipment was reported more commonly in the ambulatory sector (p < 0.001) and in East German federal states (p = 0.004). Moreover, the majority of health care professionals (72.4%) reported significant restrictions of daily work routine. Finally, over 60% of medical professionals had concerns regarding their own health, which were more pronounced among female participants (p = 0.024). Conclusion: This survey may indicate starting points on how medical professionals could be supported in carrying out their important activities during the ongoing and future healthcare challenges.

Length Polymorphisms in the Angiotensin I-Converting Enzyme Gene and the Serotonin-Transporter-Linked Polymorphic Region Constitute a Risk Haplotype for Depression in Patients with Coronary Artery Disease.

Genetic variations affecting the course of depressive symptoms in patients with coronary artery disease (CAD) have not yet been well studied. Therefore, we set out to investigate whether distinct haplotypes of the two insertion/deletion polymorphisms in the serotonin-transporter-linked polymorphic region (5-HTTLPR) and the angiotensin I-converting enzyme (ACE) gene located on chromosome 17 can be identified as risk factors for trajectories of depression. Clinical and genotyping data were derived from 507 depressed CAD patients participating in the randomized, controlled, multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial, of whom the majority had an acute cardiac event before study inclusion. Depression scores on the Hospital Anxiety and Depression Scale (HADS) were assessed at baseline and at five follow-up time points up to 2 years after study entrance. At baseline, depression scores did not significantly differ between patients carrying the risk haplotype ACE D/D, 5-HTTLPR I/I (n = 46) and the non-risk haplotypes (n = 461, 10.9 ± 2.7 versus 10.4 ± 2.5, p = 0.254). HADS-depression scores declined from study inclusion during the first year irrespective of the genotype. At each follow-up time point, HADS-depression scores were significantly higher in ACE D/D, 5-HTTLPR I/I carriers than in their counterparts. Two years after study inclusion, the mean HADS depression score remained 1.8 points higher in patients with the risk haplotype as compared to subjects not carrying this haplotype (9.9 ± 4.2 versus 8.1 ± 4.0, p = 0.009). In summary, the presence of the ACE D/D, 5-HTTLPR I/I haplotype may be a vulnerability factor for comorbid depressive symptoms in CAD patients.

Hematological malignancies in Ukraine in post-Chernobyl era: sources of data and their preliminary analysis.

The major sources of the data on the hematological malignancies in the post-Chernobyl period in the regions of Ukraine differing by the levels of the residual contamination with radionuclides have been analyzed. According to the data collected from the primary hematological facilities in Ukraine in 2010-2017, the incidence of lymphoid neoplasms from mature B cells, acute myeloid leukemia, and multiple myeloma in the most contaminated regions was higher than in the less contaminated ones. For the first time, the relative contribution of the several specific types of leukemia in the total diagnosed hematological malignancies has been analyzed throughout 1997-2017 based on the in-house database compiled by the Reference Laboratory of RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, the National Academy of Sciences of Ukraine. In 2011-2017, the Reference Laboratory provided the diagnostic studies in about 26% of all Ukrainian patients with tumors of hematopoietic and lymphoid tissues (34% of patients with different forms of acute and chronic leukemia). The increased proportion of acute myeloid leukemia and chronic lymphocytic leukemia in the total diagnosed cases of overall leukemia in the patients from contaminated regions has been demonstrated following Chernobyl accident.

Blended collaborative care in the secondary prevention of coronary heart disease improves risk factor control: Results of a randomised feasibility study.

BACKGROUND: Risk factor control is essential in limiting the progression of coronary heart disease, but the necessary active patient involvement is often difficult to realise, especially in patients suffering psychosocial risk factors (e.g. distress). Blended collaborative care has been shown as an effective treatment addition, in which a (non-physician) care manager supports patients in implementing and sustaining lifestyle changes, follows-up on patients, and integrates care across providers, targeting both, somatic and psychosocial risk factors. AIMS: The aim of this study was to test the feasibility, acceptance and effect of a six-month blended collaborative care intervention in Germany. METHODS: For our randomised controlled pilot study with a crossover design we recruited coronary heart disease patients with ⩾1 insufficiently controlled cardiac risk factors and randomised them to either immediate blended collaborative care intervention (immediate intervention group, n=20) or waiting control (waiting control group, n=20). RESULTS: Participation rate in the intervention phase was 67% (n=40), and participants reported high satisfaction (M=1.63, standard deviation=0.69; scale 1 (very high) to 5 (very low)). The number of risk factors decreased significantly from baseline to six months in the immediate intervention group (t(60)=3.07, p=0.003), but not in the waiting control group t(60)=-0.29, p=0.77). Similarly, at the end of their intervention following the six-month waiting period, the waiting control group also showed a significant reduction of risk factors (t(60)=3.88, p<0.001). CONCLUSION: This study shows that blended collaborative care can be a feasible, accepted and effective addition to standard medical care in the secondary prevention of coronary heart disease in the German healthcare system.