Impact of Guideline-Directed Drug Therapy after ST-Elevation Myocardial Infarction on Outcome in Young Patients-Age and Sex-Specific Factors.

Background: Specifically young women are at risk for a poor outcome after ST-elevation myocardial infarction (STEMI). We aimed to investigate sex- and age-specific differences in outcome and associate these results with adherence to a guideline-directed optimal medical therapy (OMT). Methods: Administrative insurance data (≈26 million insured) were screened for patients aged 18-60 years with STEMI. Patient demographics, details on in-hospital treatment, adherence to OMT and its effect on mortality were assessed. Adherence to OMT was analyzed using multistate models and an association of those with death was fitted using multivariable Cox regression models with time-dependent co-variables. Results: Overall, 59,401 patients (19.3% women), median age 52 (interquartile range 48, 56) presented with STEMI. Female sex was associated with a poor outcome early after STEMI (90-day mortality: odds ratio 1.22, 95% confidence interval (CI) 1.12-1.32, p < 0.001). Overall survival was reduced in women compared to same-aged men. The ten-year survival rate was 19.7% (18.1-21.2%) versus 19.6% (18.9-20.4%) in men (p < 0.001). Although long-term drug adherence was low, its intake was associated with a better outcome. Specifically younger women showed a markedly lower mortality when on OMT (hazard ratio (HR) 0.22 (95% CI 0.19-0.26) versus HR 0.31 (95% CI 0.28-0.33) in men, pint < 0.001). Conclusions: Specifically young women were at risk for a poor outcome in the early phase after STEMI. Although long-term adherence to OMT was low, it was generally associated with a lower mortality, specifically in women. Our findings emphasize on early and long-term preventive measures in all patients after STEMI.

Ex Vivo Vascular Imaging and Perfusion Studies of Normal Kidney and Tumor Vasculature.

This work describes a comprehensive study of the vascular tree and perfusion characteristics of normal kidney and renal cell carcinoma. Methods: Nephrectomy specimens were perfused ex-vivo, and the regional blood flow was determined by infusion of radioactive microspheres. The vascular architecture was characterized by micronized barium sulphate infusion. Kidneys were subsequently sagitally sectioned, and autoradiograms were obtained to show the perfusate flow in relation to adjacent contact X-ray angiograms. Vascular resistance in defined tissue compartments was quantified, and finally, the tumor vasculature was 3D reconstructed via the micro-CT technique. Results show that the vascular tree of the kidney could be distinctly defined, and autoradiograms disclosed a high cortical flow. The peripheral resistance unit of the whole perfused specimen was 0.78 ± 0.40 (n = 26), while that of the renal cortex was 0.17 ± 0.07 (n = 15 with 114 samples). Micro-CT images from both cortex and medulla defined the vascular architecture. Angiograms from the renal tumors demonstrated a significant vascular heterogeneity within and between different tumors. A dense and irregular capillary network characterized peripheral tumor areas, whereas central parts of the tumors were less vascularized. Despite the dense capillarity, low perfusion through vessels with a diameter below 15 µm was seen on the autoradiograms. We conclude that micronized barium sulphate infusion may be used to demonstrate the vascular architecture in a complex organ. The vascular resistance was low, with little variation in the cortex of the normal kidney. Tumor tissue showed a considerable vascular structural heterogeneity with low perfusion through the peripheral nutritive capillaries and very poor perfusion of the central tumor, indicating intratumoral pressure exceeding the perfusion pressure. The merits and shortcomings of the various techniques used are discussed.

Complications and Outcomes in 39,864 Patients Receiving Standard Care Plus Mechanical Circulatory Support or Standard Care Alone for Infarct-Associated Cardiogenic Shock.

BACKGROUND: Temporary mechanical circulatory support devices (tMCS) are increasingly being used in patients with infarct-associated cardiogenic shock (AMICS). Evidence on patient selection, complications and long-term outcomes is lacking. We aim to investigate differences in clinical characteristics, complications and outcomes between patients receiving no tMCS or either intra-aortic balloon pump (IABP), veno-arterial extracorporeal membrane oxygenation (V-A ECMO) or Impella® for AMICS, with a particular focus on long-term outcomes. METHODS: Using health claim data from AOK-Die Gesundheitskasse (local health care funds), we retrospectively analysed complications and outcomes of all insured patients with AMICS between 1 January 2010 and 31 December 2017. RESULTS: A total of 39,864 patients were included (IABP 5451; Impella 776; V-A ECMO 833; no tMCS 32,804). In-hospital complications, including renal failure requiring dialysis (50.3% V-A ECMO vs. 30.5% Impella vs. 29.2 IABP vs. 12.1% no tMCS), major bleeding (38.1% vs. 20.9% vs. 18.0% vs. 9.3%) and sepsis (22.5% vs. 15.9% vs. 13.9% vs. 9.3%) were more common in V-A ECMO patients. In a multivariate analysis, the use of both V-A ECMO (HR 1.57, p < 0.001) and Impella (HR 1.25, p < 0.001) were independently associated with long-term mortality, whereas use of IABP was not (HR 0.89, p < 0.001). Kaplan-Meier estimates showed better survival for patients on IABP compared with Impella, V-A ECMO and no-tMCS. Short- and long-term mortality was high across all groups. CONCLUSIONS: Our data show noticeably more in-hospital complications in patients on tMCS and higher mortality with V-A ECMO and Impella. The use of both devices is an independent risk factor for mortality, whereas the use of IABP is associated with a survival benefit.

Antisecretory factor in breastmilk is associated with reduced incidence of sepsis in preterm infants.

BACKGROUND: Antisecretory Factor (AF) is a protein present in breastmilk that regulates inflammatory processes. We aimed to investigate the level of AF in mothers' own milk (MOM) in relation to sepsis and other neonatal morbidities in preterm infants. METHODS: Samples of breastmilk and infant plasma were collected at 1, 4, and 12 weeks after birth from 38 mothers and their 49 infants born before 30 weeks gestation. AF-compleasome in MOM was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) and inflammatory markers in infant plasma by a panel of 92 inflammatory proteins. Neonatal treatments and outcomes were recorded. RESULTS: The level of AF in MOM week 1 was lower for infants with later sepsis compared to no sepsis (p = 0.005). Corrected for nutritional intake of MOM, higher levels of AF decreased the risk for sepsis, OR 0.24. AF in MOM week 1 was negatively correlated to inflammatory proteins in infant plasma week 4, markedly IL-8, which was also associated with infant sepsis. Overall, higher AF levels in MOM was associated with fewer major morbidities of prematurity. CONCLUSION: Mother's milk containing high levels of antisecretory factor is associated with reduced risk for sepsis and inflammation in preterm infants. IMPACT: High level of antisecretory factor (AF) in mothers' own milk is associated with less risk for later sepsis in preterm infants. Receiving mothers' milk with low AF levels during the first week after birth is correlated with more inflammatory proteins in infant's plasma 2-4 weeks later. Human breastmilk has anti-inflammatory properties, and antisecretory factor in mothers' own milk is a component of potential importance for infants born preterm. The findings suggest that food supplementation with AF to mothers of preterm infants to increase AF-levels in breastmilk may be a means to decrease the risk of inflammatory morbidities of prematurity.

Contemporary secondary prevention in survivors of ST-elevation myocardial infarction with and without chronic kidney disease: a retrospective analysis.

Background: Survivors of myocardial infarction have an elevated risk of long-term mortality. We sought to evaluate guideline-directed medical treatment and its impact on long-term mortality in survivors of ST-elevation myocardial infarction (STEMI) according to their chronic kidney disease (CKD) stage. Methods: Using German health insurance claims data, 157 663 hospitalized survivors of STEMI were identified. Regarding different CKD stages, we retrospectively analysed the filled prescriptions of platelet inhibitors (PAI)/oral anticoagulation, statins, beta-blocker and angiotensin-converting enzyme inhibitors/angiotensin II type 1 receptor antagonists (ACE-I/AT1-A) and their association with long-term mortality. Results: Prescription rates for all four guideline-directed drugs were highest in patients without or with mild CKD and lowest in patients on dialysis. They dropped from 73.4% to 39.2% in patients without CKD and from 47.1% to 29% in patients on dialysis within the 5-year follow-up period. Mortality rates were dramatically increased in patients with CKD compared with patients without CKD (5-year mortality: no CKD, 16.7%; CKD stage 3, 47.1%; CKD stage 5d, 69.7%). Filled prescriptions of at least one drug class [one drug: hazard ratio (HR) 0.70, 95% confidence interval (95% CI) 0.66-0.74; four drugs: HR 0.28, 95% CI 0.27-0.30; P < .001 for both] as well as the distinct drug classes (statins: HR 0.55, 95% CI 0.54-0.56; ACE-I/AT1-A: HR 0.68, 95% CI 0.67-0.70; beta-blocker: HR 0.87, 95% CI 0.85-0.90; PAI/oral anticoagulation: HR 0.97, 95% CI 0.95-1.00; all P < .05) improved long-term mortality. Conclusions: An improved long-term guideline-recommended drug therapy after STEMI regardless of renal impairment might lead to beneficial effects on long-term mortality.

Survival of Patients with Acute Coronary Syndrome and Hematologic Malignancies-A Real-World Analysis.

BACKGROUND: The impact of the encounter between coronary heart disease (CHD) and cancer, and in particular hematologic malignancies (HM), remains poorly understood. OBJECTIVE: The aim of this analysis was to clarify how HM affects the prognosis of acute coronary syndrome (ACS). We analyzed German health insurance data from 11 regional Ortskrankenkassen (AOK) of patients hospitalized for ACS between January 2010 and December 2018, matched by age, sex and all comorbidities for short- and long-term survival and major adverse cardiac events (MACE). RESULTS: Of 439,716 patients with ACS, 2104 (0.5%) also had an HM. Myelodysplastic/myeloproliferative disorders (27.7%), lymphocytic leukemias (24.8%), and multiple myeloma (22.4%) predominated. These patients were about 6 years older (78 vs. 72 years *). They had an ST-segment elevation myocardial infarction (STEMI, 18.2 vs. 34.9% *) less often and more often had a non-STEMI (NSTEMI, 81.8 vs. 65.1% *). With the exception of dyslipidemia, these patients had more concomitant and previous cardiovascular disease and a worse NYHA stage. They were less likely to undergo coronary angiography (65.3 vs. 71.6% *) and percutaneous coronary intervention (PCI, 44.3 vs. 52.0% *), although the number of bleeding events was not relevantly increased (p = 0.22). After adjustment for the patients' risk profile, the HM was associated with reduced long-term survival. However, this was not true for short-term survival. Here, there was no difference in the STEMI patients, * p < 0.001. CONCLUSION: Survival in ACS and HM is significantly lower, possibly due to the avoidance of PCI because of a perceived increased risk of bleeding.

Supine MDS-UPDRS-III Assessment: An Explorative Study.

The Movement Disorder Society Unified Parkinson's Disease Rating Scale-part III (MDS-UPDRS-III) is designed to be applied in the sitting position. However, to evaluate the clinical effect during stereotactic neurosurgery or to assess bedridden patients with Parkinson's disease (PD), the MDS-UPDRS-III is often used in a supine position. This explorative study evaluates the agreement of the MDS-UPDRS-III in the sitting and the supine positions. In 23 PD patients, the MDS-UPDRS-III was applied in both positions while accelerometric measurements were performed. Video recordings of the assessments were evaluated by two certified raters. Agreement between the sitting and supine MDS-UPDRS-III was studied using Cohen's kappa coefficient. Relationships between the MDS-UPDRS-III tremor scores and accelerometric amplitudes were calculated for both positions with linear regression. A fair to substantial agreement was found for MDS-UPDRS-III scores of individual items in the sitting and supine positions, while combining all tests resulted in a substantial agreement. The inter-rater reliability was fair to moderate for both positions. A logarithmic relationship between tremor scores and accelerometric amplitude was revealed for both the sitting and supine positions. Nevertheless, these data are insufficient to fully support the supine application of the MDS-UPDRS-III. Several recommendations are made to address the sensitivity of the scale to inter-rater variability. In conclusion, although an overall substantial agreement between sitting and supine MDS-UPDRS-III is confirmed, its application in the supine position is not endorsed for the whole range of its individual items. Caution is warranted in interpreting the supine MDS-UPDRS-III, pending additional research.

Sex disparities in guideline-recommended therapies and outcomes after ST-elevation myocardial infarction in a contemporary nationwide cohort of patients over an eight-year period.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) is the leading cause of death worldwide. Outcome has improved during the last decades due to secondary prevention and widespread coronary interventions, but recent studies still show sex differences and insufficient drug adherence. We aimed to determine differences in the treatment strategies and outcomes between women and men with ST-elevation myocardial infarction (STEMI) in Germany. METHODS: From the Federal Association of the Local Health Insurance Funds (Allgemeine Ortskrankenkasse), 175,187 patients were identified who were hospitalized due to STEMI in Germany between January 1, 2010 and December 31, 2017. RESULTS: Compared to men, women were older (median 76 vs. 64 years) and had more often diabetes, hypertension, chronic heart failure, and chronic kidney disease (all p <0.001). Women suffered from higher rates of in-hospital complications such as bleeding (9.3 vs. 6.6%), longer hospitalizations (12.2 vs. 11.7 days) and were less likely to undergo percutaneous coronary intervention (75.5 vs. 85.2%). After adjustment for patient's risk profile, female sex was associated with decreased overall survival (HR 1.02, 95% confidence interval (CI) 1.00-1.04; p=0.036). Notably, more men received all four guideline-recommended drugs after STEMI (women 65.7% vs. men 69.8% after 90 days; p <0.001). With increasing number of prescribed drugs, patients benefit even more. This concerned both sexes, but was more pronounced in men (with 4 prescribed drugs: women HR 0.52, 95%CI 0.50-0.55; men HR 0.48, 95% CI 0.47-0.50, pint = 0.014). CONCLUSIONS: In a contemporary nationwide analysis, women with STEMI were older, had more comorbidities, underwent revascularization less often and had an increased risk for major complications as well as overall survival. Guideline-recommended drug therapy was applied less frequently in women although associated with an improved overall-survival.

Distinct Cholesterol Localization in Glioblastoma Multiforme Revealed by Mass Spectrometry Imaging.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor in adults and is highly resistant to chemo- and radiotherapies. GBM has been associated with alterations in lipid contents, but lipid metabolism reprogramming in tumor cells is not fully elucidated. One of the key hurdles is to localize the lipid species that are correlated with tumor growth and invasion. A better understanding of the localization of abnormal lipid metabolism and its vulnerabilities may open up to novel therapeutic approaches. Here, we use time-of-flight secondary ion mass spectrometry (ToF-SIMS) to spatially probe the lipid composition in a GBM biopsy from two regions with different histopathologies: one region with most cells of uniform size and shape, the homogeneous part, and the other with cells showing a great variation in size and shape, the heterogeneous part. Our results reveal elevated levels of cholesterol, diacylglycerols, and some phosphatidylethanolamine in the homogeneous part, while the heterogeneous part was dominated by a variety of fatty acids, phosphatidylcholine, and phosphatidylinositol species. We also observed a high expression of cholesterol in the homogeneous tumor region to be associated with large cells but not with macrophages. Our findings suggest that ToF-SIMS can distinguish in lipid distribution between parts within a human GBM tumor, which can be linked to different molecular mechanisms.

The relative effect of climate variability on malaria incidence after scale-up of interventions in western Kenya: A time-series analysis of monthly incidence data from 2008 to 2019.

Background: Despite considerable progress made over the past 20 years in reducing the global burden of malaria, the disease remains a major public health problem and there is concern that climate change might expand suitable areas for transmission. This study investigated the relative effect of climate variability on malaria incidence after scale-up of interventions in western Kenya. Methods: Bayesian negative binomial models were fitted to monthly malaria incidence data, extracted from records of patients with febrile illnesses visiting the Lwak Mission Hospital between 2008 and 2019. Data pertaining to bed net use and socio-economic status (SES) were obtained from household surveys. Climatic proxy variables obtained from remote sensing were included as covariates in the models. Bayesian variable selection was used to determine the elapsing time between climate suitability and malaria incidence. Results: Malaria incidence increased by 50% from 2008 to 2010, then declined by 73% until 2015. There was a resurgence of cases after 2016, despite high bed net use. Increase in daytime land surface temperature was associated with a decline in malaria incidence (incidence rate ratio [IRR] = 0.70, 95% Bayesian credible interval [BCI]: 0.59-0.82), while rainfall was associated with increased incidence (IRR = 1.27, 95% BCI: 1.10-1.44). Bed net use was associated with a decline in malaria incidence in children aged 6-59 months (IRR = 0.78, 95% BCI: 0.70-0.87) but not in older age groups, whereas SES was not associated with malaria incidence in this population. Conclusions: Variability in climatic factors showed a stronger effect on malaria incidence than bed net use. Bed net use was, however, associated with a reduction in malaria incidence, especially among children aged 6-59 months after adjusting for climate effects. To sustain the downward trend in malaria incidence, this study recommends continued distribution and use of bed nets and consideration of climate-based malaria early warning systems when planning for future control interventions.

Contemporary in-hospital and long-term prognosis of patients with acute ST-elevation myocardial infarction depending on renal function: a retrospective analysis.

BACKGROUND: Cardiovascular disease is often associated with chronic kidney disease (CKD), resulting in an increased risk for poor outcome. We sought to determine short-term mortality and overall survival in ST-elevation myocardial infarction (STEMI) patients with different stages of CKD. METHODS: In our retrospective cohort study with health insurance claims data of the Allgemeine Ortskrankenkasse (AOK), anonymized data of all STEMI patients hospitalized between 2010 and 2017 were analyzed regarding presence and severity of concomitant CKD. RESULTS: A total of 175,187 patients had an index-hospitalisation for STEMI (without CKD: 78.6% patients, CKD stage 1: 0.8%, CKD stage 2: 4.8%, CKD stage 3: 11.7%, CKD stage 4: 2.8%, CKD stage 5: 0.7%, CKD stage 5d: 0.6%). Patients with CKD were older and had more co-morbidities than patients without CKD. With increasing CKD severity, patients received less revascularization therapies (91.2%, 85.9%, 87.0%, 81.8%, 71.7%, 76.9% and 78.6% respectively, p < 0.001). After 1 year, guideline-recommended medications were prescribed less frequently in advanced CKD (83.4%, 79.3%, 81.5%, 74.7%, 65.0%, 59.4% and 53.7%, respectively, p < 0.001). CKD stages 4, 5 and 5d as well as chronic limb threatening ischemia (CLTI) were associated with decreased overall survival [CKD stage 4: hazard ratio (HR) 1.72; 95% CI 1.66-1.78; CKD stage 5: HR 2.55; 95% CI 2.37-2.73; CKD stage 5d: 5.64; 95% CI 5.42-5.86; CLTI: 2.06; 95% CI 1.98-2.13; all p < 0.001]. CONCLUSIONS: CKD is a frequent co-morbidity in patients with STEMI and is associated with a worse prognosis especially in advanced stages. Guideline-recommended therapies in patients with STEMI and CKD are still underused.

The Intraoperative Microlesion Effect Positively Correlates With the Short-Term Clinical Effect of Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: During the surgical procedure of deep brain stimulation (DBS), insertion of an electrode in the subthalamic nucleus (STN) frequently causes a temporary improvement of motor symptoms, known as the microlesion effect (MLE). The objective of this study was to determine the correlation between the intraoperative MLE and the clinical effect of DBS. MATERIALS AND METHODS: Thirty Parkinson's disease (PD) patients with Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) part III (MDS-UPDRS III) scores during bilateral STN-DBS implantation were included in this retrospective study. MDS-UPDRS III subscores (resting tremor, rigidity, and bradykinesia) of the contralateral upper extremity were used. During surgery, these subscores were assessed directly before and after insertion of the electrode. Also, these subscores were determined in the outpatient clinic after 11 weeks on average (on-stimulation). All assessments were performed in an off-medication state (at least 12 hours of medication washout). RESULTS: Postinsertion MDS-UPDRS motor scores decreased significantly compared to preinsertion scores (p < 0.001 for both hemispheres). The MLE showed a positive correlation with the clinical effect of DBS in both hemispheres (rho = 0.68 for the primarily treated hemisphere, p < 0.001, and rho = 0.59 for the secondarily treated hemisphere, p < 0.01). CONCLUSION: The MLE has a clinically relevant correlation with the effect of DBS in PD patients. These results suggest that the MLE can be relied upon as evidence of a clinically effective DBS electrode placement.

STN-DBS electrode placement accuracy and motor improvement in Parkinson's disease: systematic review and individual patient meta-analysis.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective neurosurgical treatment for Parkinson's disease. Surgical accuracy is a critical determinant to achieve an adequate DBS effect on motor performance. A two-millimetre surgical accuracy is commonly accepted, but scientific evidence is lacking. A systematic review and meta-analysis of study-level and individual patient data (IPD) was performed by a comprehensive search in MEDLINE, EMBASE and Cochrane Library. Primary outcome measures were (1) radial error between the implanted electrode and target; (2) DBS motor improvement on the Unified Parkinson's Disease Rating Scale part III (motor examination). On a study level, meta-regression analysis was performed. Also, publication bias was assessed. For IPD meta-analysis, a linear mixed effects model was used. Forty studies (1391 patients) were included, reporting radial errors of 0.45-1.86 mm. Errors within this range did not significantly influence the DBS effect on motor improvement. Additional IPD analysis (206 patients) revealed that a mean radial error of 1.13±0.75 mm did not significantly change the extent of DBS motor improvement. Our meta-analysis showed a huge publication bias on accuracy data in DBS. Therefore, the current literature does not provide an unequivocal upper threshold for acceptable accuracy of STN-DBS surgery. Based on the current literature, DBS-electrodes placed within a 2 mm range of the intended target do not have to be repositioned to enhance motor improvement after STN-DBS for Parkinson's disease. However, an indisputable upper cut-off value for surgical accuracy remains to be established. PROSPERO registration number is CRD42018089539.

[Sex Disparities in Treatment and Outcome of Patients with Lower Extremity Arterial Disease: A Secondary Data Analysis]. / Geschlechtsspezifische Unterschiede in der Versorgung und dem Outcome von pAVK Patienten ­ Eine Sekundärdatenanalyse.

AIM OF THE STUDY: The aim of our study was to analyse sex-specific differences in diagnosis and treatment of patients with lower extremity artery disease (LEAD) at Rutherford stage (RF) 1-3, based on secondary data. Furthermore, we focussed on the influence of the biological sex on short- and long-term outcome. METHODS: The GenderVasc project is carried out in cooperation with the AOK Research Institute (WIdO). As data basis, anonymized routine data from all insured patients of the AOK were used. All patients hospitalized due to a main diagnosis of LEAD at RF 1-3 were included and in addition to the multisectoral cross-sectional analysis, longitudinal analysis (follow-up of up to 10 years) of the health claims data was performed and evaluated. RESULTS: Our secondary data analysis of 42,197 patients with intermittent claudication (IC, LEAD at RF 1-3) showed that male patients were more often hospitalized due to LEAD, while women were older at time-point of index hospitalisation (female: 72.6 vs. male: 66.4 years). Fewer vascular procedures (diagnostic angiography and revascularisation) were carried out in females. Moreover, the prescription of guideline-recommended medications (statins and antithrombotic therapy) was lower in women compared to men. Multivariable Cox regression showed, after adjusting for age, cardiovascular risk profile and performed vascular procedure, that female sex was protective with respect to overall survival and progression of LEAD (progress to chronic limb-threatening ischemia or ischemic amputation). CONCLUSION: In Germany, female LEAD patients were older and less likely to receive guideline-recommended therapy, while female sex is protective in terms of overall survival and progression of LEAD. The extent to which increased age or the presence of other comorbidities influence the decision for or against a vascular procedure can only be assumed from a secondary data analysis. Furthermore, the prescription of drugs in multimorbid patients is challenging and the compliance of the patients with prescribed medication intake is not part of our analysis. Nevertheless, targeted analysis, as in the GenderVasc project, are urgently needed to identify and describe differences in the medical care between the sexes.

Involvement of GABAA receptors containing α6 subtypes in antisecretory factor activity on rat cerebellar granule cells studied by two-photon uncaging.

The antisecretory factor (AF) is an endogenous protein that counteracts intestinal hypersecretion and various inflammation conditions in vivo. It has been detected in many mammalian tissues and plasma, but its mechanisms of action are largely unknown. To study the pharmacological action of the AF on different GABAA receptor populations in cerebellar granule cells, we took advantage of the two-photon uncaging method as this technique allows to stimulate the cell locally in well-identified plasma membrane parts. We compared the electrophysiological response evoked by releasing a caged GABA compound on the soma, the axon initial segment and neurites before and after administering AF-16, a 16 amino acids long peptide obtained from the amino-terminal end of the AF protein. After the treatment with AF-16, we observed peak current increases of varying magnitude depending on the neuronal region. Thus, studying the effects of furosemide and AF-16 on the electrophysiological behaviour of cerebellar granules, we suggest that GABAA receptors, containing the α6 subunit, may be specifically involved in the increase of the peak current by AF, and different receptor subtype distribution may be responsible for differences in this increase on the cell.

Upregulation of the Endogenous Peptide Antisecretory Factor Enhances Hippocampal Long-term Potentiation and Promotes Learning in Wistar Rats.

Antisecretory Factor (AF) is an endogenous peptide known for its powerful antisecretory and anti-inflammatory properties. We have previously shown that AF also acts as a neuromodulator of GABAergic synaptic transmission in rat hippocampus in a way that results in disinhibition of CA1 pyramidal neurons. Disinhibition is expected to facilitate the induction of long-term potentiation (LTP), and LTP is known to play a crucial role in learning and memory acquisition. In the present study we investigated the effect of AF on LTP in CA3-CA1 synapses in rat hippocampus. In addition, endogenous AF plasma activity was upregulated by feeding the rats with specially processed cereals (SPC) and spatial learning and memory was studied in the Morris Water Maze (MWM). We found that LTP was significantly enhanced in the presence of AF, both when added exogenously in vitro as well as when upregulated endogenously by SPC-feeding. In the presence of the GABAA-receptor antagonist picrotoxin (PTX) there was however no significant enhancement of LTP. Moreover, rats fed with SPC demonstrated enhanced spatial learning and short-term memory, compared with control animals. These results show that the disinhibition of GABAergic transmission in the hippocampus by the endogenous peptide AF enhances LTP as well as spatial learning and memory.

Sex-related differences in treatment and outcome of chronic limb-threatening ischaemia: a real-world cohort.

AIMS: The prevalence of chronic limb-threatening ischaemia (CLTI) is increasing and available data often derive from cohorts with various selection criteria. In the present study, we included CLTI patients and studied sex-related differences in their risk profile, vascular procedures, and long-term outcome. METHODS AND RESULTS: We analysed 199 953 unselected patients of the largest public health insurance in Germany (AOK: Local healthcare funds), hospitalized between 2010 and 2017 for a main diagnosis of CLTI. A baseline period of 2 years before index hospitalization to assess comorbidities and previous procedures, and a follow-up period until 2018 were included. Female CLTI patients were older (median 81.4 vs. 73.8 years in males; P < 0.001) and more often diagnosed with hypertension, atrial fibrillation, chronic heart failure, and chronic kidney disease. Male patients suffered more frequently from diabetes mellitus, dyslipidaemia, smoking, cerebrovascular disease, and chronic coronary syndrome (all P < 0.001). Within hospitalized CLTI patients, females represent the minority (43% vs. 57%; P < 0.001) and during index hospitalization, women underwent less frequently diagnostic angiographies (67 vs. 70%) and revascularization procedures (61 vs. 65%; both P < 0.001). Moreover, women received less frequently guideline-recommended drugs like statins (35 vs. 43%) and antithrombotic therapy (48 vs. 53%; both P < 0.001) at baseline. Interestingly, after including age and comorbidities in a Cox regression analysis, female sex was associated with increased overall-survival (OS) [hazard ratio (HR) 0.95; 95% confidence interval (CI) 0.94-0.96] and amputation-free survival (AFS) (HR 0.84; 95% CI 0.83-0.85; both P < 0.001). CONCLUSION: Female patients with CLTI were older, underwent less often vascular procedures, and received less frequently guideline-recommended medication. Nevertheless, female sex was independently associated with better OS and AFS during follow-up.

Coronary Artery Disease and Cancer: Treatment and Prognosis Regarding Gender Differences.

Cardiovascular disease and cancer remain the leading causes of hospitalization and mortality in high-income countries. Survival after myocardial infarction has improved but there is still a difference in clinical outcome, mortality, and developing heart failure to the disadvantage of women with myocardial infarction. Most major cardiology trials and registries have excluded patients with cancer. As a result, there is only very limited information on the effects of coronary artery disease in cancer patients. In particular, the outcomes in women with cancer and coronary artery disease and its management remain empiric. We reviewed studies of over 27 million patients with coronary artery disease and cancer. Our review focused on the most important types of cancer (breast, colon, lung, prostate) and hematological malignancies with particular attention to sex-specific differences in treatment and prognosis.

Changes in Antisecretory Factor in Human Milk During the Postpartum and Length of Gestation.

BACKGROUND: Preterm infants are more susceptible to inflammatory complications than term infants. Human milk contains numerous bioactive components protecting the newborn infant. Antisecretory factor, a protein regulating secretory and inflammatory processes by complex binding with complement factors, is present in human milk. RESEARCH AIMS: To describe antisecretory factor (1) in mother's own milk in term and preterm infants; and (2) in donor milk before and after Holder pasteurization. METHODS: The study was prospective, longitudinal, explorative, and descriptive. Antisecretory factor-compleasome was determined using sandwich enzyme-linked immunosorbent assay in longitudinal human milk samples over 12 weeks from mothers (N = 87) of term (n = 41) and of preterm (n = 46) infants and 20 anonymized donor human milk samples before and after Holder pasteurization. RESULTS: Antisecretory factor-compleasome was overall higher in colostrum versus mature milk (p < .001) and no difference was found in term or preterm colostrum (p = .82). In mature milk, compleasome was higher and more variable in the preterm group (p = .01). After Holder pasteurization, compleasome levels increased (p < .001). CONCLUSION: Antisecretory factor followed the pattern of other immunological factors with high levels in colostrum. After preterm birth, levels of antisecretory factor were higher and more variable in mature milk. Holder pasteurization did not degrade antisecretory factor, indicating preserved anti-inflammatory properties in donor human milk.