Scientific guidelines for preclinical research on potentised preparations manufactured according to current pharmacopoeias-the PrePoP guidelines.

OBJECTIVE: Pharmacopoeias regulate the manufacture of potentised pharmaceutical preparations used in different branches of complementary and integrative medicine. The physicochemical properties and biological activity of these preparations are often investigated in preclinical research, yet no guidelines for experimental research currently exist in this area. The present PrePoP guidelines aim to provide recommendations to promote high-quality, statistically sound, and reproducible preclinical research on potentised preparations. METHODS: Input was gathered from researchers nominated by the relevant scientific societies using a simplified Delphi consensus approach covering the most relevant aspects of basic research methodology in the field including appropriate controls, sample preparation and handling, and statistics. After three rounds of feedback, a consensus was finally reached on the most important aspects and considerations for conducting high-quality research on potentised preparations. RESULTS: We present a series of recommendations on a range of topics including experimental controls, system stability, blinding and randomisation, environmental influences, and procedures for the preparation of potentised samples and controls, and we address some specific challenges of this research field. CONCLUSION: This expert consensus process resulted in a robust set of methodological guidelines for research on potentised preparations and provides a valuable framework that will inform and improve the quality of subsequent research in this emerging field. PLEASE CITE THIS ARTICLE AS: Tournier AL, Bonamin LV, Buchheim-Schmidt S, Cartwright S, Dombrowsky C, Doesburg P, Holandino C, Kokornaczyk MO, van de Kraats EB, López-Carvallo JA, Nandy P, Mazón-Suástegui JM, Mirzajani F, Poitevin B, Scherr C, Thieves K, Würtenberger S, Baumgartner S. Scientific guidelines for preclinical research on potentised preparations manufactured according to current pharmacopoeias-the PrePoP guidelines. J Integr Med. 2024; Epub ahead of print.

[COVID-19 deaths among residents of inpatient nursing homes in Munich-causes and places of death]. / COVID-19-Sterbefälle bei Bewohnern vollstationärer Pflegeeinrichtungen in München ­ Todesursachen und Sterbeorte.

INTRODUCTION: The new infectious disease COVID-19 first appeared in China in December 2019. So far, a systematic evaluation of death certificates of COVID-19-associated deaths of residents in inpatient nursing homes has not been presented. METHODS: Death certificates of all deaths in Munich in the death period from 1 March to 31 July 2020 were analyzed. Inclusion criteria were the presence of "Corona, COVID-19, SARS-CoV-2" on the death certificates. Standardized, anonymized data entry was performed. The collected data were analyzed descriptively. RESULTS: During the study period, a total of 5840 persons died, 281 (4.8%) of whom died of confirmed COVID-19 disease. Of those, 72 deaths involved residents of Munich nursing facilities. The most frequent causes of death were respiratory insufficiency (54 cases) and multiple organ failure (9 cases). On the death certificates, an average of two preexisting diseases had been reported; the average age at death was 88 years. All deaths of nursing home residents occurred in association with nosocomial COVID-19 outbreaks, which affected one-third of the facilities. The vast majority of these homes did not have a COVID-19 hygiene plan in place at the time. DISCUSSION: One quarter of all COVID-19 deaths in Munich occurred in the context of nosocomial outbreaks in elderly, chronically ill residents of nursing facilities. Evidence of inadequate risk assessment and inadequate hygiene management emerged. In the opinion of the authors, the appropriate structures for adequate hygiene management must be created and a hygiene regulation must be issued in which the tasks and responsibilities of the facility operators are defined.

[COVID-19- and influenza-associated deaths in Munich as of March 2020-a standardized analysis of death certificates]. / COVID-19- und influenzaassoziierte Sterbefälle in München ab März 2020 ­ eine standardisierte Auswertung von Todesbescheinigungen.

INTRODUCTION: In light of the current COVID-19 pandemic, the idea arose to conduct a study to comparatively evaluate deaths from two respiratory transmissible infectious diseases (pandemic COVID-19 and seasonal influenza) by means of death certificates received by the health department. METHODS: Death certificates of all deaths in Munich in the death period from 1 March-31 December 2020 were analyzed. The predefined inclusion criteria were the indication of "Corona, COVID-19, SARS-CoV­2, Influenza (A/B)" on the death certificates. Standardized data entry was performed. The collected data were analyzed descriptively in aggregated form. RESULTS: A total of 12,441 persons died during the study period, 1029 (8.3%) from confirmed COVID-19 and 22 (0.1%) from influenza. The two collectives matched well in the parameters studied. The mean age at death was approximately 80 years and the most common site of death was in hospital. Infectious disease was the cause of death in more than 90% of cases. The most common causes of death were acute respiratory distress syndrome/respiratory failure and multiorgan failure. An average of two previous illnesses were reported, most commonly diseases of the circulatory system and nervous system. There was no influenza death in the second pandemic wave. DISCUSSION: In this study, COVID-19- and influenza-associated deaths were compared for the first time. The deaths of both collectives matched well in the parameters studied, but still require verification in a larger study given the small numbers of influenza cases. An English full-text version of this article is available at SpringerLink as Supplementary Information.

In vitro evaluation of the anti-pathogenic activity of Okoubaka aubrevillei on the human gastrointestinal tract.

BACKGROUND: Okoubaka aubrevillei is used in traditional West African medicine and in homeopathy for treatment and prevention of several gastrointestinal problems. The aim of this in vitro study was to evaluate the effect of repeated doses of two Okoubaka products (10 % ethanolic tincture, mother tincture (MT); 3rd decimal potency, 3X) on the microbial activity of physiological human colon microbiota using a Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) and to investigate any preventive effect against infections with diarrhea-causing pathogens. METHODS: Upon inoculation with fecal microbiota from a healthy donor, 4 parallel proximal colon compartments of the SHIME were treated either with Okoubaka MT, Okoubaka 3X, ethanol control or blank control for 7 days. Using the Okoubaka-adapted microbial community from SHIME, 48 h challenge tests were performed with enterotoxigenic Escherichia coli (ETEC) and Salmonella enteritidis in 4 different doses (103-108 colony forming units as typical in vivo infectious doses). Pathogen concentrations, short-chain fatty acids (SCFAs) and branched SCFA production were measured in triplicate at 0, 24 and 48 h. RESULTS: In the challenge tests, both Okoubaka products were able to restrict the colonization of ETEC and Salmonella at 3 of the 4 pathogen doses (except the highest doses), with a stronger anti-pathogenic effect for MT, which included a reduction of 2.0 log-units of ETEC (p < 0.0001) and 1.1 log-units of Salmonella (p < 0.0001). Total SCFA levels remained unaffected, but butyrate increased during the first 24 h (p < 0.0001 for ETEC), accompanied by decreased acetate production. CONCLUSION: We observed in vitro a systemic activating effect of Okoubaka on intestinal microbiome resistance, which resulted in an anti-pathogenic effect, especially against ETEC. We hypothesize that the mode of action in vivo is also based on systemic regulative effects.

The Effect of N, C, Cr, and Nb Content on Silicon Nitride Coatings for Joint Applications.

Ceramic coatings deposited on orthopedic implants are an alternative to achieve and maintain high wear resistance of the metallic device, and simultaneously allow for a reduction in metal ion release. Silicon nitride based (SiNx) coatings deposited by high power impulse magnetron sputtering (HiPIMS) have shown potential for use in joint replacements, as a result of an improved chemical stability in combination with a good adhesion. This study investigated the effect of N, C, Cr, and Nb content on the tribocorrosive performance of 3.7 to 8.8 µm thick SiNx coatings deposited by HiPIMS onto CoCrMo discs. The coating composition was assessed from X-ray photoelectron spectroscopy and the surface roughness by vertical scanning interferometry. Hardness and Young's modulus were measured by nanoindentation and coating adhesion was investigated by scratch tests. Multidirectional wear tests against ultrahigh molecular weight polyethylene pins were performed for 2 million cycles in bovine serum solution (25%) at 37 °C, at an estimated contact pressure of 2.1 MPa. Coatings with a relatively low hardness tended to fail earlier in the wear test, due to chemical reactions and eventually dissolution, accelerated by the tribological contact. In fact, while no definite correlation could be observed between coating composition (N: 42.6-55.5 at %, C: 0-25.7 at %, Cr: 0 or 12.8 at %, and Nb: 0-24.5 at %) and wear performance, it was apparent that high-purity and/or -density coatings (i.e., low oxygen content and high nitrogen content) were desirable to prevent coating and/or counter surface wear or failure. Coatings deposited with a higher energy fulfilled the target profile in terms of low surface roughness (Ra < 20 nm), adequate adhesion (Lc2 > 30 N), chemical stability over time in the tribocorrosive environment, as well as low polymer wear, presenting potential for a future application in joint bearings.

The Effect of Coating Density on Functional Properties of SiNx Coated Implants.

Ceramic coatings may be applied onto metallic components of joint replacements for improved wear and corrosion resistance as well as enhanced biocompatibility, especially for metal-sensitive patients. Silicon nitride (SiNx) coatings have recently been developed for this purpose. To achieve a high coating density, necessary to secure a long-term performance, is however challenging, especially for sputter deposited SiNx coatings, since these coatings are insulating. This study investigates the time-dependent performance of sputter-deposited SiNx based coatings for joint applications. SiNx coatings with a thickness in the range of 4.3-6.0 µm were deposited by reactive high power impulse magnetron sputtering onto flat discs as well as hip heads made of CoCrMo. SiNx compositional analysis by X-ray photoelectron spectroscopy showed N/Si ratios between 0.8 and 1.0. Immersion of the flat disks in fetal bovine serum solution over time as well as short-term wear tests against ultra-high molecular weight polyethylene (UHMWPE) discs showed that a high coating density is required to inhibit tribocorrosion. Coatings that performed best in terms of chemical stability were deposited using a higher target power and process heating.

Plasma CVD of hydrogenated boron-carbon thin films from triethylboron.

Low-temperature chemical vapor deposition (CVD) of B-C thin films is of importance for neutron voltaics and semiconductor technology. The highly reactive trialkylboranes, with alkyl groups of 1-4 carbon atoms, are a class of precursors that have been less explored for low-temperature CVD of B-C films. Herein, we demonstrate plasma CVD of B-C thin films using triethylboron (TEB) as a single source precursor in an Ar plasma. We show that the film density and B/C ratio increases with increasing plasma power, reaching a density of 2.20 g/cm3 and B/C = 1.7. This is attributed to a more intense energetic bombardment during deposition and more complete dissociation of the TEB molecule in the plasma at higher plasma power. The hydrogen content in the films ranges between 14 and 20 at. %. Optical emission spectroscopy of the plasma shows that BH, CH, C2, and H are the optically active plasma species from TEB. We suggest a plasma chemical model based on ß-hydrogen elimination of C2H4 to form BH3, in which BH3 and C2H4 are then dehydrogenated to form BH and C2H2. Furthermore, C2H2 decomposes in the plasma to produce C2 and CH, which together with BH and possibly BH3-x(C2H5)x are the film forming species.

Influence of Substrate Heating and Nitrogen Flow on the Composition, Morphological and Mechanical Properties of SiNx Coatings Aimed for Joint Replacements.

Silicon nitride (SiNx) coatings are promising for joint replacement applications due to their high wear resistance and biocompatibility. For such coatings, a higher nitrogen content, obtained through an increased nitrogen gas supply, has been found to be beneficial in terms of a decreased dissolution rate of the coatings. The substrate temperature has also been found to affect the composition as well as the microstructure of similar coatings. The aim of this study was to investigate the effect of the substrate temperature and nitrogen flow on the coating composition, microstructure and mechanical properties. SiNx coatings were deposited onto CoCrMo discs using reactive high power impulse magnetron sputtering. During deposition, the substrate temperatures were set to 200 °C, 350 °C or 430 °C, with nitrogen-to-argon flow ratios of 0.06, 0.17 or 0.30. Scanning and transmission electron spectroscopy revealed that the coatings were homogenous and amorphous. The coatings displayed a nitrogen content of 23-48 at.% (X-ray photoelectron spectroscopy). The surface roughness was similar to uncoated CoCrMo (p = 0.25) (vertical scanning interferometry). The hardness and Young's modulus, as determined from nanoindentation, scaled with the nitrogen content of the coatings, with the hardness ranging from 12 ± 1 GPa to 26 ± 2 GPa and the Young's moduli ranging from 173 ± 8 GPa to 293 ± 18 GPa, when the nitrogen content increased from 23% to 48%. The low surface roughness and high nano-hardness are promising for applications exposed to wear, such as joint implants.

Gender-related differences in self-reported dental care in adults with congenital heart disease at increased risk of infective endocarditis.

OBJECTIVE: Adults with congenital heart disease (CHD) are at increased risk of infective endocarditis (IE). Women with CHD have a lower IE risk, potentially due to gender-related differences in dental care. We aimed to assess self-reported dental hygiene measures in adults with CHD, and to identify factors associated with good oral hygiene. METHODS AND RESULTS: Descriptive study includes 187 adults with CHD at increased risk of IE. The patients' IE knowledge was assessed using an adapted version of the Leuven Knowledge Questionnaire for CHD. Their mean age was 34.9±14.9 years, 73 of them (39%) were women, 91 (49%) were at high risk for IE, including 66 (35%) with a prosthetic valve, 14 (7%) with a history of IE and 11 (6%) with cyanotic CHD or residual shunts/valvular regurgitation in the proximity of prosthetic material. The self-defined IE knowledge score did not differ between men and women (21.6±10.0 vs 23.4±10.0; p=0.225). 126 patients (67%) reported to have a good oral hygiene. Female gender (OR 2.4, 95% CI 1.1 to 4.4), and a higher IE knowledge score (OR 1.2, 95% CI 1.1 to 1.5, per 5 points) were the variables independently associated with good oral hygiene. CONCLUSIONS: In adults with CHD, patients with a higher IE knowledge score and women are more likely to practise dental care as recommended. Gender differences in oral hygiene practise may explain the observed lower female IE incidence rate. Efforts to improve patients' knowledge on IE are encouraged.

SiNx Coatings Deposited by Reactive High Power Impulse Magnetron Sputtering: Process Parameters Influencing the Nitrogen Content.

Reactive high power impulse magnetron sputtering (rHiPIMS) was used to deposit silicon nitride (SiNx) coatings for biomedical applications. The SiNx growth and plasma characterization were conducted in an industrial coater, using Si targets and N2 as reactive gas. The effects of different N2-to-Ar flow ratios between 0 and 0.3, pulse frequencies, target power settings, and substrate temperatures on the discharge and the N content of SiNx coatings were investigated. Plasma ion mass spectrometry shows high amounts of ionized isotopes during the initial part of the pulse for discharges with low N2-to-Ar flow ratios of <0.16, while signals from ionized molecules rise with the N2-to-Ar flow ratio at the pulse end and during pulse-off times. Langmuir probe measurements show electron temperatures of 2-3 eV for nonreactive discharges and 5.0-6.6 eV for discharges in transition mode. The SiNx coatings were characterized with respect to their composition, chemical bond structure, density, and mechanical properties by X-ray photoelectron spectroscopy, X-ray reflectivity, X-ray diffraction, and nanoindentation, respectively. The SiNx deposition processes and coating properties are mainly influenced by the N2-to-Ar flow ratio and thus by the N content in the SiNx films and to a lower extent by the HiPIMS frequencies and power settings as well as substrate temperatures. Increasing N2-to-Ar flow ratios lead to decreasing growth rates, while the N content, coating densities, residual stresses, and the hardness increase. These experimental findings were corroborated by density functional theory calculations of precursor species present during rHiPIMS.

Dissolution behaviour of silicon nitride coatings for joint replacements.

In this study, the dissolution rate of SiNx coatings was investigated as a function of coating composition, in comparison to a cobalt chromium molybdenum alloy (CoCrMo) reference. SiNx coatings with N/Si ratios of 0.3, 0.8 and 1.1 were investigated. Electrochemical measurements were complemented with solution (inductively coupled plasma techniques) and surface analysis (vertical scanning interferometry and x-ray photoelectron spectroscopy). The dissolution rate of the SiNx coatings was evaluated to 0.2-1.4 nm/day, with a trend of lower dissolution rate with higher N/Si atomic ratio in the coating. The dissolution rates of the coatings were similar to or lower than that of CoCrMo (0.7-1.2 nm/day). The highest nitrogen containing coating showed mainly Si-N bonds in the bulk as well as at the surface and in the dissolution area. The lower nitrogen containing coatings showed Si-N and/or Si-Si bonds in the bulk and an increased formation of Si-O bonds at the surface as well as in the dissolution area. The SiNx coatings reduced the metal ion release from the substrate. The possibility to tune the dissolution rate and the ability to prevent release of metal ions encourage further studies on SiNx coatings for joint replacements.

Tuning the Emission Energy of Chemically Doped Graphene Quantum Dots.

Tuning the emission energy of graphene quantum dots (GQDs) and understanding the reason of tunability is essential for the GOD function in optoelectronic devices. Besides material-based challenges, the way to realize chemical doping and band gap tuning also pose a serious challenge. In this study, we tuned the emission energy of GQDs by substitutional doping using chlorine, nitrogen, boron, sodium, and potassium dopants in solution form. Photoluminescence data obtained from (Cl- and N-doped) GQDs and (B-, Na-, and K-doped) GQDs, respectively exhibited red- and blue-shift with respect to the photoluminescence of the undoped GQDs. X-ray photoemission spectroscopy (XPS) revealed that oxygen functional groups were attached to GQDs. We qualitatively correlate red-shift of the photoluminescence with the oxygen functional groups using literature references which demonstrates that more oxygen containing groups leads to the formation of more defect states and is the reason of observed red-shift of luminescence in GQDs. Further on, time resolved photoluminescence measurements of Cl- and N-GQDs demonstrated that Cl substitution in GQDs has effective role in radiative transition whereas in N-GQDs leads to photoluminescence (PL) quenching with non-radiative transition to ground state. Presumably oxidation or reduction processes cause a change of effective size and the bandgap.

Outcome of super-responders to cardiac resynchronization therapy defined by endpoint-derived parameters of left ventricular remodeling: a two-center retrospective study.

AIMS: Various studies have attempted to identify super-responders to cardiac resynchronization therapy (CRT) by echocardiographic parameters of reverse remodeling. However, scientific evidence regarding those parameters is scarce. This study aimed at validating the definition of super-response to CRT based on the following frequently employed echocardiographic parameters: left ventricular ejection fraction (LVEF), end-diastolic volume index (EDVI), and end-systolic volume index (ESVI). METHODS AND RESULTS: We retrospectively investigated echocardiographic data and outcomes of 542 patients after CRT implantation. The primary endpoint comprised all-cause mortality, heart transplantation, ventricular assist device implantation (VAD), and hospitalization for heart failure. Secondary endpoints were hospitalization for heart failure, and the combination of all-cause mortality, heart transplantation and VAD. Two approaches were employed defining super-response based on improvement of echocardiographic parameters: one derived from the negative predictive value (NPV) for clinical endpoints, and second from best quartiles of improvement. Using the NPV method, an absolute 25 % increase in LVEF, a relative 38 % reduction in EDVI, and 46 % in ESVI were calculated as optimal cut-offs identifying 4.9, 18.5, and 21.3 % as super-responders. The best quartiles method resulted in lower cut-off values, i.e. 14 % increase in LVEF, 26 % reduction in EDVI, and 36 % in ESVI. All cut-offs except LVEF ≥ 25% were significantly associated with improved outcomes after 5 years (median follow-up 35.7 months). CONCLUSIONS: NPV- and best quartile-based cut-offs validate previously applied empirical echocardiographic cut-offs to define super-response to CRT. These data provide evidence for using these empirical cut-offs in daily practice and facilitate inter-study comparability.

Long-term performance of modern coronary sinus leads in cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has become an important pillar of contemporary heart failure therapy. The efficacy of CRT, however, critically relies on proper LV lead placement and performance, which is why data regarding the long-term performance of CS leads are of considerable interest. Available studies are limited by a restricted variety of lead vendors, earlier lead models and / or very short follow-up periods. In the current study, we therefore investigated the long-term performance of modern LV leads in a large "real world" cohort of patients undergoing CRT implantation. METHODS AND RESULTS: All 193 patients who had successfullyundergone CRT implantation at the University Hospital Zurich between September 2003 and January 2010 were included in the study. An overall stable course of stimulation energy was observed over time; neither ischemic etiology, lead configuration, or severely reduced EF had an influence on the evolution of energy thresholds over time. Interestingly, patients with a high energy threshold at baseline experienced a significant reduction during follow-up. In contrast, a significant drop in impedance was seen following implantation, followed by a steady course for the rest of the observation period. Only 15 patients (9.7%) showed an impedance > 1000 Ohm at any time during their follow-up. Seven lead dislocations were observed during follow up. CONCLUSION: The current comprehensive analysis of long-term performance of modern coronary sinus leads demonstrates excellent stability, performance and safety. These data may have important implications for physicians involved in biventricular pacemaker implantations and in the follow-up care of these patients.

Comprehensive cardiac resynchronization therapy optimization in the real world.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients suffering from chronic heart failure (CHF). Optimal device programming is crucial for maximum patient benefit. The goal of the present study was to assess device settings from CHF patients undergoing CRT optimization in a "real world" setting, and to delineate parameters most frequently requiring adjustment. METHODS: All patients who underwent CRT device implantation in the Cardiology Clinicat the University Hospital Zurich between January 2011 and September 2012 and in whom follow-up was available were included in this analysis. RESULTS: A total of 170 CHF patients were included in this analysis. True biventricular pacing was present in 44% of all patients, while QRS fusion was detected in 49.9%. The majority of the patients presented with suboptimal atrioventricular (AV) delays requiring adjustment. AV delays were therefore shortened due to the presence of QRS fusion in 53.3% and 38.1% of patients (sAV and pAV, respectively) or prolonged because of truncation of the A wave in the left ventricular inflow pulse wave Doppler measurement (17.5% and 28.4% for sAV and pAV, respectively). In contrast, interventricular delay (VV delay) was rarely changed (11.9%). CONCLUSIONS: In our "real world" cohort, a substantial proportion of patients presented to their first post-operative consultation with suboptimal device settings. Our data indicate that the opportunity to optimize device settings is frequently wasted in the "real world", underlining the necessity for expert device follow-up to deliver optimal care to this challenging group of heart failure patients.

Treatment with higher dosages of heart failure medication is associated with improved outcome following cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is associated with improved morbidity and mortality in patients with chronic heart failure (CHF) on optimal medical therapy. The impact of CHF medication optimization following CRT, however, has never been comprehensively evaluated. In the current study, we therefore investigated the effect of CHF medication dosage on morbidity and mortality in CHF patients after CRT implantation. METHODS AND RESULTS: Chronic heart failure medication was assessed in 185 patients after CRT implantation. During an overall mean follow-up of 44.6 months, 83 patients experienced a primary endpoint (death, heart transplantation, assist device implantation, or hospitalization for CHF). Treatment with higher dosages of angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blockers (ARBs) (P = 0.001) and beta-blockers (P < 0.001) as well as with lower dosages of loop diuretics (P < 0.001) was associated with a reduced risk for the primary combined endpoint as well as for all-cause mortality. Echocardiographic super-responders to CRT were treated with higher average dosages of ACE-I/ARBs (68.1 vs. 52.4%, P < 0.01) and beta-blockers (59 vs. 42.2%, P < 0.01). During follow-up, the average dosage of loop diuretics was decreased by 20% in super-responders, but increased by 30% in non-super-responders (P < 0.03). CONCLUSION: The use of higher dosages of neurohormonal blockers and lower dosages of diuretics is associated with reduced morbidity and mortality following CRT implantation. Our data imply a beneficial effect of increasing neurohormonal blockade whenever possible following CRT implantation.