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Enhanced antifungal activity of siRNA-loaded anionic liposomes against the human pathogenic fungus Aspergillus fumigatus
No full textWe developed siRNA-loaded anionic liposomes, co-encapsulating low-dose amphotericin B, to enhance siRNA penetration through the fungal cell wall of . Targeting mRNAs of three key genes, these liposomes visibly inhibited fungal growth, demonstrating for the first time the antifungal potential of siRNA against human fungal pathogens
rDNA copy number variation and methylation in human and mouse sperm
No full textIn this study, droplet digital PCR and deep bisulfite sequencing were used to study the absolute and active rDNA copy number (CN) and the effect of paternal age on human and mouse sperm. The absolute CN ranged from 98 to 404 (219 ± 47) in human and from 98 to 177 (133 ± 14) in mouse sperm. Methylation of the human upstream control element/core promoter (UCE/CP) region and the 5′ external transcribed spacer, as well as that of the mouse CP, the spacer promoter, and 28S rDNA, significantly increased with donor age and absolute CN. Overall, rDNA hypomethylation was much more pronounced in mouse sperm, with 101.7 ± 11.4 copies showing a completely (0%) unmethylated and 11.3 ± 2.8 (8.5%) a slightly methylated (1–10%) CP region, compared to humans with 25.7 ± 9.5 (12%) completely unmethylated and 83.0 ± 19.8 slightly methylated UCE/CP regions. Although the absolute CN was much higher in human sperm, the number of copies with a hypomethylated (0–10%) promoter was comparable in humans (108.7 ± 28.3) and mice (113.0 ± 12.2). However, in mice, the majority (77%) of all copies were completely unmethylated, whereas in humans a high percentage (38%) showed one or two single CpG methylation errors. These different germline methylation dynamics may be due to species differences in reproductive strategies and lifespan. Complete demethylation of the sperm rDNA promoter in mice may be essential for embryonic genome activation, which already occurs at the 2-cell stage in mice and at the 4–8-cell stage in humans. The paternal age effect has been conserved between humans and mice with some notable differences. In humans, the number of hypomethylated (0–10%) copies decreased with age, whereas in mice only the completely unmethylated copies decreased with age. The number of methylated rDNA copies (>1% in mice and >10% in humans) significantly increased with age
Assistive artificial intelligence in epilepsy and its impact on epilepsy care in low- and middle-income countries
No full textEpilepsy, one of the most common neurological diseases in the world, affects around 50 million people, with a notably disproportionate prevalence in individuals residing in low- and middle-income countries (LMICs). Alarmingly, over 80% of annual epilepsy-related fatalities occur within LMICs. The burden of the disease assessed using Disability Adjusted Life Years (DALYs) shows that epilepsy accounts for about 13 million DALYs per year, with LMICs bearing most of this burden due to the disproportionately high diagnostic and treatment gaps. Furthermore, LMICs also endure a significant financial burden, with the cost of epilepsy reaching up to 0.5% of the Gross National Product (GNP) in some cases. Difficulties in the appropriate diagnosis and treatment are complicated by the lack of trained medical specialists. Therefore, in these conditions, adopting artificial intelligence (AI)-based solutions may improve epilepsy care in LMICs. In this theoretical and critical review, we focus on epilepsy and its management in LMICs, as well as on the employment of AI technologies to aid epilepsy care in LMICs. We begin with a general introduction of epilepsy and present basic diagnostic and treatment approaches. We then explore the socioeconomic impact, treatment gaps, and efforts made to mitigate these issues. Taking this step further, we examine recent AI-related developments and their potential as assistive tools in clinical application in LMICs, along with proposals for future directions. We conclude by suggesting the need for scalable, low-cost AI solutions that align with the local infrastructure, policy and community engagement to improve epilepsy care in LMICs
Outcomes of anatomic total shoulder arthroplasty: evaluation of implant-related, radiographic, and demographic factors influencing durability and revision rates
No full textPurpose
To evaluate the impact of implant-associated and radiographic factors on survival rates and revisions of total shoulder arthroplasty (TSA) in patients with primary osteoarthritis (OA).
Methods
This retrospective study included 68 patients who underwent TSA for primary OA at a single institution between 2008 and 2015, with a minimum follow-up of 60 months. Patients with prior shoulder surgeries, perioperative infections, or revisions within 12 months postoperatively were excluded. Patients were divided into Group A (Survivors) and Group B (Revisions) based on implant survival. Radiographic parameters analyzed included critical shoulder angle (CSA), acromiohumeral distance (AHD), lateral offset (LO), humeral head-stem index (HSI), centre of rotation (COR), and glenoid erosion, categorized using Sirveaux, Lévigne, Franceschi, and Walch classifications. Demographic data were also assessed.
Results
Of 68 patients, 57 were in Group A (mean age: 58.5 ± 10.1 years; follow-up: 115.8 months) and 11 in Group B (mean age: 61.4 ± 8.3 years; follow-up: 113.9 months). Implant survival was 84% after 115.8 ± 34.5 months. Baseline demographics were comparable (e.g., smoking: p = 0.75), as was osteolysis prevalence (Group A: 47%; Group B: 45%; p = 0.91). HSI was significantly higher in Group B (0.5 ± 0.1 vs. 0.4 ± 0.1; p = 0.03). No other radiographic differences were significant.
Conclusion
Patients undergoing anatomic total shoulder arthroplasty can expect favourable mid- to long-term outcomes, with implant survival rates of 84% and relatively low complication rates. Although osteolysis is common, it rarely necessitates revision surgery. The role of the humeral head-stem index (HSI) warrants further investigation.
Study design
Level IV; retrospective case study
Current trends in the treatment of rhegmatogenous retinal detachment and perioperative positioning strategies in Germany: results of a retina.net survey
No full textHintergrund
Die rhegmatogene Netzhautablösung (Amotio retinae) ist ein ophthalmologischer Notfall mit steigender Inzidenz in Deutschland. Trotz etablierter Methoden bleibt die perioperative Lagerung, insbesondere bei immobilen Patienten, eine Herausforderung, die Erfolg und Komplikationsrate maßgeblich beeinflusst. Eine Analyse der aktuellen Trends in der chirurgischen Behandlung und perioperativen Versorgung der Amotio im Vergleich zu 2018 ist essenziell.
Material und Methoden
Online-Umfrage mit 5 hypothetischen Fällen akuter rhegmatogener Amotio wurde an vitreoretinale Chirurg*innen des retina.net gesendet; 27 Fragebögen wurden hinsichtlich demografischer Daten, Operationsmethoden, Anästhesieform, perioperativer Lagerung und Nachsorgestrategien ausgewertet.
Ergebnisse
Es waren 50 % der Befragten über 50 Jahre alt, 86 % tätig an Universitätsaugenkliniken, und 89 % hatten über 1000 vitreoretinale Operationen durchgeführt. Prä- und postoperativ wird bei einer Amotio des temporal oberen Quadranten Temporalseitenlagerung empfohlen; 86 % sehen die postoperative Lagerung zur Vermeidung von Makulafalten als entscheidend an. Eine vollständige Drainage subretinaler Flüssigkeit streben 82 % an. Die häufigste Trokargröße war 23 G (77 %). Bei phaken Augen mit einfacher Lochsituation würden 86 % Buckelchirurgie anwenden; 50 % der Operateure nutzen bei komplexen inferioren Amotiones Silikonöl. Vollnarkose war die bevorzugte Anästhesieform (61 %), stets unter stationären Bedingungen.
Zusammenfassung
Bei Amotiones des temporal oberen Quadranten wird prä- und postoperativ bevorzugt die Temporalseiten-, gefolgt von der Bauchlagerung angeordnet. Für inferiore Amotiones wird bei Silikonöl- oder Buckelchirurgie meist keine spezielle Lagerung empfohlen; 86 % sehen die postoperative Lagerung nach Pars-plana-Vitrektomie (ppV) und Gasendotamponade als entscheidend zur Vermeidung von Makulafalten. Das 23-G-Trokarsystem bleibt die erste Wahl trotz kleinerer Alternativen. In bestimmten Fällen behält die Buckelchirurgie ihren Stellenwert.Background
Rhegmatogenous retinal detachment (RRD) is an ophthalmological emergency with an increasing incidence in Germany. Despite established methods, perioperative positioning is important to improve outcomes and avoid complications but may be challenging, particularly in immobile patients. An analysis of the current trends in surgical treatment and perioperative positioning practices for RRD in Germany compared to historical data from 2018 is essential.
Material and methods
An online survey with five hypothetical cases of acute RRD was distributed to vitreoretinal surgeons via the retina.net research network. A total of 27 questionnaires were analyzed focusing on participant demographic data, surgical techniques, anesthesia types, perioperative positioning and aftercare strategies.
Results
Of the respondents 50% were over 50 years old, 86% worked at university eye clinics and 89% had performed over 1000 vitreoretinal procedures. For RRD in the temporal upper quadrant, preoperative and postoperative temporal lateral positioning is recommended. Of the respondents 86% consider postoperative positioning crucial to prevent macular folds. Complete subretinal fluid drainage is favored by 82% and 23 G trocars were used by 77%. For phakic eyes with uncomplicated RRD 86% chose buckling surgery, while 50% opted for silicone oil in complex inferior RRD cases. General anesthesia was preferred by 61%, always in an in-patient setting.
Conclusion
Preoperative and postoperative temporal lateral positioning followed by prone positioning is favored for temporal upper quadrant RRD, whereas no specific positioning is recommended for inferior RRD managed with silicone oil or buckling surgery. Postoperative positioning after pars plana vitrectomy (ppV) and gas endotamponade is considered by 86% to be decisive in preventing macular folds. The 23 G trocar system remains the preferred choice despite smaller alternatives. In certain cases buckling is still of importance
Laparoscopic vs. Robotic transabdominal adrenalectomy- propensity matched analysis and learning curve
No full textBackground
While laparoscopic transabdominal or retroperitoneal adrenalectomy is standard care for adrenal tumors, benefits of robotic adrenalectomy (RA) are yet unclear. We evaluated the costs (including disposables), outcomes as well as the learning curve of robotic and laparoscopic adrenalectomy (LA) in a specialized center.
Methods
In retrospective analysis of our prospective database (ethical approval number 88/11) 263 LA were compared to 27 RA in the study period between 2018 and 2023. A propensity score match analysis was used to exclude possible confounders. Furthermore, the learning curve of RA was investigated.
Results
Intraoperative Riva Rocci (RR) fluctuations (> 160mmHg, < 90 mmHg), early complications (within 30 days) and intraoperative blood loss were comparable in both groups. However, length of stay was decreased following robotic adrenalectomy (3.50d ± 1.81d compared to 4.61d ± 2.75d; p = 0.04). Due to this, overall costs of RA were lower compared to LA even if cost for disposables were slightly higher in the robotic group. An analysis of the learning curve of robotic adrenalectomy revealed that learning curve is completed after 5- 6th procedure.
Conclusions
Taken together our study supports the fact that RA is as secure and feasible as LA. Furthermore, it might provide advantages due to shorter length of stay, a short learning curve and similar costs compared to LA
The impact of the COVID-19 pandemic on administrative eating disorder prevalence in the outpatient sector and on severity of anorexia nervosa
No full textThe COVID-19 pandemic appears to have had a considerable impact on the mental health of children and adolescents, particularly regarding eating disorders. However, it remains unclear whether the pandemic affected only the frequency or also the severity of eating disorders. We examined potential pandemic-related changes in the administrative prevalence of eating disorders in the outpatient sector compared with other mental disorders using German statutory health insurance data for the age group 10 to 16 years. We also examined disorder severity of anorexia nervosa using data from the multicenter German Registry of Children and Adolescents with Anorexia Nervosa in the same age group. Our results showed a marked increase in the administrative prevalence of eating disorders (based on documented diagnoses) in the outpatient sector among girls but not among boys. A similar pattern was found for internalizing disorders, whereas the administrative prevalences of externalizing disorders decreased. Regarding the severity of anorexia nervosa among inpatients, we found no pandemic-related changes in body mass index standard deviation score at admission, body weight loss before admission, psychiatric comorbidities and psychopharmacological medication. Given the administrative prevalence increase in the outpatient sector, the lack of impact of the pandemic on the inpatient sector may also be partly due to a shift in healthcare utilization towards outpatient services during the pandemic. Thus, the higher number of children and adolescents requiring specialized and timely outpatient care may be a major concern under pandemic conditions
A post-hoc internal validation of arginine-stimulated copeptin cut-offs for diagnosing AVP deficiency (central diabetes insipidus)
No full textBackground
Distinguishing arginine vasopressin (AVP) deficiency (central diabetes insipidus) from primary polydipsia is challenging. While hypertonic saline-stimulated copeptin testing provides the highest diagnostic accuracy, it is often restricted to specialised centres, requiring close monitoring and potentially causing patient discomfort. Initially, arginine-stimulated copeptin was proposed as a simpler alternative, but a head-to-head comparison study found it less precise than hypertonic saline stimulation. However, the same study identified two new high sensitivity and specificity cut-offs for arginine-stimulated copeptin, though these cut-offs have yet to be validated.
Methods
This is a secondary post-hoc analysis of the initial prospective multicentre study, including adult patients with confirmed AVP deficiency or primary polydipsia. Participants underwent the arginine stimulation test, with plasma copeptin measured at baseline and 60- and 90 min after arginine infusion. The primary objective was to revisit the original study to internally validate the proposed arginine-stimulated copeptin cut-offs of > 5.2pmol/L (high specificity cut-off with > 90% specificity for primary polydipsia) and ≤ 3.0 pmol/L (high specificity cut-off with > 90% specificity for AVP deficiency).
Findings
In total, 96 patients were included between May 2013 and June 2018: n = 38 [40%] with AVP deficiency and n = 58 [60%] with primary polydipsia. At 60 min after arginine infusion, a copeptin level ≤ 3.0 pmol/L showed a specificity of 95% (95% CI: 0.88-1.00) for AVP deficiency, while a copeptin level > 5.2 pmol/L demonstrated a specificity of 97% (95% CI: 0.92-1.00) for primary polydipsia. The ≤ 3.0 pmol/L cut-off accurately identified 71% (n = 27/38) of patients with AVP deficiency, and the > 5.2 pmol/L cut-off correctly identified 69% (n = 40/58) of patients with primary polydipsia.
Interpretation
This analysis validates two new copeptin cut-offs of the arginine stimulation test to distinguish AVP deficiency from primary polydipsia: >5.2 pmol/L for high specificity in diagnosing primary polydipsia and ≤ 3.0 pmol/L for high specificity in diagnosing AVP deficiency. These thresholds might offer a practical initial alternative to hypertonic saline testing
Comparing robotic ventral transabdominal preperitoneal repair (rvTAPP) and laparoscopic enhanced view totally extraperitoneal repair (eTEP): a multicentre observational study
No full textThis study compares two emerging minimally invasive techniques—laparoscopic enhanced-view totally extraperitoneal (eTEP) and robotic ventral transabdominal preperitoneal repair (rvTAPP)—for the repair of small and mid-sized ventral hernias. A prospective observational study was conducted using data from the international CROSSFIRE database with patients treated between January 2023 and December 2024. The inclusion criteria were primary and incisional midline ventral hernias ≤ 4 cm, treated with eTEP or rvTAPP. The group comparisons were conducted using propensity score matching, adjusting for differences in body mass index, sex, and hernia defect. A total of 165 patients from three centers were included (120 eTEP, 45 rvTAPP). After propensity score matching, 100 patients were included (57 eTEP and 43 rvTAPP). The pain scores after eTEP and rvTAPP at 2 days postoperatively (2.9 vs. 3.3, p = 0.385) and at 6 weeks (2.1 vs. 2.1, p = 0.888) were comparable. The mean comprehensive complication index was similar between eTEP and rvTAPP (1.7 vs. 1.5, p = 0.561). The operation time was 88.8 min for eTEP and 110.1 min for rvTAPP (p = 0.003), whereas rvTAPP involved more teaching procedures (32.6% versus 8.8%; p = 0.004). Surgeon workload, as assessed by NASA Task Load Index, was higher in eTEP than rvTAPP (36.3 vs. 17.1; p < 0.001), indicating greater physical and mental strain. Both posterior minimally invasive ventral hernia repair techniques—eTEP and rvTAPP—are safe and show comparable pain levels at 2 days and 6 weeks. Robotically assisted ventral TAPP has a longer operative time than eTEP but imposes less workload on the surgeon
Supply Chains unentbehrlicher Arzneimittel – Transparenzstudie zu Ibuprofen
No full textOb Krebsmedikamente, Antibiotika oder herkömmliche Schmerzmittel: Seit Jahren kommt es in Deutschland zu Lieferengpässen bei versorgungskritischen Arzneimitteln. So meldete das Bundesinstitut für Arzneimittel und Medizinprodukte für das Jahr 2023 bei etwa 391 Präparaten einen Lieferengpass. Die Lieferschwierigkeiten haben besonders im Generikasegment zwei Hauptursachen. Zum einen Europas Abhängigkeit von kostengünstigen Wirkstoffen und Arzneimittelnaus Asien mit einer zunehmenden Marktkonzentration auf wenige Hersteller aus China und Indien. Zum anderen unterliegen deutsche und europäische Hersteller aufgrund von diversen Preisregulierungsmechanismen einem starken Kostendruck. Daher ist es notwendig, die Hintergründe dieser Ursachen besser nachzuvollziehen, um geeignete strategische Maßnahmen zur Stärkung der Versorgung mit unentbehrlichen Arzneimitteln zu entwickeln. Die im Rahmen der vorliegenden Thesis durchgeführte Transparenzstudie präsentiert neue Einblicke in die globale Supply Chain und die Kostenstrukturen der Produktion des Schmerzmittels Ibuprofen.
Im ersten Teil der Thesis konnte die strategische Abhängigkeit Europas von asiatischen Herstellern für die Rohstoffe und insbesondere für den Wirkstoff von Ibuprofen bestätigt werden. So stammen fünf der insgesamt sieben Hauptakteure des globalen Ibuprofen Wirkstoffmarkts aus Indien und China, deren Produktionskapazitäten etwa 78 % des gesamten Marktvolumens von Ibuprofen decken. Zudem ist Indien globaler Marktführer bei dem wichtigsten Ausgangsrohstoff der Ibuprofensynthese, dem Isobutylbenzol. Darüber hinaus konnten Hinweise auf eine Kostendruckproblematik bedingt durch strenge Preisregulierungsmechanismen bei europäischen Ibuprofen Filmtablettenherstellern identifiziert werden. So reduzierte sich zum einen die Anzahl der europäischen Ibuprofen 400 Filmtablettenhersteller auf dem deutschen Apothekenabsatzmarkt zwischen den Jahren 2014 und 2023 um 35 %. Zum anderen deuten die sinkenden Absatzzahlen selbst bei den drei größten Ibuprofen 400 Filmtablettenherstellern auf wirtschaftlich bedingte Produktionsrückgänge hin. Zusammengefasst bestätigen diese Erkenntnisse qualitativ, dass die häufigsten Ursachen von Versorgungsschwierigkeiten auch für die Supply Chain von Ibuprofen vorliegen.
Im zweiten Teil der Arbeit wurde Deutschlands Abhängigkeit von kostengünstigen Produktionsstandorten in Asien quantitativ mithilfe einer Kostenstrukturanalyse für die Herstellung von Ibuprofen 400 Filmtabletten an den Indien, China und Deutschland belegt. So liegt der Preis der in Deutschland produzierten Tabletten im Vergleich zu Indien und China etwa 1,8-mal bzw. 2,4-mal höher. Diese Kostenunterschiede sind vor allem auf niedrigere Betriebskosten sowie Staatliche Wirtschafts- und Infrastrukturförderungen in Asien zurückzuführen.
Zusammenfassend liefern die Erkenntnisse der Transparenzstudie wertvolle Einblicke in den globalen Generikamarkt und bieten eine fundierte Grundlage, um geeignete strategische Maßnahmen für die Stärkung der Resilienz der Ibuprofen Supply Chain zu entwickeln. So wurden abschließend die derzeit in der Politik und Industrie am häufigsten diskutierten Ansätze wie die Reform der industriepolitischen Rahmenbedingungen, die strategische Sicherheitsreserve und das Re-/Nearshoring zur Stärkung der Resilienz der Ibuprofen Supply Chain evaluiert. Lediglich eine ausgewogene Kombination dieser Maßnahmen sowie eine EU-weite kollaborative Zusammenarbeit zwischen Industrie, Politik und Krankenkassen kann zu einer langfristigen Verbesserung der deutschen Versorgungslage und der Diversifizierung generischer Supply Chains wie der von Ibuprofen beitragen.Whether cancer drugs, antibiotics or conventional painkillers, supply bottlenecks of supply-critical medicines have been occurring in Germany for years. For example, the Federal Institute for Drugs and Medical Devices reported a supply bottleneck for around 391 preparations in 2023. The supply difficulties have two main causes, particularly in the generics segment. Firstly, Europe's dependence on low-cost active pharmaceutical ingredients and medicinal products from Asia with an increasing market concentration on a few manufacturers from China and India. On the other hand, German and European manufacturers are subject to strong cost pressure due to various price regulation mechanisms. It is therefore necessary to better understand the background to these causes in order to develop suitable strategic measures to strengthen the supply of essential medicines. The transparency study carried out as part of this thesis presents new insights into the global supply chain and the cost structures of the production of the painkiller ibuprofen.
The first part of the thesis confirmed Europe's strategic dependence on Asian manufacturers for the raw materials and in particular for the active ingredient of ibuprofen. Five of the seven major players in the global ibuprofen active ingredient market come from India and China, whose production capacities cover around 78% of the total market volume of ibuprofen. India is also the global market leader in the most important raw material for ibuprofen synthesis, isobutylbenzene. In addition, there were indications of cost pressure problems due to strict price regulation mechanisms for European ibuprofen film tablets. On the one hand, the number of European ibuprofen 400 film-coated tablet manufacturers in the German pharmacy sales market fell by 35 % between 2014 and 2023. On the other hand, the declining sales figures even among the three largest ibuprofen 400 film-coated tablet manufacturers indicate economically induced production declines. In summary, these findings qualitatively confirm that the most common causes of supply difficulties also apply to the ibuprofen supply chain.
In the second part of the thesis, Germany's dependence on low-cost production sites in Asia was quantitatively demonstrated with the help of a cost structure analysis for the production of ibuprofen 400 film-coated tablets in India, China and Germany. The price of the tablets produced in Germany is approximately 1.8 times and 2.4 times higher than in India and China respectively. These cost differences are primarily due to lower operating costs as well as government subsidies for economy and infrastructure in Asia. In summary, the findings of the transparency study provide valuable insights into the global generics market and offer a sound basis for developing suitable strategic measures to strengthen the resilience of the ibuprofen supply chain. In conclusion, the most frequently discussed approaches in politics and industry, such as the reform of the Industrial policy framework, the strategic safety reserve and re-/nearshoring to strengthen the resilience of the ibuprofen supply chain, were evaluated. Only a balanced combination of these measures and EU-wide collaborative co-operation between industry, politics and health insurers can contribute to a long-term improvement of the German supply situation and the diversification of generic supply chains such as that of ibuprofen