Potential Conflicts Of Interest Research Articles

The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. N/A.

Analgesic Effectiveness of Liposomal Bupivacaine versus Plain Local Anesthetics for Abdominal Fascial Plane Blocks: A Systematic Review and Meta-analysis of Randomized Trials.

Liposomal bupivacaine is reported to prolong the duration of analgesia when used for abdominal fascial plane blocks compared to plain local anesthetics; however, evidence from randomized trials is mixed. This meta-analysis aims to compare the analgesic effectiveness of liposomal bupivacaine to plain local anesthetics in adults receiving abdominal fascial plane blocks. Randomized trials comparing liposomal bupivacaine and plain (nonliposomal) local anesthetics in abdominal fascial plane blocks were sought. The primary outcome was area under the curve rest pain between 24 to 72 h postoperatively. Secondary outcomes included rest pain at individual timepoints (1, 6, 12, 24, 48, and 72 h); analgesic consumption at 0 to 24, 25 to 48, and 49 to 72 h; time to analgesic request; hospital stay duration; and opioid-related side effects. Data were pooled using the Hartung-Knapp-Sidik-Jonkman random effects method. Sixteen trials encompassing 1,287 patients (liposomal bupivacaine, 667; plain local anesthetics, 620) were included. The liposomal bupivacaine group received liposomal bupivacaine mixed with plain bupivacaine in 10 studies, liposomal bupivacaine alone in 5 studies, and both preparations in 1 three-armed study. No difference was observed between the two groups for area under the curve pain scores, with a standardized mean difference (95% CI) of -0.21 cm.h (-0.43 to 0.01; P = 0.058; I2 = 48%). Results were robust to subgroup analysis based on (1) potential conflict of interest and (2) mixing of plain local anesthetics with liposomal bupivacaine. The two groups were not different for any of the day 2 or day 3 secondary outcomes. This systematic review and meta-analysis suggests similar analgesic effectiveness between liposomal bupivacaine and plain local anesthetics when used for fascial plane block of the abdominal wall. The authors' analysis does not support an evidence-based preference for liposomal bupivacaine compared to plain local anesthetics for abdominal fascial plane blocks.

A Time Series Analysis of Noninterest to Interest-Earning Dynamics Between 1984 to 2023 in the US Commercial Banking Sector

Both interest and noninterest earnings form the two critical components of the income stream of commercial banks. While interest earnings are tied to the lending volume and prevailing interest rates primarily dictated by the monetary policy and central bank interventions, noninterest earnings can come from diversified sources like income from fiduciary activities, trading revenue, service charges on deposit accounts, fee income, etc. Noninterest earnings can be unrelated to lending volume and prevailing interest rates and possibly uncorrelated with the monetary policies. Noninterest earnings may be a more robust source of income, especially during the low-interest rate regimes. Managing the noninterest to interest earnings is a critical component of income smoothing used by the banks. Noninterest earnings have become a significant component of banks’ overall earnings in the last four decades, and the ratio of noninterest to interest earnings has also grown significantly, raising questions about the primary role of the banking sector in financial intermediation as defined by the collection and disbursement of loanable funds throughout the economy. The rise in noninterest earnings also raises questions about the potential conflict of interest especially if banks earn significant consulting income from the same entities that borrow heavily from the banks. In this paper, I look at the time series dynamics of the ratio of noninterest-to-interest earnings spanning nearly four decades from 1984:Q1 to 2023:Q3 for the USA’s FDIC-insured commercial banking sector. Although the ratio has fluctuated over the period and risen from the baseline, it does not exhibit any non-stationarity. The presence of unit root cannot be found during the time period studied. In other words, the ratio of noninterest-to-interest earnings in the US commercial banking sector does not show any explosive and unstainable growth. In a nutshell, the rise in the ratio seems to be an outcome of the broader income diversification strategy used by the banks and not necessarily a dramatic change in the business model of US commercial banking industry.

Standards of Disciplinary Conduct for the Corporate Directors: Perspective of the United States of America

Administration of corporate activity is the daily preoccupation of corporate directors. Delegation of decision-making to the director, who is an independent player within the company, can clearly create the risk of conflicting his interests with the interests of the shareholders. This potential conflict of interests is a consequence of the division of ownership of the company and the control powers of the company's commercial activity. The delegation of decision-making authority to the directors of the company may cause the risk of the temptation of the director to the assets of the company. In addition, directors may also be tempted by opportunities for profit that arise during the exercise of their function, instead of using these opportunities for the company. For this reason, it is necessary to foresee clear disciplinary parameters, to avoid and eliminate the conflict of interest, as well as the prohibition of competition. In the present paper, through a legal assessment, special attention has been paid to the main categories of standards: elimination of conflict of interest and prohibition of competition. The main aim of this paper is to analyze the US doctrine, legal provisions, which regulate the two standards of disciplinary conduct for the corporate directors, as well as the court practice in this regard. Also, an important objective of this paper is that it may serve as an important basis for further comparative studies in this field with other jurisdictions. Such analysis is based on the qualitative method, which contains also the research, analytical, descriptive, interpretive methods. The result of this paper will stimulate debate in the academic level and contribute to further improvements of our company legislation, as well to the legal doctrine in Albania that lacks such.

Payments to healthcare organisations reported by the medical device industry in Europe from 2017 to 2019: An observational study

ObjectiveMedical device industry payments to healthcare organisations (HCOs) can create conflicts of interest which can undermine patient care. One way of addressing this concern is by enhancing transparency of industry financial support to HCOs. MedTech Europe, a medical device trade body, operate a system of disclosure of education payments to European HCOs. This study aimed to characterise payments reported in this database and to evaluate the disclosure system. MethodsAn observational study of education-related payments to HCOs reported by the medical device industry in Europe was conducted. Data was manually extracted from transparentmedtech.eu. The primary outcome variable is the value of the payments, overall, and for each year, payment type, and country. The accessibility, availability and quality of the database was also analysed, using a proforma with 15 measures. ResultsOverall, 116 medical device companies reported education-related payments in 53 European and non-European countries, valuing over €425 million between 2017 and 2019, increasing in value between 2017 and 2019, from €93,798,419 to €175,414,302. Ten countries accounted for 94% of all payments and ten companies accounted for 80% of all payments. The accessibility, availability and quality of the database rated low for six measures, medium for six measures, and high for three measures. ConclusionThere is a large amount of education-related payments from medical device companies to European HCOs, creating substantial potential for conflicts of interest. MedTech Europe's disclosure system has many shortcomings. A European-wide publicly mandated disclosure system for both the medical device and pharmaceutical industries should be introduced. Public interest summaryThe medical device industry pay healthcare organisations (e.g. hospitals) large amounts of money. Industry states that this money is to help pay for healthcare professionals’ education. However, these payments can have a negative impact on healthcare professionals’ decision-making. This study sought to examine a website run by MedTech Europe, a representative body for the medical device industry, which outlines details of some of these payments (www.transparentmedtech.eu). Our analysis found that between 2017 and 2019 the medical device industry made ‘education’ payments valuing €425 million to healthcare organisations in Europe. We also assessed how comprehensive and user-friendly the database was and found a range of issues. For example, the database is not downloadable and some other important types of payments, such as payments for consultancy, are not included. We concluded that a mandatory database for both the medical device and pharmaceutical industry run by the European Union, would significantly improve transparency.

Diagnostic Discordance Among Histopathological Reviewers for Difficult-to-Diagnose Melanocytic Lesions

Purpose: Histopathological examination is adequate for most melanocytic neoplasms. However, there is a subset of lesions with uncertain malignant potential that are difficult-to-diagnose where utilization of ancillary tests may be considered to aid in providing a more definitive diagnosis.&#x0D; Study design: Under an IRB-approved protocol, 3,317 melanocytic lesions underwent independent diagnostic review by up to 9 unique board-certified dermatopathologists. Each lesion received ≥ 3 diagnoses via electronic whole slide images with zoom-in capability as benign, malignant, or unknown malignant potential (UMP). Lesions were subsequently binned according to the results of dermatopathology review in the following manner: concordant (all diagnoses of the same designation); conflicting (both benign and malignant designations); majority (a single designation with the highest number of diagnoses); and equivocal (equal number of different designations). Here we describe the identification of lesions suitable for ancillary testing.&#x0D; Results: 30% of lesions were concordant benign and 46.3% were concordant malignant, indicating 76.3% of all lesions were not difficult-to-diagnose. 23.7% of lesions had some level of diagnostic difficulty and/or ambiguity defined by disagreement between reviewers and would be suitable for ancillary testing. Within these ~24%, 7.3% of lesions were majority benign, 4.8% of lesions were majority malignant, 2.7% were majority UMP, 6.9% of lesions were conflicting, and 1.6% of lesions were equivocal.&#x0D; &#x0D; Conclusions: We demonstrate that in a large cohort of suspicious pigmented lesions, ~24% were difficult-to-diagnose, supporting the need for additional objective diagnostic tools. Patient care would benefit from ancillary testing to aid the diagnosing pathologist in identification of the most appropriate diagnosis to optimize patient management.&#x0D; Potential conflicts of interest: This study was supported by Castle Biosciences, Inc. GAH and JAP have served as consultants for Castle Biosciences, Inc. MSG is an employee shareholder of Castle Biosciences, Inc. SIE is a consultant and shareholder for Castle Biosciences, Inc. Editorial assistance was provided by Brooke H. Russell, PhD, and Jason H Rogers, MSc, both employee shareholders of Castle Biosciences, Inc.

Genomic alterations in ovarian endometriosis and subsequently diagnosed ovarian carcinoma.

Can the alleged association between ovarian endometriosis and ovarian carcinoma be substantiated by genetic analysis of endometriosis diagnosed prior to the onset of the carcinoma? The data suggest that ovarian carcinoma does not originate from ovarian endometriosis with a cancer-like genetic profile; however, a common precursor is probable. Endometriosis has been implicated as a precursor of ovarian carcinoma based on epidemiologic studies and the discovery of common driver mutations in synchronous disease at the time of surgery. Endometrioid ovarian carcinoma and clear cell ovarian carcinoma are the most common endometriosis-associated ovarian carcinomas (EAOCs). The pathology biobanks of two university hospitals in Sweden were scrutinized to identify women with surgically removed endometrioma who subsequently developed ovarian carcinoma (1998-2016). Only 45 archival cases with EAOC and previous endometriosis were identified and after a careful pathology review, 25 cases were excluded due to reclassification into non-EAOC (n = 9) or because ovarian endometriosis could not be confirmed (n = 16). Further cases were excluded due to insufficient endometriosis tissue or poor DNA quality in either the endometriosis, carcinoma, or normal tissue (n = 9). Finally 11 cases had satisfactory DNA from all three locations and were eligible for further analysis. Epithelial cells were collected from formalin-fixed and paraffin-embedded (FFPE) sections by laser capture microdissection (endometrioma n = 11) or macrodissection (carcinoma n = 11) and DNA was extracted. Normal tissue from FFPE sections (n = 5) or blood samples collected at cancer diagnosis (n = 6) were used as the germline controls for each included patient. Whole-exome sequencing was performed (n = 33 samples). Somatic variants (single-nucleotide variants, indels, and copy number alterations) were characterized, and mutational signatures and kataegis were assessed. Microsatellite instability and mismatch repair status were confirmed with PCR and immunohistochemistry, respectively. The median age for endometriosis surgery was 42 years, and 54 years for the subsequent ovarian carcinoma diagnosis. The median time between the endometriosis and ovarian carcinoma was 10 (7-30) years. The data showed that all paired samples harbored one or more shared somatic mutations. Non-silent mutations in cancer-associated genes were frequent in endometriosis; however, the same mutations were never observed in subsequent carcinomas. The degree of clonal dominance, demonstrated by variant allele frequency, showed a positive correlation with the time to cancer diagnosis (Spearman's rho 0.853, P < 0.001). Mutations in genes associated with immune escape were the most conserved between paired samples, and regions harboring these genes were frequently affected by copy number alterations in both sample types. Mutational burdens and mutation signatures suggested faulty DNA repair mechanisms in all cases. Datasets are available in the supplementary tables. Even though we located several thousands of surgically removed endometriomas between 1998 and 2016, only 45 paired samples were identified and even fewer, 11 cases, were eligible for sequencing. The observed high level of intra- and inter-heterogeneity in both groups (endometrioma and carcinoma) argues for further studies of the alleged genetic association. The observation of shared somatic mutations in all paired samples supports a common cellular origin for ovarian endometriosis and ovarian carcinoma. However, contradicting previous conclusions, our data suggest that cancer-associated mutations in endometriosis years prior to the carcinoma were not directly associated with the malignant transformation. Rather, a resilient ovarian endometriosis may delay tumorigenesis. Furthermore, the data indicate that genetic alterations affecting the immune response are early and significant events. The present work has been funded by the Sjöberg Foundation (2021-01145 to K.S.; 2022-01-11:4 to A.S.), Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (965552 to K.S.; 40615 to I.H.; 965065 to A.S.), Swedish Cancer Society (21-1848 to K.S.; 21-1684 to I.H.; 22-2080 to A.S.), BioCARE-A Strategic Research Area at Lund University (I.H. and S.W.-F.), Mrs Berta Kamprad's Cancer Foundation (FBKS-2019-28, I.H.), Cancer and Allergy Foundation (10381, I.H.), Region Västra Götaland (A.S.), Sweden's Innovation Agency (2020-04141, A.S.), Swedish Research Council (2021-01008, A.S.), Roche in collaboration with the Swedish Society of Gynecological Oncology (S.W.-F.), Assar Gabrielsson Foundation (FB19-86, C.M.), and the Lena Wäpplings Foundation (C.M.). A.S. declares stock ownership and is also a board member in Tulebovaasta, SiMSen Diagnostics, and Iscaff Pharma. A.S. has also received travel support from EMBL, Precision Medicine Forum, SLAS, and bioMCC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

A Clinical Practice Guideline on the Timing of Surgical Decompression and Hemodynamic Management of Acute Spinal Cord Injury and the Prevention, Diagnosis, and Management of Intraoperative Spinal Cord Injury: Introduction, Rationale, and Scope.

Protocol for the development of clinical practice guidelines following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Acute SCI or intraoperative SCI (ISCI) can have devastating physical and psychological consequences for patients and their families. The treatment of SCI has dramatically evolved over the last century as a result of preclinical and clinical research that has addressed important knowledge gaps, including injury mechanisms, disease pathophysiology, medical management, and the role of surgery. In an acute setting, clinicians are faced with critical decisions on how to optimize neurological recovery in patients with SCI that include the role and timing of surgical decompression and the best strategies for hemodynamic management. The lack of consensus surrounding these treatments has prevented standardization of care across centers and has created uncertainty with respect to how to best manage patients with SCI. ISCI is a feared complication that can occur in the best of hands. Unfortunately, there are no systematic reviews or clinical practice guidelines to assist spine surgeons in the assessment and management of ISCI in adult patients undergoing spinal surgery. Given these limitations, it is the objective of this initiative to develop evidence-based recommendations that will inform the management of both SCI and ISCI. This protocol describes the rationale for developing clinical practice guidelines on (i) the timing of surgical decompression in acute SCI; (ii) the hemodynamic management of acute SCI; and (iii) the prevention, identification, and management of ISCI in patients undergoing surgery for spine-related pathology. Systematic reviews were conducted according to PRISMA standards in order to summarize the current body of evidence and inform the guideline development process. The guideline development process followed the approach proposed by the GRADE working group. Separate multidisciplinary, international groups were created to perform the systematic reviews and formulate the guidelines. All potential conflicts of interest were vetted in advance. The sponsors exerted no influence over the editorial process or the development of the guidelines. This process resulted in both systematic reviews and clinical practice guidelines/care pathways related to the role and timing of surgery in acute SCI; the optimal hemodynamic management of acute SCI; and the prevention, diagnosis and management of ISCI. The ultimate goal of this clinical practice guideline initiative was to develop evidence-based recommendations for important areas of controversy in SCI and ISCI in hopes of improving neurological outcomes, reducing morbidity, and standardizing care across settings. Throughout this process, critical knowledge gaps and future directions were also defined.

Numerical Analysis of Residual Stresses Effect in Multi-materials

Background: In this study, the effect of mechanical and physical properties of the metal and temperature is highlighted. The purpose of this study is to analyze the effect of these stresses on multi-materials. This work aimed to conduct a three-dimensional numerical study by the finite element method on the levels and distributions of the stresses in the Al2O3/NI/HAYNES multi-materials. These stresses of thermal and mechanical origin are generally detrimental to the service life of multi-material. Methods: The use of numerical resolution by finite element method is the most suitable for complex mechanical problems. It allows a more in-depth analysis of all points of the structure. In this study, a fundamental tool was constructed to resolve the mechanical behavior of materials subjected to complex solicitations. Therefore, the ABAQUS calculation code version 6.14 was used to analyze the residual stresses. Results: By interpreting the results in terms of stress variation, we identified the areas at risk; in particular, the nature of a joint effect plays a decisive role in the assembly of the right material in its mechanical resistance. This nature is defined in terms of stiffness (Young's modulus) and differential expansion (coefficient of thermal expansion). Conclusion: The presence of strong residual stresses can constitute a risk of damage to several materials. The difference between the coefficients of thermal expansion of the two materials (metal and ceramic) linked together induces, in these two constituents, normal internal stresses. This difference determines the level and distribution of these constraints. Moreover, the sign of this difference determines the state of the normal stresses.

Identification of two hidden clinical subgroups among men with idiopathic cryptozoospermia.

Are there subgroups among patients with cryptozoospermia pointing to distinct etiologies? We reveal two distinct subgroups of cryptozoospermic (Crypto) patients based on testicular tissue composition, testicular volume, and FSH levels. Cryptozoospermic patients present with a sperm concentration below 0.1 million/ml. While the etiology of the severely impaired spermatogenesis remains largely unknown, alterations of the spermatogonial compartment have been reported including a reduction of the reserve stem cells in these patients. To assess whether there are distinct subgroups among cryptozoospermic patients, we applied the statistical method of cluster analysis. For this, we retrospectively selected 132 cryptozoospermic patients from a clinical database who underwent a testicular biopsy in the frame of fertility treatment at a university hospital. As controls (Control), we selected 160 patients with obstructive azoospermia and full spermatogenesis. All 292 patients underwent routine evaluation for endocrine, semen, and histological parameters (i.e. the percentage of tubules with elongated spermatids). Moreover, outcome of medically assisted reproduction (MAR) was assessed for cryptozoospermic (n = 73) and Control patients (n = 87), respectively. For in-depth immunohistochemical and histomorphometrical analyses, representative tissue samples from cryptozoospermic (n = 27) and Control patients (n = 12) were selected based on cluster analysis results and histological parameters. This study included two parts: firstly using clinical parameters of the entire cohort of 292 patients, we performed principal component analysis (PCA) followed by hierarchical clustering on principal components (i.e. considering hormonal values, ejaculate parameters, and histological information). Secondly, for histological analyses seminiferous tubules were categorized according to the most advanced germ cell type present in sections stained with Periodic acid Schif. On the selected cohort of 39 patients (12 Control, 27 cryptozoospermic), we performed immunohistochemistry for spermatogonial markers melanoma-associated antigen 4 (MAGEA4) and piwi like RNA-mediated gene silencing 4 (PIWIL4) followed by quantitative analyses. Moreover, the morphologically defined Adark spermatogonia, which are considered to be the reserve stem cells, were quantified. The PCA and hierarchical clustering revealed three different clusters, one of them containing all Control samples. The main factors driving the sorting of patients to the clusters were the percentage of tubules with elongated spermatids (Cluster 1, all Control patients and two cryptozoospermic patients), the percentage of tubules with spermatocytes (Cluster 2, cryptozoospermic patients), and tubules showing a Sertoli cells only phenotype (Cluster 3, cryptozoospermic patients). Importantly, the percentage of tubules containing elongated spermatids was comparable between Clusters 2 and 3. Additional differences were higher FSH levels (P < 0.001) and lower testicular volumes (P < 0.001) in Cluster 3 compared to Cluster 2. In the spermatogonial compartment of both cryptozoospermic Clusters, we found lower numbers of MAGEA4+ and Adark spermatogonia but higher proportions of PIWIL4+ spermatogonia, which were significantly correlated with a lower percentage of tubules containing elongated spermatids. In line with this common alteration, the outcome of MAR was comparable between Controls as well as both cryptozoospermic Clusters. While we have uncovered the existence of subgroups within the cohort of cryptozoospermic patients, comprehensive genetic analyses remain to be performed to unravel potentially distinct etiologies. The novel insight that cryptozoospermic patients can be divided into two subgroups will facilitate the strategic search for underlying genetic etiologies. Moreover, the shared alterations of the spermatogonial stem cell compartment between the two cryptozoospermic subgroups could represent a general response mechanism to the reduced output of sperm, which may be associated with a progressive phenotype. This study therefore offers novel approaches towards the understanding of the etiology underlying the reduced sperm formation in cryptozoospermic patients. German research foundation CRU 326 (grants to: SDP, NN). Moreover, we thank the Faculty of Medicine of the University of Münster for the financial support of Lena Charlotte Schülke through the MedK-program. We acknowledge support from the Open Access Publication Fund of the University of Münster. The authors have no potential conflicts of interest. N/A.

Conflict of interest disclosure by US cardiothoracic surgeons.

Surgeon-industry collaboration is a key driver of advancement in surgical technology and practice. Disclosures of financial relationships between investigators and industries are important to ensure transparent and critical evaluation of literature. All American cardiothoracic (CT) surgeons who published in three major CT surgery journals in 2019 were identified. Whether these surgeons disclosed any conflicts of interest was recorded and compared to actual payments received within 5years of publication as reported by the Centers for Medicare and Medicaid Services data. In the study period, there were 1079 unique manuscripts involving 885 American CT surgeons as authors, which combined for 2719 author instances. Of these, 96.2% of authors (851 of 885) received payments from companies. The authors who received payments produced 2651 author instances (97.4%). Financial disclosure was reported in only 11.4% (301 of 2651) of these instances. In total, 851 surgeons received more than $187 million over 5years, with the highest-paid surgeon receiving an average of over $5.9 million per year. The largest individual payments were from "Associated Research Funding," with over $115 million being paid to 277 surgeons over 5years. The top paying company issued over $96.5 million to American CT surgeons over 5years. Nearly all the reviewed publications in three top CT surgery journals were by surgeons who received payments from companies, but very few of these payments were recorded as potential conflicts of interest. A more consistent and robust policy of COI disclosure is needed to reduce perceptions of bias.

Monoclonal antibodies for treating early Alzheimer disease-a commentary on recent 'positive' trials.

Recent phase 3 randomised controlled trials of amyloid-targeting monoclonal antibodies in people with pre-clinical or early Alzheimer disease have reported positive results, raising hope of finally having disease-modifying drugs. Given their far-reaching implications for clinical practice, the methods and findings of these trials, and the disease causation theory underpinning the mechanism of drug action, need to be critically appraised. Key considerations are the representativeness of trial populations; balance of prognostic factors at baseline; psychometric properties and minimal clinically important differences of the primary efficacy outcome measures; level of study fidelity; consistency of subgroup analyses; replication of findings in similar trials; sponsor role and potential conflicts of interest; consistency of results with disease causation theory; cost and resource estimates; and alternative prevention and treatment strategies. In this commentary, we show shortcomings in each of these areas and conclude that monoclonal antibody treatment for early Alzheimer disease is lacking high-quality evidence of clinically meaningful impacts at an affordable cost.

Policy Actors' Perceptions of Conflicts of Interest and Alcohol Industry Engagement in UK Policy Processes.

Alcohol industry organisations occupy a prominent position in UK alcohol policy, but their involvement has been contested by public health bodies on the basis that a conflict of interest (COI) exists between their economic objectives and those of public health. There are ongoing debates in the research literature about how to conceptualise COI and mitigate this in health research and practise. However, less attention has been paid to these issues in relation to the alcohol industry specifically. This article explores similarities and differences in beliefs among alcohol policy actors regarding COI and the implications of engagement with the alcohol industry in the context of UK public health policy. Semi-structured interviews with a range of policy actors (n=26) including medical professionals, parliamentarians, civil servants, academic researchers, health campaigners, and alcohol industry representatives. Interviews with alcohol industry representatives were supplemented with an analysis of industry responses to a public consultation. All data was thematically coded using NVivo software. Two competing "coalitions" were identified, expressing beliefs about COI linked to alcohol industry engagement. Both divergent and convergent beliefs were expressed by the two coalitions in relation to the type of industry actor, form of engagement, the policy issue under discussion and the stage of policy process. Alcohol policy is a complex and contested space in which policy actors have differing, nuanced and contingent understandings of COI and identify varying risks associated with alcohol industry engagement. In identifying the areas of convergence and diversion in both understanding and evaluation of COI in alcohol-specific settings, these findings will assist both decision-makers and non-governmental actors in developing policies and guidelines to manage potential COI in future.

Analyzing the Interplay of Incentive Pay and Governance in the Boeing 737 MAX Incident: Implications for Corporate Structure and Ethics

This study delves into the relationship between incentive-based compensation models and corporate governance, focusing on the Boeing 737 MAX incident as a critical case study. It thoroughly examines data from annual reports of Boeing Company (2007–2014) and the proxy statements issued between 2008 and 2015 (Boeing Company, 2008–2015), highlighting the impact of incentive-driven decisions, particularly by Boeing’s CEO. Post-2011, the CEO’s compensation, heavily linked to a risk reduction strategy, saw a substantial increase. This strategy received backing from a compensation committee, members of which shared the CEO’s General Electric background, raising concerns about potential conflicts of interest. The research emphasizes the urgent need to reassess corporate governance norms, focusing on executive pay structures and the independence of corporate boards. The Boeing 737 MAX incident starkly warns of the dangers and ethical issues associated with misaligned incentive frameworks. The study calls for reforms to ensure corporate decisions are ethically responsible and in harmony with long-term, sustainable business practices.

Patients with Atopic Dermatitis Not on Systemic Therapy have High Rates of Severe, Uncontrolled Disease, and Considerable Impact on Quality of Life

Patients with Atopic Dermatitis Not on Systemic Therapy have High Rates of Severe, Uncontrolled Disease, and Considerable Impact on Quality of Life

The WHO Foundation in global health governance: Depoliticizing corporate philanthropy

The creation of the WHO Foundation during the COVID-19 pandemic represents a significant institutional development in the politics of financing the World Health Organization (WHO). In the context of longstanding acute financial pressures, the objective of the WHO Foundation is to widen WHO's resource base by attracting philanthropic donations from the commercial sector. In placing funding decisions ‘at one remove’ from WHO, the stated expectation is that the WHO Foundation will act as an intermediary, insulating the WHO from potential conflicts of interest and reputational risk through a combination of strategic distance from WHO and proximity with its norms and rules of engagement with non-state actors. Yet, whether this model has translated into practice remains understudied. In this article, we focus on emerging institutional practices within the WHO Foundation, highlighting a drift from its stated governance model. Based on analysis of WHO Foundation documents, we demonstrate how due diligence and transparency practices within the Foundation have been redesigned in ways that contradict or subvert its claims to applying alignment with WHO's governance norms, notably relating to its engagement with health harming industries such as alcohol and petrochemical companies. While this situation may seem paradoxical, we argue that, in placing funding decisions ‘at one remove’ from the formal institutions and structures of WHO, the creation of the Foundation has served to displace this issue to a more secluded arena where drifts in practice are less exposed to political oversight and scrutiny. Focusing on the discursive aspects of this process of depoliticisation, we contend that the Foundation has strategically managed ‘fictional expectations’ of accountable and transparent governance in order to mitigate concerns about its mandate and functions. This assessment provides new and important insights into the depoliticizing functions of the WHO Foundation and the significant implications this may have for global health governance.

Safeguarding scientific integrity: A case study in examining manipulation in the peer review process

ABSTRACT This case study analyzes the expertise, potential conflicts of interest, and objectivity of editors, authors, and peer reviewers involved in a 2022 special journal issue on fertility, pregnancy, and mental health. Data were collected on qualifications, organizational affiliations, and relationships among six papers’ authors, three guest editors, and twelve peer reviewers. Two articles were found to have undisclosed conflicts of interest between authors, an editor, and multiple peer reviewers affiliated with anti-abortion advocacy and lobbying groups, indicating compromised objectivity. This lack of transparency undermines the peer review process and enables biased research and disinformation proliferation.Our study is limited by a few factors including: difficulty collecting peer reviewer data, potentially missing affiliations, and a small sample without comparisons. While this is a case study of one special issue, we do have suggestions for increasing integrity.

ADVANCING THE FABRICATION OF 3D MINI-TISSUE ENTHESIS CONSTRUCTS: CHARACTERIZATION OF BONE, TENDON, AND BMSC SPHEROIDS

AbstractObjectivesThe enthesis is a specialised structure at the interface between bone and tendon with gradual integration to maintain functionality and integrity. In the process of fabricating an in-vitro model of this complex structure, this study aims to investigate growth and maturation of bone, tendon and BMSC spheroids followed by 3D mini-tissue production.MethodsCell spheroids Spheroids of differentiated rat osteoblasts (dRObs), rat tendon fibroblasts (RTFs) and bone marrow stem cells (BMSC) were generated by culturing in 96 well U bottom cell repellent plates. With dROb spheroids previously analysed [1], RTF spheroids were examined over a duration of up to 28 days at different seeding densities 1×104, 5×104, 1×105, 2×105 in different media conditions with and without FBS (N=3). Spheroid diameter was analysed by imageJ/Fiji; Cell proliferation and viability was assessed by trypan blue staining after dissociating with accutase + type II collagenase mix; necrotic core by H&amp;E staining; and extracellular matrix by picro-sirius red (RTFs) staining to visualise collagen fibres under bright-field and polarised light microscope.3D mini-tissue constructs15 day old mineralised dROb spheroids (∼1.5mm diameter) were deposited in pillar array supports using a customised spheroid deposition system to allow 3D mini-tissue formation via fusion (N=3). Similarly BMSC and RTF spheroids were deposited after determining the seeding density that produced spheroid size equivalent to 15 day old dROb spheroids. Gentle removal of spheroids from supports was performed on day 2, 4 and 6 to assess spheroid fusion. Histological staining was performed to observe cellular arrangement and extracellular matrix.ResultsRTF spheroids diameter reduced over the course of 28 days regardless of the seeding density. A substantial decline in cell numbers over time was observed and suggests lack of cell proliferation due to tenogenic differentiation. Absence of a necrotic core in RTF spheroids, in all seeding densities, reveals their inherent capacity to maintain cell viability in avascular conditions. Picro-sirius red staining demonstrated the presence of collagen type I fibres predominantly in peripheral regions of spheroids maintaining its shape. Small amounts of collagen type III were also noticed. The dROb spheroids fused rapidly within 2 days resulting in the formation of a mini-tissue. 2×105 RTFs and 3×105 BMSCs produced spheroids of ∼1.5mm on day 3 and day 1 respectively. When these spheroids were deposited in pillar array supports, they did not undergo fusion even up to 6 days. This suggests inadequate aggregation of spheroids and insufficient ECM production at this early stage.ConclusionsThis study has demonstrated the ability of RTFs to produce necrotic core-free spheroids with collagen fibres maintaining their structural integrity. For mini-tissue formation, we predict a longer initial culture time of RTF and BMSC spheroids will allow increased cellular interaction and ECM production before deposition, and will facilitate spheroid fusion. These findings will be applied in producing heterogenous mini-tissues, serving as a 3D in-vitro enthesis model.Declaration of Interest(a) fully declare any financial or other potential conflict of interest

ATTUNE TOTAL KNEE REPLACEMENT: IS THERE EVIDENCE OF INCREASED TIBIAL COMPONENT LOOSENING? A RETROSPECTIVE ANALYSIS OF 10,202 KNEES

AbstractObjectiveUp to 20% of patients can remain dissatisfied following TKR. A proportion of TKRs will need early revision with aseptic loosening the most common. The ATTUNE TKR was introduced in 2011 as successor to its predicate design The PFC Sigma (DePuy Synthes, Warsaw, In). However, following reports of early failures of the tibial component there have been ongoing concerns of increased loosening rates with the ATTUNE TKR. In 2017 a redesigned tibial baseplate (S+) was introduced, which included cement pockets and an increased surface roughness to improve cement bonding. Given the concerns of early tibial loosening with the ATTUNE knee system, this study aimed to compare revision rates and those specific to aseptic loosening of the ATTUNE implant in comparison to an established predicate as well as other implant designs used in a high-volume arthroplasty centre.MethodsThe Attune TKR was introduced to our unit in December 2011. Prior to this we routinely used a predicate design with an excellent long-term track record (PFC Sigma) which remains in use. In addition, other designs were available and used as per surgeon preference. Using a prospectively maintained database, we identified 10,202 patients who underwent primary cemented TKR at our institution between 01/04/2003–31/03/2022 with a minimum of 1 year follow-up (Mean 8.4years, range 1–20years): 1) 2406 with ATTUNE TKR (of which 557 were S+) 2) 4652 with PFC TKR 3) 3154 with other cemented designs. All implants were cemented using high viscosity cement. The primary outcome measures were all-cause revision, revision for aseptic loosening, and revision for tibial loosening. Kaplan-Meier survival analysis and Cox regression models were used to compare the primary outcomes between groups. Matched cohorts were selected from the ATTUNE subsets (original and S+) and PFC groups using the nearest neighbor method for radiographic analysis. Radiographs were assessed to compare the presence of radiolucent lines in the Attune S+, standard Attune, and PFC implants.ResultsAt a mean of 8.4 years follow-up, 308 implants underwent revision equating to 3.58 revisions per 1000 implant-years. The lowest risk of revision was noted in the ATTUNE cohort with 2.98 per 1000-implant-years where the PFC and All Other Implant groups were 3.15 and 4.4 respectively. Aseptic loosing was the most common cause for revision across all cemented implants with 76% (65/88) of involving loosening of the tibia. Survival analysis comparing the ATTUNE cohort to the PFC and All Other Cemented Implant cohorts showed no significant differences for: all-cause revision, aseptic loosening, or tibial loosening (p=0.15,0.77,0.47). Radiolucent lines were detected in 4.6%, 5.8%, and 5.0% of the ATTUNE S+, standard ATTUNE, and PFC groups respectively. These differences were not significant.ConclusionThis study represents the largest non-registry review of the original and S+ ATTUNE TKR in comparison to its predicate design as well as other cemented implants. There appears to be no significant increased revision rate for all-cause revision or aseptic loosening. Radiographic analysis also showed no significant difference in peri-implant radiolucency. It appears that concerns of early loosening may be unfounded.Declaration of Interest(a) fully declare any financial or other potential conflict of interest

PATIENT-SPECIFIC DISTAL FEMORAL OSTEOTOMY REDUCES SURGICAL TIME: DEMONSTRATION OF A NOVEL PATIENT-SPECIFIC TECHNIQUE

AbstractBackgroundDistal femoral osteotomy is an established successful procedure which can delay the progression of arthritis and the need for knee arthroplasty. The surgery, however, is complex and lengthy and consequently it is generally the preserve of highly experienced specialists and thus not widely offered. Patient specific instrumentation is known to reduce procedural complexity, time, and surgeons’ anxiety levels1 in proximal tibial osteotomy procedures. This study evaluated a novel patient specific distal femoral osteotomy procedure (Orthoscape, Bath, UK) which aimed to use custom-made implants and instrumentation to provide a precision correction while also simplifying the procedure so that more surgeons would be comfortable offering the procedure.Presenting problemThree patients (n=3) with early-stage knee arthritis presented with valgus malalignment, the source of which was predominantly located within the distal femur, rather than intraarticular. Using conventional techniques and instrumentation, distal femoral knee osteotomy cases typically require 1.5–2 hours surgery time. The use of bi-planar osteotomy cuts have been shown to improve intraoperative stability as well as bone healing times2. This normally also increases surgical complexity; however, multiple cutting slots can be easily incorporated into patient specific instrumentation.Clinical managementAll three cases were treated at a high-volume tertiary referral centre (Istituto Ortopedico Rizzoli, Bologna) using medial closing wedge distal femoral knee osteotomies by a team experienced in using patient specific osteotomy systems3. Virtual surgical planning was conducted using CT-scans and long-leg weight-bearing x-rays (Orthoscape, Bath, UK). Patient specific surgical guides and custom-made locking plates were design for each case. The guides were designed to allow temporary positioning, drilling and bi-planar saw-cutting. The drills were positioned such that the drills above and below the osteotomy became parallel on closing following osteotomy wedge removal. This gave reassurance of the achieved correction allowed the plate to be located precisely over the drills. All screw lengths were pre-measured.DiscussionThe surgical time reduced to approximately 30 minutes by the third procedure. It was evident that surgical time was saved because no intraoperative screw length measurements were required, relatively few x-rays were used to confirm the position of the surgical guide, and the use of custom instrumentation significantly reduced the surgical inventory. The reduced invasiveness and ease of surgery may contribute to faster patient recovery compared to conventional techniques. The final post-operative alignment was within 1° of the planned alignment in all cases.Declaration of Interest(a) fully declare any financial or other potential conflict of interest