Lessons learnt from assessing and improving accuracy and positive predictive value of the national HIV testing algorithm in Nigeria.

Background: HIV testing remains an entry point into HIV care and treatment services. In 2007, Nigeria adopted and implemented a two-test rapid HIV testing algorithm of three HIV rapid test kits, following the sequence: Alere Determine (first test), UnigoldTM (second test), and STAT-PAK® as the tie-breaker. Sub-analysis of the 2018 Nigeria HIV/AIDS Indicator and Impact Survey data showed significant discordance between the first and second tests, necessitating an evaluation of the algorithm. This manuscript highlights lessons learnt from that evaluation. Intervention: A two-phased evaluation method was employed, including abstraction and analysis of retrospective HIV testing data from January 2017 to December 2019 from 24 selected sites supported by the United States President's Emergency Plan for AIDS Relief programme. A prospective evaluation of HIV testing was done among 2895 consecutively enrolled and consented adults, aged 15-64 years, accessing HIV testing services from three selected sites per state across the six geopolitical zones of Nigeria between July 2020 and September 2020. The prospective evaluation was performed both in the field and at the National Reference Laboratory under controlled laboratory conditions. Stakeholder engagements, strategic selection and training of study personnel, and integrated supportive supervision were employed to assure the quality of evaluation procedures and outcomes. Lessons learnt: The algorithm showed higher sensitivity and specificity in the National Reference Laboratory compared with the field. The approaches to quality assurance were integral to the high-quality study outcomes. Recommendations: We recommend comparison of testing algorithms under evaluation against a gold standard. What this study adds: This study provides context-specific considerations in using World Health Organization recommendations to evaluate the Nigerian national HIV rapid testing algorithm.

Prospective Validation of the Pancreatic Fistula Risk Classification by the International Study Group for Pancreatic Surgery (PARIS trial).

OBJECTIVE: The aim of this study was a prospective validation of the recently established ISGPS pancreas classification as a parenchymal risk classification system for pancreatic fistula after pancreatoduodenectomy. SUMMARY BACKGROUND DATA: Postoperative pancreatic fistula (POPF) is the major driver for complications after partial pancreatoduodenectomy (PD). Recently, the International Study Group for Pancreatic Surgery (ISGPS) published a pancreas classification containing the parameters main pancreatic duct diameter (MPD) and pancreatic texture to help assess the risk of POPF development following pancreatoduodenectomy. METHODS: From January 2020 to July 2021, 271 patients receiving elective PD were included after informed consent. The postoperative course was documented prospectively up to postoperative day 30. Among the pancreas characteristics, MPD and pancreatic texture were assessed intraoperatively at the pancreatic resection margin and the pancreatic glands were assigned to one of the four pancreas classes according to the ISGPS (A to D). The primary endpoint was POPF according to the updated ISGPS definition. Secondary endpoints comprised other post-PD morbidity and mortality. RESULTS: Of 271 patients, 264 had available data according to the ISGPS pancreas classification. Of those, 78 were assigned to class A (30%), 53 to class B (20%), 50 to class C (19%) and 83 to class D (31%). POPF occurred in 54 of 271 patients (19.9%). The 30-day mortality was 7/271 (2.6%), with 6/7 having developed POPF (86%). POPF rates within the classes A, B, C and D were 9.0%, 11.3%, 20.0% and 37.4%, respectively (P<0.001). In the univariable regression analysis, only patients in pancreas class D demonstrated a significantly higher risk for POPF when compared to class A (OR 6.05, 95%-CI: 2.6-15.9, P<0.001). In the multivariable regression model, patients in class D had a significantly higher risk for POPF compared to class A (OR 3.45, 95%-CI: 1.15-11.3, P=0.032). The model comprised Body Mass Index, surgery duration, microscopic fibrosis and the ISGPS pancreas classification, demonstrating an AUC-value of approximately 0.82 when tested on the PARIS dataset. CONCLUSION: This prospective trial shows that the ISGPS pancreas classification is valid. Patients in risk class D are prone to POPF independently of other factors. Therefore, all future publications on pancreatic surgery should report the risk class according to the ISGPS pancreas classification to allow for a better comparison of reported cohorts.

Childhood Trauma Questionnaire-based child maltreatment profiles to predict efficacy of the Cognitive Behavioral Analysis System of Psychotherapy versus non-specific psychotherapy in adults with early-onset chronic depression: cluster analysis of data from a randomised controlled trial.

BACKGROUND: Child maltreatment is a broadly confirmed risk factor for mental and physical illness. Some psychological treatments specifically target mental health conditions associated with child maltreatment. For example, the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) focuses on maladaptive interpersonal behaviours in chronic depression. However, how the assessment of child maltreatment could inform personalised treatment is unclear. We used data from a previously published clinical trial to investigate whether a pre-established child maltreatment clustering approach predicts differential outcomes after CBASP versus non-specific supportive psychotherapy in patients with early-onset chronic depression. METHODS: We did a cluster analysis of data from a previous randomised controlled trial of unmedicated adult outpatients with early-onset chronic depression who were treated at eight university clinics and psychological institutes in Germany with 32 sessions of CBASP or non-specific supportive psychotherapy. Participants were eligible for the original trial if they were aged 18-65 years; had major depressive disorder (MDD) with an early onset and duration of at least 2 years, current MDD superimposed on a pre-existing dysthymic disorder, or recurrent MDD with incomplete remission between episodes as defined by DSM-IV; and had a score of at least 20 points on the 24-item Hamilton Rating Scale for Depression (HRSD-24). Participants were included in the current study if they had completed the short form of the Childhood Trauma Questionnaire (CTQ) at trial baseline. We used an agglomerative hierarchical clustering approach to derive child maltreatment clusters from individual patterns across the five domains of the CTQ. We used linear mixed models to investigate whether clustering could predict differential clinical outcomes (change in symptom severity on the HRSD-24) up to 2 years after treatment onset. People with lived experience were involved in the current study. FINDINGS: 253 patients (129 [51%] treated with CBASP and 124 [49%] with supportive psychotherapy) had complete CTQ records and were included in the analysis. 169 (67%) participants were women, 84 (33%) were men, and the mean age was 45·9 years (SD 11·7). We identified seven child maltreatment clusters and found significant differences in treatment effects of CBASP and supportive psychotherapy between the clusters (F(6,948·76)=2·47; p=0·023); differences were maintained over the 2-year follow-up. CBASP was superior in distinct clusters of co-occurring child maltreatment: predominant emotional neglect (change in ß -6·02 [95% CI -11·9 to -0·13]; Cohen's d=-0·98 [95% CI -1·94 to -0·02]; p=0·045), predominant emotional neglect and abuse (-6·39 [-10·22 to -2·56]; -1·04 [-1·67 to -0·42]; p=0·0011), and emotional neglect and emotional and physical abuse (-9·41 [-15·91 to -2·91]; -1·54 [-2·6 to -0·47]; p=0·0046). INTERPRETATION: CTQ-based cluster analysis can facilitate identification of patients with early-onset chronic depression who would specifically benefit from CBASP. Child maltreatment clusters could be implemented in clinical assessments and serve to develop and personalise trauma-informed care in mental health. FUNDING: The German Research Foundation and the German Federal Ministry of Education and Research.

Prevalence and prognostic role of thoracic lymphadenopathy in Covid-19. / Prävalenz und prognostische Rolle der thorakalen Lymphadenopathie bei Covid-19.

PURPOSE: The prevalent coronavirus disease 2019 (COVID-19) pandemic has spread throughout the world and is considered a serious threat to global health. The prognostic role of thoracic lymphadenopathy in COVID-19 is unclear. The aim of the present meta-analysis was to analyze the prognostic role of thoracic lymphadenopathy for the prediction of 30-day mortality in patients with COVID-19. MATERIALS AND METHODS: The MEDLINE library, Cochrane, and SCOPUS databases were screened for associations between CT-defined features and mortality in COVID-19 patients up to June 2021. In total, 21 studies were included in the present analysis. The quality of the included studies was assessed by the Newcastle-Ottawa Scale. The meta-analysis was performed using RevMan 5.3. Heterogeneity was calculated by means of the inconsistency index I2. DerSimonian and Laird random-effect models with inverse variance weights were performed without any further correction. RESULTS: The included studies comprised 4621 patients. The prevalence of thoracic lymphadenopathy varied between 1 % and 73.4 %. The pooled prevalence was 16.7 %, 95 % CI = (15.6 %; 17.8 %). The hospital mortality was higher in patients with thoracic lymphadenopathy (34.7 %) than in patients without (20.0 %). The pooled odds ratio for the influence of thoracic lymphadenopathy on mortality was 2.13 (95 % CI = [1.80-2.52], p < 0.001). CONCLUSION: The prevalence of thoracic lymphadenopathy in COVID-19 is 16.7 %. The presence of thoracic lymphadenopathy is associated with an approximately twofold increase in the risk for hospital mortality in COVID-19. KEY POINTS: · The prevalence of lymphadenopathy in COVID-19 is 16.7 %.. · Patients with lymphadenopathy in COVID-19 have a higher risk of mortality during hospitalization.. · Lymphadenopathy nearly doubles mortality and plays an important prognostic role.. CITATION FORMAT: · Bucher AM, Sieren M, Meinel F et al. Prevalence and prognostic role of thoracic lymphadenopathy in Covid-19. Fortschr Röntgenstr 2024; DOI: 10.1055/a-2293-8132.

Potentially Inappropriate End of Life Care and Healthcare Costs in the Last 30 Days of Life in Regions Providing Integrated Palliative Care in the Netherlands: A Registration-based Study.

Introduction: This study aimed to assess the effect of integrated palliative care (IPC) on potentially inappropriate end- of-life care and healthcare-costs in the last 30 days of life in the Netherlands. Methods: Nationwide health-insurance claims data were used to assess potentially inappropriate end-of-life care (≥2 emergency room visits; ≥2 hospital admissions; >14 days hospitalization; chemotherapy; ICU admission; hospital death) and healthcare-costs in all deceased adults in IPC regions pre- and post- implementation and in those receiving IPC compared to a 1:2 matched control group. Results: In regions providing IPC deceased adults (n = 37,468) received significantly less potentially inappropriate end-of-life care post-implementation compared to pre-implementation (26.5% vs 27.9%; p < 0.05). Deceased adults who received IPC (n = 210) also received significantly less potentially inappropriate end-of-life care compared to a matched control group (14.8% vs 28.3%; p < 0.05). Mean hospital costs significantly decreased for deceased adults who received IPC (€2,817), while mean costs increased for general practitioner services (€311) and home care (€1,632). Discussion: These results highlight the importance of implementation of integrated palliative care and suitable payment. Further research in a larger sample is needed. Conclusion: This study shows less potentially inappropriate end-of-life care and a shift in healthcare costs from hospital to general practitioner and home care with IPC.

pyCEPS: A cross-platform electroanatomic mapping data to computational model conversion platform for the calibration of digital twin models of cardiac electrophysiology.

BACKGROUND AND OBJECTIVE: Data from electro-anatomical mapping (EAM) systems are playing an increasingly important role in computational modeling studies for the patient-specific calibration of digital twin models. However, data exported from commercial EAM systems are challenging to access and parse. Converting to data formats that are easily amenable to be viewed and analyzed with commonly used cardiac simulation software tools such as openCARP remains challenging. We therefore developed an open-source platform, pyCEPS, for parsing and converting clinical EAM data conveniently to standard formats widely adopted within the cardiac modeling community. METHODS AND RESULTS: pyCEPS is an open-source Python-based platform providing the following functions: (i) access and interrogate the EAM data exported from clinical mapping systems; (ii) efficient browsing of EAM data to preview mapping procedures, electrograms (EGMs), and electro-cardiograms (ECGs); (iii) conversion to modeling formats according to the openCARP standard, to be amenable to analysis with standard tools and advanced workflows as used for in silico EAM data. Documentation and training material to facilitate access to this complementary research tool for new users is provided. We describe the technological underpinnings and demonstrate the capabilities of pyCEPS first, and showcase its use in an exemplary modeling application where we use clinical imaging data to build a patient-specific anatomical model. CONCLUSION: With pyCEPS we offer an open-source framework for accessing EAM data, and converting these to cardiac modeling standard formats. pyCEPS provides the core functionality needed to integrate EAM data in cardiac modeling research. We detail how pyCEPS could be integrated into model calibration workflows facilitating the calibration of a computational model based on EAM data.

Fate, inducibility, and behavior of Latilactobacillus curvatus temperate phage TMW 1.591 P1 during sausage fermentation.

AIMS: Temperate phages insert their genome into the host's chromosome. As prophages, they remain latent in the genome until an induction event leads to lytic phage production. When this occurs in a starter culture that has been added to food fermentation, this can impair the fermentation success. This study aimed to analyze prophage inducibility in the Latilactobacillus curvatus TMW 1.591 strain during meat fermentation and investigate whether an induction signal before cryopreservation is maintained during storage and can lead to phage-induced lysis after culture activation. METHODS AND RESULTS: A prophage-free isogenic derivative of the model starter organism, L. curvatus TMW 1.591, was developed as a negative control (L. curvatus TMW 1.2406). Raw meat fermentation was performed with the wild-type (WT) and phage-cured strains. The WT strain produced high numbers of phages (5.2 ± 1.8 × 107 plaque-forming units g-1) in the meat batter. However, the prophage did not significantly affect the meat fermentation process. Induction experiments suggested an acidic environment as a potential trigger for prophage induction. Phage induction by ultraviolet light before strain cryopreservation remains functional for at least 10 weeks of storage. CONCLUSIONS: Intact prophages are active during meat fermentation. However, in this study, this has no measurable consequences for fermentation, suggesting a high resiliency of meat fermentation against phages. Inadequate handling of lysogenic starter strains, even before preservation, can lead to phage introduction into food fermentation and unintended host lysis.

Functional Characterization of the Lysosomal Peptide/Histidine Transporter PHT1 (SLC15A4) by Solid Supported Membrane Electrophysiology (SSME).

The peptide/histidine transporter PHT1 (SLC15A4) is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H+-coupled/histidine symporter that can transport a wide range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response. Not surprisingly, PHT1 has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Unfortunately, the pharmacological development of PHT1 modulators has been hampered by the lack of suitable transport assays. To address this shortcoming, a novel transport assay based on solid-supported membrane-based electrophysiology (SSME) is presented. Key findings of the present SSME studies include the first recordings of electrophysiological properties, a pH dependence analysis, an assessment of PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates. In contrast to previous work, PHT1 is studied in its native lysosomal environment. Moreover, observed substrate selectivity is validated by molecular docking. Overall, this new SSME-based assay is expected to contribute to unlocking the pharmacological potential of PHT1 and to deepen the understanding of its functional properties.

Electron Diffraction Tomography on Two-Phase Nanolamellae of Topochemically Synthesized Cu(Sb2S3)Cl.

The dark red semiconductor Cu(Sb2S3)Cl was obtained by leaching the layered precursor Cu(Sb2S3)[AlCl4] in a 0.1 M aqueous HCl solution. The selective extraction of AlCl3 yielded a mica-like lamellar product of poor crystallinity. Misalignment of lamellae down to the nanoscale prevented structure determination by conventional single-crystal X-ray diffraction, but a combination of transmission electron microscopy, selected area electron diffraction, and selected area electron precession diffraction tomography on a nanoscale spot with largely ordered crystalline lamellae revealed the crystal structures of two intergrown modifications. Orthorhombic o-Cu(Sb2S3)Cl and monoclinic m-Cu(Sb2S3)Cl have similar layers to the precursor and differ only in the stacking of the layers. These consist of uncharged Sb2S3 strands, whose sulfide ions, together with chloride ions, coordinate the copper(I) cations. Only one chloride ion remained from the [AlCl4]- group. DFT calculations confirm the structure solution for the orthorhombic form and suggest that the monoclinic structure is metastable against transformation to o-Cu(Sb2S3)Cl.

Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation.

Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.

Arthroscopic Repair of Posterosuperior Rotator Cuff Tears Using a Modified Mason-Allen Suture Technique With a Transosseous-Equivalent Construct: A Technical Note.

Iterative evolutions in arthroscopic rotator cuff repair aim to improve its biomechanical and biological properties. This technical note describes an arthroscopic rotator cuff repair technique that combines the advantages of a modified Mason-Allen suture technique with the advantages of an arthroscopic transosseous-equivalent construct. Two alternatives for creating this construct are described. The Mason-Allen stitch is easy to perform, is cost-effective, and increases tissue security without tendon strangulation. The arthroscopic transosseous-equivalent construct increases footprint contact pressure and coverage, aiding healing of the repaired rotator cuff.

Navigated augmented reality through a head-mounted display leads to low deviation between planned, intra- and postoperative parameters during glenoid component placement of reverse shoulder arthroplasty: a proof-of-concept case series.

BACKGROUND: Navigated augmented reality (AR) through a head-mounted display (HMD) has led to accurate glenoid component placement in reverse shoulder arthroplasty (RSA) in an in-vitro setting. The purpose of this study is to evaluate the deviation between planned, intraoperative, and postoperative inclination, retroversion, entry point, and depth of the glenoid component placement during RSA, assisted by navigated AR through an HMD, in a surgical setting. METHODS: A prospective, multicenter study was conducted. All consecutive patients undergoing RSA in 2 institutions, between August 2021 and January 2023, were considered potentially eligible for inclusion in the study. Inclusion criteria were as follows: age >18 years, surgery assisted by AR through an HMD, and postoperative computed tomography (CT) scans at 6 weeks. All participants agreed to participate in the study and informed consent was provided in all cases. Preoperative CT scans were undertaken for all cases and used for 3-dimensional (3D) planning. Intraoperatively, glenoid preparation and component placement were assisted by a navigated AR system through an HMD in all patients. Intraoperative parameters were recorded by the system. A postoperative CT scan was undertaken at 6 weeks, and 3D reconstruction was performed to obtain postoperative parameters. The deviation between planned, intraoperative, and postoperative inclination, retroversion, entry point, and depth of the glenoid component placement was calculated. Outliers were defined as >5° for inclination and retroversion and >5 mm for entry point. RESULTS: Seventeen patients (9 females, 12 right shoulders) with a mean age of 72.8 ± 9.1 years (range, 47.0-82.0) met inclusion criteria. The mean deviation between intra- and postoperative measurements was 1.5° ± 1.0° (range, 0.0°-3.0°) for inclination, 2.8° ± 1.5° (range, 1.0°-4.5°) for retroversion, 1.8 ± 1.0 mm (range, 0.7-3.0 mm) for entry point, and 1.9 ± 1.9 mm (range, 0.0-4.5 mm) for depth. The mean deviation between planned and postoperative values was 2.5° ± 3.2° (range, 0.0°-11.0°) for inclination, 3.4° ± 4.6° (range, 0.0°-18.0°) for retroversion, 2.0 ± 2.5 mm (range, 0.0°-9.7°) for entry point, and 1.3 ± 1.6 mm (range, 1.3-4.5 mm) for depth. There were no outliers between intra- and postoperative values and there were 3 outliers between planned and postoperative values. The mean time (minutes : seconds) for the tracker unit placement and the scapula registration was 03:02 (range, 01:48 to 04:26) and 08:16 (range, 02:09 to 17:58), respectively. CONCLUSION: The use of a navigated AR system through an HMD in RSA led to low deviations between planned, intraoperative, and postoperative parameters for glenoid component placement.

MRI-Derived Dural Sac and Lumbar Vertebrae 3D Volumetry Has Potential for Detection of Marfan Syndrome.

PURPOSE: To assess the feasibility and diagnostic accuracy of MRI-derived 3D volumetry of lower lumbar vertebrae and dural sac segments using shape-based machine learning for the detection of Marfan syndrome (MFS) compared with dural sac diameter ratios (the current clinical standard). MATERIALS AND METHODS: The final study sample was 144 patients being evaluated for MFS from 01/2012 to 12/2016, of whom 81 were non-MFS patients (46 [67%] female, 36 ± 16 years) and 63 were MFS patients (36 [57%] female, 35 ± 11 years) according to the 2010 Revised Ghent Nosology. All patients underwent 1.5T MRI with isotropic 1 × 1 × 1 mm3 3D T2-weighted acquisition of the lumbosacral spine. Segmentation and quantification of vertebral bodies L3-L5 and dural sac segments L3-S1 were performed using a shape-based machine learning algorithm. For comparison with the current clinical standard, anteroposterior diameters of vertebral bodies and dural sac were measured. Ratios between dural sac volume/diameter at the respective level and vertebral body volume/diameter were calculated. RESULTS: Three-dimensional volumetry revealed larger dural sac volumes (p < 0.001) and volume ratios (p < 0.001) at L3-S1 levels in MFS patients compared with non-MFS patients. For the detection of MFS, 3D volumetry achieved higher AUCs at L3-S1 levels (0.743, 0.752, 0.808, and 0.824) compared with dural sac diameter ratios (0.673, 0.707, 0.791, and 0.848); a significant difference was observed only for L3 (p < 0.001). CONCLUSION: MRI-derived 3D volumetry of the lumbosacral dural sac and vertebral bodies is a feasible method for quantifying dural ectasia using shape-based machine learning. Non-inferior diagnostic accuracy was observed compared with dural sac diameter ratio (the current clinical standard for MFS detection).

m6A Methylation of Transcription Leader Sequence of SARS-CoV-2 Impacts Discontinuous Transcription of Subgenomic mRNAs.

The SARS-CoV-2 genome has been shown to be m6A methylated at several positions in vivo. Strikingly, a DRACH motif, the recognition motif for adenosine methylation, resides in the core of the transcriptional regulatory leader sequence (TRS-L) at position A74, which is highly conserved and essential for viral discontinuous transcription. Methylation at position A74 correlates with viral pathogenicity. Discontinuous transcription produces a set of subgenomic mRNAs that function as templates for translation of all structural and accessory proteins. A74 is base-paired in the short stem-loop structure 5'SL3 that opens during discontinuous transcription to form long-range RNA-RNA interactions with nascent (-)-strand transcripts at complementary TRS-body sequences. A74 can be methylated by the human METTL3/METTL14 complex in vitro. Here, we investigate its impact on the structural stability of 5'SL3 and the long-range TRS-leader:TRS-body duplex formation necessary for synthesis of subgenomic mRNAs of all four viral structural proteins. Methylation uniformly destabilizes 5'SL3 and long-range duplexes and alters their relative equilibrium populations, suggesting that the m6A74 modification acts as a regulator for the abundance of viral structural proteins due to this destabilization.

Murine iPSC-Loaded Scaffold Grafts Improve Bone Regeneration in Critical-Size Bone Defects.

In certain situations, bones do not heal completely after fracturing. One of these situations is a critical-size bone defect where the bone cannot heal spontaneously. In such a case, complex fracture treatment over a long period of time is required, which carries a relevant risk of complications. The common methods used, such as autologous and allogeneic grafts, do not always lead to successful treatment results. Current approaches to increasing bone formation to bridge the gap include the application of stem cells on the fracture side. While most studies investigated the use of mesenchymal stromal cells, less evidence exists about induced pluripotent stem cells (iPSC). In this study, we investigated the potential of mouse iPSC-loaded scaffolds and decellularized scaffolds containing extracellular matrix from iPSCs for treating critical-size bone defects in a mouse model. In vitro differentiation followed by Alizarin Red staining and quantitative reverse transcription polymerase chain reaction confirmed the osteogenic differentiation potential of the iPSCs lines. Subsequently, an in vivo trial using a mouse model (n = 12) for critical-size bone defect was conducted, in which a PLGA/aCaP osteoconductive scaffold was transplanted into the bone defect for 9 weeks. Three groups (each n = 4) were defined as (1) osteoconductive scaffold only (control), (2) iPSC-derived extracellular matrix seeded on a scaffold and (3) iPSC seeded on a scaffold. Micro-CT and histological analysis show that iPSCs grafted onto an osteoconductive scaffold followed by induction of osteogenic differentiation resulted in significantly higher bone volume 9 weeks after implantation than an osteoconductive scaffold alone. Transplantation of iPSC-seeded PLGA/aCaP scaffolds may improve bone regeneration in critical-size bone defects in mice.

Effect of patient-specific scapular morphology on the glenohumeral joint force and shoulder muscle force equilibrium: a study of rotator cuff tear and osteoarthritis patients.

Introduction: Osteoarthritis (OA) and rotator cuff tear (RCT) pathologies have distinct scapular morphologies that impact disease progression. Previous studies examined the correlation between scapular morphology and glenohumeral joint biomechanics through critical shoulder angle (CSA) variations. In abduction, higher CSAs, common in RCT patients, increase vertical shear force and rotator cuff activation, while lower CSAs, common in OA patients, are associated with higher compressive force. However, the impact of the complete patient-specific scapular morphology remains unexplored due to challenges in establishing personalized models. Methods: CT data of 48 OA patients and 55 RCT patients were collected. An automated pipeline customized the AnyBody™ model with patient-specific scapular morphology and glenohumeral joint geometry. Biomechanical simulations calculated glenohumeral joint forces and instability ratios (shear-to-compressive forces). Moment arms and torques of rotator cuff and deltoid muscles were analyzed for each patient-specific geometry. Results and discussion: This study confirms the increased instability ratio on the glenohumeral joint in RCT patients during abduction (mean maximum is 32.80% higher than that in OA), while OA patients exhibit a higher vertical instability ratio in flexion (mean maximum is 24.53% higher than that in RCT) due to the increased inferior vertical shear force. This study further shows lower total joint force in OA patients than that in RCT patients (mean maximum total force for the RCT group is 11.86% greater than that for the OA group), attributed to mechanically advantageous muscle moment arms. The findings highlight the significant impact of the glenohumeral joint center positioning on muscle moment arms and the total force generated. We propose that the RCT pathomechanism is related to force magnitude, while the OA pathomechanism is associated with the shear-to-compressive loading ratio. Overall, this research contributes to the understanding of the impact of the complete 3D scapular morphology of the individual on shoulder biomechanics.

ForCEPSS-A framework for cardiac electrophysiology simulations standardization.

BACKGROUND AND OBJECTIVE: Simulation of cardiac electrophysiology (CEP) is an important research tool that is increasingly being adopted in industrial and clinical applications. Typical workflows for CEP simulation consist of a sequence of processing stages starting with building an anatomical model and then calibrating its electrophysiological properties to match observable data. While the calibration stages are common and generalizable, most CEP studies re-implement these steps in complex and highly variable workflows. This lack of standardization renders the execution of computational CEP studies in an efficient, robust, and reproducible manner a significant challenge. Here, we propose ForCEPSS as an efficient and robust, yet flexible, software framework for standardizing CEP simulation studies. METHODS AND RESULTS: Key processing stages of CEP simulation studies are identified and implemented in a standardized workflow that builds on openCARP1 Plank et al. (2021) and the Python-based carputils2 framework. Stages include (i) the definition and initialization of action potential phenotypes, (ii) the tissue scale calibration of conduction properties, (iii) the functional initialization to approximate a limit cycle corresponding to the dynamic reference state according to an experimental protocol, and, (iv) the execution of the CEP study where the electrophysiological response to a perturbation of the limit cycle is probed. As an exemplar application, we employ ForCEPSS to prepare a CEP study according to the Virtual Arrhythmia Risk Prediction protocol used for investigating the arrhythmogenic risk of developing infarct-related ventricular tachycardia (VT) in ischemic cardiomyopathy patients. We demonstrate that ForCEPSS enables a fully automated execution of all stages of this complex protocol. CONCLUSION: ForCEPSS offers a novel comprehensive, standardized, and automated CEP simulation workflow. The high degree of automation accelerates the execution of CEP simulation studies, reduces errors, improves robustness, and makes CEP studies reproducible. Verification of simulation studies within the CEP modeling community is thus possible. As such, ForCEPSS makes an important contribution towards increasing transparency, standardization, and reproducibility of in silico CEP experiments.

Paget-Schroetter Syndrome in a Patient With Posterior Shoulder Subluxation: A Case Report.

ABSTRACT: Paget-Schroetter syndrome describes a primary thrombosis of the subclavian vein induced by effort. In most cases, the clinical presentation includes painful swelling, discoloration, and visible collateral circulation in the arm. Paget-Schroetter syndrome is treated with anticoagulation, rest, and physical therapy. In certain cases, invasive treatment such as thrombolysis and decompression surgery (first rib resection) may be necessary. We present the case of a 28-year-old healthy male patient with effort-induced deep vein thrombosis of the upper extremity after posterior shoulder subluxation. Anticoagulation, rest, and physical therapy were used to treat the patient, who became asymptomatic and was able to resume normal activities without restriction. To our knowledge, this is the first case of effort-induced upper extremity deep vein thrombosis after posterior shoulder subluxation. Paget-Schroetter syndrome is rare diagnosis that requires vigilance during musculoskeletal assessment for shoulder pain and swelling. The early detection, radiological confirmation, and prompt initiation of treatment are essential to successful management of Paget-Schroetter syndrome. The impact of associated posterior shoulder subluxation remains unclear.

Lower trapezius and latissimus dorsi transfer relieve teres minor activity into the physiological range in Collin D irreparable posterosuperior massive rotator cuff tears: a biomechanical analysis.

BACKGROUND: Tendon transfers are established techniques to regain external rotation mobility in patients with an irreparable, posterosuperior massive rotator cuff tear (MRCT). Posterosuperior MRCT with intact teres minor (type D MRCT) can lead to excessive teres minor loading to maintain external rotation. We hypothesize that tendon transfers are effective in relieving teres minor loading in type D MRCTs. Our aim was to biomechanically assess muscle synergism with latissimus dorsi (LD transfer) and lower trapezius (LT transfer) tendon transfer during external rotation at different abduction heights. METHODS: Using musculoskeletal modeling, we analyzed and compared the moment arm, muscle torque, and muscle activity between a healthy and type D MRCT pathologic model with and without the LD- or LT transfer at infraspinatus and teres minor insertion sites. Output measures were analyzed during external rotation at different abduction angles and 10-50 N resistance against external rotation. We assessed its impact on teres minor loading in a type D MRCT. Morphologic variations were parameterized using the critical shoulder angle and the acromiohumeral distance to address variations among patients. RESULTS: Both transfer types reduced teres minor torque and activity significantly, reaching physiological state at 40 N external resistance (P < .001), with insertion to infraspinatus site being more effective than teres minor site (P < .001). External rotation moment arms of LD transfer were larger than LT transfer at 90° abduction (25.1 ± 0.8 mm vs. 21.2 ± 0.6 mm, P < .001) and vice versa at 0° abduction (17.4 ± 0.5 mm vs. 24.0 ± 0.2 mm, P < .001). Although the healthy infraspinatus was the main external rotator in all abduction angles (50%-70% torque), a type D MRCT resulted in a 70%-90% increase of teres minor torque and an up to 7-fold increase in its activity leading to excessive loadings beyond 10 N resistance against external rotation. Varying the critical shoulder angle and the acromiohumeral distance led to minor variations in muscle moment arm and muscle activity. CONCLUSION: We identified biomechanical efficacy of both tendon transfers in type D MRCT regarding teres minor load relief and superior performance of the transfers at the infraspinatus insertion site.

Hypofractionated re-irradiation for diffuse intrinsic pontine glioma.

BACKGROUND: Re-irradiation (reRT) increases survival in locally recurrent diffuse intrinsic pontine glioma (DIPG). There is no standard dose and fractionation for reRT, but conventional fractionation (CF) is typically used. We report our institutional experience of reRT for DIPG, which includes hypofractionation (HF). METHODS: We reviewed pediatric patients treated with brainstem reRT for DIPG at our institution from 2012 to 2022. Patients were grouped by HF or CF. Outcomes included steroid use, and overall survival (OS) was measured from both diagnosis and start of reRT. RESULTS: Of 22 patients who received reRT for DIPG, two did not complete their course due to clinical decline. Of the 20 who completed reRT, the dose was 20-30 Gy in 2-Gy fractions (n = 6) and 30-36 Gy in 3-Gy fractions (n = 14). Median age was 5 years (range: 3-14), median interval since initial RT was 8 months (range: 3-20), and 12 received concurrent bevacizumab. Median OS from diagnosis was 18 months [95% confidence interval: 17-24]. Median OS from start of reRT for HF versus CF was 8.2 and 7.5 months, respectively (p = .20). Thirteen (93%) in the HF group and three (75%) in the CF group tapered pre-treatment steroid dose down or off within 2 months after reRT due to clinical improvement. There was no significant difference in steroid taper between HF and CF (p = .4). No patients developed radionecrosis. CONCLUSION: reRT with HF achieved survival duration comparable to published outcomes and effectively palliated symptoms. Future investigation of this regimen in the context of new systemic therapies and upfront HF is warranted.