Development of Hsp90 C-terminal inhibitors with noviomimetics that manifest anti-proliferative activities.

Inhibition of the Hsp90 C-terminal domain offers a promising opportunity to treat numerous diseases/indications. Furthermore, the development of Hsp90 C-terminal inhibitors (CTIs) is advantageous over N-terminal inhibitors because it avoids the detriments associated with induction of the heat shock response (HSR). However, the lack of co-crystal structures of small molecules bound to the C-terminus have hindered their development. Therefore, structure-activity relationship (SAR) studies have been pursued to optimize such inhibitors. Noviose sugar surrogates, also known as noviomimetics have been prepared to investigate the size and nature of the C-terminal domain binding pocket. Herein, we report the synthesis and anti-proliferative activity manifested by this new series of Hsp90 C-terminal inhibitors.

Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease.

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10-8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10-5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases.

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.

Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program: Bariatric Surgical Risk/Benefit Calculator: 1-year comorbidity remission.

BACKGROUND: Clinical calculators can provide patient-personalized estimates of treatment risks and health outcomes. The American College of Surgeons Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) set out to create a publicly available tool to assess both short-term postoperative risk and long-term benefits for prospective adult patients eligible for 1 of 4 primary bariatric procedures. The calculator is comprised of multiple prediction elements: (1) 30-day postoperative risk, (2) 1-year body mass index projections, and (3) 1-year comorbidity remission. OBJECTIVES: To assess the performance of the 1-year comorbidity remission prediction feature of the calculator. SETTING: Not-for-profit organization clinical data registry. METHODS: MBSAQIP data across 4.5 years from 240,227 total patients indicating at least 1 comorbidity of interest present preoperatively and who had a 1-year follow-up record documenting their comorbidity status were included. Six models were constructed, stratified by the presence of the respective preoperative comorbidity: hypertension, hyperlipidemia, gastroesophageal reflux disease, sleep apnea, non-insulin-dependent diabetes, and insulin-dependent diabetes. A multinomial logistic regression model was used to predict 1-year remission (total, partial, or no remission) of insulin-dependent diabetes. All other outcomes were binary (yes or no at 1 yr), and ordinary logistic regression models were used. RESULTS: All models showed adequate discrimination (C statistics ranging from .58 to .68). Plots of observed versus predicted remission (%) showed excellent calibration across all models. CONCLUSION: All remission models were well calibrated with sufficient discrimination. The MBSAQIP Bariatric Surgical Risk/Benefit Calculator is a publicly available tool intended for integration into clinical practice to enhance patient-clinician discussions and informed consent.

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.

National Multi-Institutional Validation of a Surgical Transfusion Risk Prediction Model.

BACKGROUND: Accurate estimation of surgical transfusion risk is important for many aspects of surgical planning, yet few methods for estimating are available for estimating such risk. There is a need for reliable validated methods for transfusion risk stratification to support effective perioperative planning and resource stewardship. STUDY DESIGN: This study was conducted using the American College of Surgeons NSQIP datafile from 2019. S-PATH performance was evaluated at each contributing hospital, with and without hospital-specific model tuning. Linear regression was used to assess the relationship between hospital characteristics and area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 1,000,927 surgical cases from 414 hospitals were evaluated. Aggregate AUROC was 0.910 (95% CI 0.904 to 0.916) without model tuning and 0.925 (95% CI 0.919 to 0.931) with model tuning. AUROC varied across individual hospitals (median 0.900, interquartile range 0.849 to 0.944), but no statistically significant relationships were found between hospital-level characteristics studied and model AUROC. CONCLUSIONS: S-PATH demonstrated excellent discriminative performance, although there was variation across hospitals that was not well-explained by hospital-level characteristics. These results highlight the S-PATH's viability as a generalizable surgical transfusion risk prediction tool.

Delphi Consensus on Clinical Applications of GOLD 2023 Recommendations in COPD Management: How Aligned are Recommendations with Clinical Practice?

INTRODUCTION: The objective of this Delphi study was to understand and assess the level of consensus among respiratory experts on the clinical application of GOLD 2023 recommendations in management of patients with chronic obstructive pulmonary disease (COPD). METHODS: The study comprised two online surveys and a participant meeting with 34 respiratory experts from 16 countries. Responses of 73 questions were recorded using a Likert scale ranging from 0 (disagreement) to 9 (agreement). The consensus threshold was 75%. RESULTS: Survey 1 and survey 2 had 34 and 32 participants, respectively; and 25 attended the participant meeting. Consensus was reached on survey 1: 28/42; survey 2: 18/30 close-ended questions. A consensus was reached on the clinical relevance of most updates in definitions and diagnosis of COPD. Mixed results for the treatment recommendations by GOLD were noted: 74% agreed with the recommendation to initiate treatment with dual bronchodilators for group E patients; 63% agreed for including inhaled corticosteroids (ICS)/long-acting ß2 agonist(LABA)/ Long-acting muscarinic receptor antagonists (LAMA) as a treatment option for GOLD B patients. Also, consensus lacked on removing ICS + LABA as an initial therapeutic option, in countries with challenges in access to other treatment option;. 88% agreed that they use GOLD recommendations in their daily clinical practice. CONCLUSIONS: This Delphi study demonstrated a high level of consensus regarding key concepts of GOLD 2023 report, with most participants favoring recent updates in definitions, diagnosis, management, and prevention of COPD. More evidence on the etiotype based management and treatment options for group B and E are required which could further strengthen clinical application of the GOLD report.

The goal of this Delphi study was to understand and assess the level of alignment among the respiratory experts on the application of key changes and recommendations proposed by the GOLD 2023 report in their routine clinical practice for the management of patients with chronic obstructive pulmonary disease (COPD). There were two online surveys in this study, and experts from 16 countries (primarily focused on developing countries) were invited to participate. Using the Delphi method, expert representatives shared their insights with the aim of optimizing patient care. The alignment was assessed in six well-defined themes: 1) Overall view on GOLD/other recommendations; 2) Assessing patients with COPD; 3) Initial pharmacological treatment in patients with COPD; 4) Vaccination for patients with COPD; 5) Follow-up pharmacological treatment in patients with COPD; and 6) Survival evidence in patients with COPD. Participants expressed a high level of agreement regarding key concepts of the GOLD 2023 report, with most of them agreeing with recent updates in definitions, diagnosis, management, and prevention of COPD. The results also highlighted the need to publish GOLD reports in multiple languages and in a shorter, pocket-sized format to increase awareness and adaptation among healthcare providers.

Angle Kappa Influence on Multifocal IOL Outcomes.

PURPOSE: To characterize angle kappa and study the relationship between preoperative angle kappa and postoperative refractive accuracy, visual outcomes, and patient satisfaction in a large population of eyes with multifocal intraocular lens (MIOL) implantation. METHODS: A comprehensive electronic medical record chart review of 26,470 consecutive eyes that underwent immediate sequential bilateral cataract or refractive lens exchange with MIOLs was conducted. The primary outcome measures were postoperative monocular uncorrected distance visual acuity (UDVA), manifest refraction sphere and cylinder, spherical equivalent (SEQ), defocus equivalent (DEQ), subjective quality of vision at near, intermediate, and distance, and the likelihood of recommending the procedure. Relationships between preoperative angle kappa and postoperative outcomes were assessed with Pearson correlations. RESULTS: Angle kappa followed a right-skewed normal distribution (R2 = 0.99) with a mean ± standard deviation of 0.64 ± 0.27 mm. No clinically meaningful relationship was found between preoperative angle kappa and postoperative sphere, cylinder, SEQ, and DEQ, all with R2 ⩽ 0.0005. Similarly, there was no clinically meaningful relationship between preoperative angle kappa and postoperative UDVA (R2 = 0.001), postoperative satisfaction for near, intermediate, and distance vision (all R2 ⩽ 0.0023), or for recommending the MIOL surgery to friends and relatives (R2 = 0.0000). CONCLUSIONS: Preoperative angle kappa does not have a predictive clinical impact on postoperative MIOL visual outcomes, refractive accuracy, or subjective patient satisfaction. Angle kappa as a single variable cannot be used to determine MIOL candidacy. [J Refract Surg. 2023;39(12):840-849.].

Carpal Joint Malalignment With Distal Radius Malunion and Factors in Correction After Distal Radius Osteotomy.

Purpose: There is a paucity of data regarding recommendations on when to correct for distal radius malunions and if the initial severity of the radiographic outcomes is correlated with the ability to correct to baseline. We evaluated the effects of distal radius corrective osteotomy on preoperative carpal joint malalignment resulting from distal radius malunions, correlated injury severity and osteotomy timing to radiographic outcomes, and developed a straightforward classification system for predicting radiocarpal and midcarpal maladaptive patterns. Methods: A retrospective review included 26 patients (27 wrists) who reported initial closed treatment for a distal radius fracture and who subsequently underwent a corrective osteotomy for malunion. Data included patient demographics, range of motion, preoperative fracture deformity, fracture deformity correction, and preoperative and postoperative radiographic measurements of the radiocarpal and midcarpal alignment patterns. Results: Of 27 dorsally angulated malunions, 16 were classified as type 1 midcarpal adaptation and 11 as type 2 radiocarpal adaptation. The midcarpal group showed significant improvements in distal radius and carpal alignment parameters after surgery, except for the ulnar variance. The radiocarpal group showed significant improvements in distal radius and carpal alignment parameters, except for the radiolunate angle, radioscaphoid angle, and capitolunate angle. The radiocarpal group exhibited an overall decrease in range of motion compared with that of the midcarpal group. Severity of the fracture and time taken from injury to corrective osteotomy correlated with the ability to correct carpal radiographic parameters in dorsally angulated malunions of the distal radius, especially beyond 40 weeks. Conclusions: The severity of the initial fracture and time taken from injury to corrective osteotomy correlate with the ability to correct radiographic parameters in dorsally angulated malunions of the distal radius. Early correction of distal radius malunions is recommended, especially in radiocarpal malalignment patterns. A useful analysis for predicting midcarpal and radiocarpal adaptation patterns is the direct measurement of the distal articular surface of the radius to the lunate, termed the relative-radiolunate angle. Type of study/level of evidence: Therapeutic IV.

The Accuracy of the NSQIP Universal Surgical Risk Calculator Compared to Operation-Specific Calculators.

Objective: To compare the performance of the ACS NSQIP "universal" risk calculator (N-RC) to operation-specific RCs. Background: Resources have been directed toward building operation-specific RCs because of an implicit belief that they would provide more accurate risk estimates than the N-RC. However, operation-specific calculators may not provide sufficient improvements in accuracy to justify the costs in development, maintenance, and access. Methods: For the N-RC, a cohort of 5,020,713 NSQIP patient records were randomly divided into 80% for machine learning algorithm training and 20% for validation. Operation-specific risk calculators (OS-RC) and OS-RCs with operation-specific predictors (OSP-RC) were independently developed for each of 6 operative groups (colectomy, whipple pancreatectomy, thyroidectomy, abdominal aortic aneurysm (open), hysterectomy/myomectomy, and total knee arthroplasty) and 14 outcomes using the same 80%/20% rule applied to the appropriate subsets of the 5M records. Predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC), the area under the precision-recall curve (AUPRC), and Hosmer-Lemeshow (H-L) P values, for 13 binary outcomes, and mean squared error for the length of stay outcome. Results: The N-RC was found to have greater AUROC (P = 0.002) and greater AUPRC (P < 0.001) compared to the OS-RC. No other statistically significant differences in accuracy, across the 3 risk calculator types, were found. There was an inverse relationship between the operation group sample size and magnitude of the difference in AUROC (r = -0.278; P = 0.014) and in AUPRC (r = -0.425; P < 0.001) between N-RC and OS-RC. The smaller the sample size, the greater the superiority of the N-RC. Conclusions: While operation-specific RCs might be assumed to have advantages over a universal RC, their reliance on smaller datasets may reduce their ability to accurately estimate predictor effects. In the present study, this tradeoff between operation specificity and accuracy, in estimating the effects of predictor variables, favors the N-R, though the clinical impact is likely to be negligible.

Characterization of postoperative LASIK ectasia features on higher-order aberration excimer ablation maps.

BACKGROUND: To characterize anterior corneal higher-order aberration (HOA) excimer ablation map patterns in postoperative LASIK ectasia (POE) and to examine correlations between newly identified corneal HOA ablation map features of POE and known topographic indices. METHODS: Prospective multicenter non-interventional descriptive study. A total of 28 eyes from 22 POE patients were enrolled. The postoperative HOA ablation map was derived from Topolyzer Vario corneal imaging at the time of POE diagnosis. Features that recurred were identified and then analyzed. Correlations to Orbscan indices were studied. RESULTS: An arrangement of two elliptical paracentral ablation islands, deep inferior and shallow superior, in direct mirror-like opposition to each other, were identified on all HOA maps. The paracentral islands were accompanied by peripheral ablation crescents. The deep paracentral inferior island 'hot spot' coincided with the topographical apical POE cone and was highly reproducible in angular position (249.3 ± 17.3°). There was significant variation in ablation depth (shallow superior island: 11.5 ± 6.9 µm and deep inferior island: 32.5 ± 18.8 µm). The superior crescents had high variability in depth (34.8 ± 18.9 µm). Strong correlations were found between the corneal irregularity index and the ablation depth difference between the deep and shallow paracentral islands (R = 0.96; P < 0.0001). CONCLUSION: The corneal HOA excimer ablation map revealed a recurring, distinct, easily recognizable pattern in POE eyes. Validated Orbscan POE indices and HOA ablation map islands showed a strong correlation. It is possible to extract useful information from the corneal HOA ablation map, potentially making it suitable for diagnosing and monitoring POE although more studies are needed.

Coats Plus Syndrome Presenting in an Adult.

Purpose: To present a case of retinal vascular disease characterized primarily by capillary nonperfusion in an adult with Coats plus syndrome (CPS). Methods: A case and its findings were analyzed. Results: A 38-year-old woman with a history of poliosis, thrombocytopenia, seizures, and white-matter brain lesions was referred for evaluation of bilateral blurred central vision. Fluorescein angiography showed extensive bilateral retinal capillary nonperfusion with retinal arteriolitis in the right eye. Genetic testing found 2 pathological mutations in the conserved telomere maintenance component 1 (CTC1) gene, diagnostic of CPS. Conclusions: Genetic testing may be diagnostic in patients who present with retinal vascular disease and systemic disease suggestive of CPS.

Efficient transmission of human prion diseases to a glycan-free prion protein-expressing host.

It is increasingly evident that the association of glycans with the prion protein (PrP), a major post-translational modification, significantly impacts the pathogenesis of prion diseases. A recent bioassay study has provided evidence that the presence of PrP glycans decreases spongiform degeneration (SD) and disease-related PrP (PrPD) deposition in a murine model. We challenged (PRNPN181Q/197Q) transgenic (Tg) mice expressing glycan-free human PrP (TgGlyc-), with isolates from sCJDMM2, sporadic fatal insomnia, and familial fatal insomnia, three human prion diseases that are distinct but share histotypic and PrPD features. TgGlyc- mice accurately replicated the basic histotypic features associated with the three diseases but the transmission was characterized by high attack rates, shortened incubation periods, and a greatly increased severity of the histopathology, including the presence of up to 40 times higher quantities of PrPD that formed prominent deposits. Although the engineered protease-resistant PrPD shared at least some features of the secondary structure and the presence of the anchorless PrPD variant with the wild-type PrPD, it exhibited different density gradient profiles of the PrPD aggregates and a higher stability index. The severity of the histopathological features including PrP deposition appeared to be related to the incubation period duration. These findings are clearly consistent with the protective role of the PrP glycans but also emphasize the complexity of the conformational changes that impact PrPD following glycan knock-out. Future studies will determine whether these features apply broadly to other human prion diseases or are PrPD-type dependent.

Social Psychological Perspectives on Political Polarization: Insights and Implications for Climate Change.

Political polarization is a barrier to enacting policy solutions to global issues. Social psychology has a rich history of studying polarization, and there is an important opportunity to define and refine its contributions to the present political realities. We do so in the context of one of the most pressing modern issues: climate change. We synthesize the literature on political polarization and its applications to climate change, and we propose lines of further research and intervention design. We focus on polarization in the United States, examining other countries when literature was available. The polarization literature emphasizes two types of mechanisms of political polarization: (1) individual-level psychological processes related to political ideology and (2) group-level psychological processes related to partisan identification. Interventions that address group-level processes can be more effective than those that address individual-level processes. Accordingly, we emphasize the promise of interventions leveraging superordinate identities, correcting misperceived norms, and having trusted leaders communicate about climate change. Behavioral interventions like these that are grounded in scientific research are one of our most promising tools to achieve the behavioral wedge that we need to address climate change and to make progress on other policy issues.

Evolving prion-like tau conformers differentially alter postsynaptic proteins in neurons inoculated with distinct isolates of Alzheimer's disease tau.

OBJECTIVES: Although accumulation of misfolded tau species has been shown to predict cognitive decline in patients with Alzheimer's disease (AD) and other tauopathies but with the remarkable diversity of clinical manifestations, neuropathology profiles, and time courses of disease progression remaining unexplained by current genetic data. We considered the diversity of misfolded tau conformers present in individual AD cases as an underlying driver of the phenotypic variations of AD and progressive loss of synapses. METHODS: To model the mechanism of tau propagation and synaptic toxicity of distinct tau conformers, we inoculated wild-type primary mouse neurons with structurally characterized Sarkosyl-insoluble tau isolates from the frontal cortex of six AD cases and monitored the impact for fourteen days. We analyzed the accumulation rate, tau isoform ratio, and conformational characteristics of de novo-induced tau aggregates with conformationally sensitive immunoassays, and the dynamics of synapse formation, maintenance, and their loss using a panel of pre-and post-synaptic markers. RESULTS: At the same concentrations of tau, the different AD tau isolates induced accumulation of misfolded predominantly 4-repeat tau aggregates at different rates in mature neurons, and demonstrated distinct conformational characteristics corresponding to the original AD brain tau. The time-course of the formation of misfolded tau aggregates and colocalization correlated with significant loss of synapses in tau-inoculated cell cultures and the reduction of synaptic connections implicated the disruption of postsynaptic compartment as an early event. CONCLUSIONS: The data obtained with mature neurons expressing physiological levels and adult isoforms of tau protein demonstrate markedly different time courses of endogenous tau misfolding and differential patterns of post-synaptic alterations. These and previous biophysical data argue for an ensemble of various misfolded tau aggregates in individual AD brains and template propagation of their homologous conformations in neurons with different rates and primarily postsynaptic interactors. Modeling tau aggregation in mature differentiated neurons provides a platform for investigating divergent molecular mechanisms of tau strain propagation and for identifying common structural features of misfolded tau and critical interactors for new therapeutic targets and approaches in AD.

Wound Complications Following Olecranon Fracture Fixation: Implant and Soft Tissue Considerations.

BACKGROUND: The aim of this multicenter, retrospective, case-control series was to investigate patient- and treatment-specific factors associated with wound breakdown following olecranon fracture fixation.  Methods: We identified patients at our two participating academic centers who were operatively treated for olecranon fractures and those who subsequently underwent a re-operation secondary to postoperative wound breakdown. Demographic and historical information was collected, including BMI and Charlson comorbidity index (CCI) scores. The primary outcome measure was the standardized radiographic measurement of plate prominence and soft tissue thickness posterior to the plate tip.  Results: We identified 32 patients who underwent internal fixation and subsequent wound breakdown. This was compared to a cohort of 35 matched controls that did not have wound issues. Cases with wound breakdown were of higher energy, nine being open cases compared to two in the control group (p<0.05). No differences were identified in plate prominence, soft tissue thickness, and plate type.  Conclusions: Wound breakdown following olecranon fracture fixation is more commonly seen in high-energy open injuries. Plate prominence, soft tissue thickness, and patient-specific factors do not correlate with wound breakdown. Further investigation into the factors influencing plate placement and how they may contribute to wound complications is needed.

A Soft-Tissue Landmark to Assess Humeral Component Rotation in Total Elbow Arthroplasty.

HYPOTHESIS: Assessing the rotational alignment of the humeral component during total elbow arthroplasty is dependent upon bony landmarks that can be absent or altered in cases of distal humerus fractures, revision arthroplasty, severe bone loss, or deformity. We hypothesize that the intermuscular septum can be used as a reliable soft-tissue landmark to set the rotation of the humeral component intra-operatively when previously described bony landmarks are not reliable or present. MATERIALS AND METHODS: Forty-eight unpaired cadaveric human subjects (mean age and standard deviation 63 ± 12 years; 24 males, 24 females) underwent computed tomography (CT) scans. The geometric centers of the trochlea and capitellum were assessed, and the line through these two points was set as the flexion-extension axis (FEA) of the elbow. The intermuscular septum axis (IMSA) was drawn proximal to the olecranon fossa and at least 4 cm proximal to the most distal point of the articular surface, where the posterior humeral cortex was flat. The angles between the FEA and IMSA were calculated and compared using a two-tailed t-test. Regression analysis was used to assess the inter- and intra-observer reliability of the IMSA. RESULTS: The IMSA was externally rotated 10.3° ± 2.8 compared to the FEA (p < 0.001 and confidence interval (CI) of 2.8 with α set to 0.01). The inter- and intra-observer reliability of the IMSA was high, with an R-value of 0.91 and 0.97, respectively. CONCLUSIONS: The intermuscular septum can be used as a soft-tissue landmark to set humeral component rotation and is 10.3° externally rotated with respect to the FEA of the ulnohumeral joint.

Novel histotypes of sporadic Creutzfeldt-Jakob disease linked to 129MV genotype.

The MV1 and MV2 subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) are linked to the heterozygous methionine (M)/valine (V) polymorphism at codon 129 of the prion protein (PrP) gene. MV2 is phenotypically heterogeneous, whereas MV1, due to its low prevalence, is one of the least well characterized subtypes. In this study, we investigated the biochemical properties of PrPSc and phenotypic expression of cases diagnosed as sCJD MV1 and MV2. We describe four MV2 histotypes: 2C, with cortical (C) coarse pathology; 2K, with kuru (K) plaque deposits; 2C-K, with co-existing C and K histotypic features; and the novel histotype 2C-PL that mimics 2C in the cerebral cortex and cerebellum, but exhibits plaque-like (PL) PrP deposits in subcortical regions (e.g., basal nuclei, thalamus and midbrain). Histotype prevalence is highest for 2C-K (55%), intermediate for 2C (31%), and lowest for 2C-PL and 2K (7%). Nearly every MV2 case expressed both PrPSc types, with T2 being the predominant type ("MV2-1"). MV1 cases typically show a rapid disease course (≤ 4 months), and feature the 1C histotype, phenotypically identical to sCJDMM1. Co-existing PrPSc types, with T1 significantly exceeding T2 ("MV1-2"), are detected in patients diagnosed as MV1 with longer disease courses. We observed four histotypes among MV1-2 cases, including two novel histotypes: 1V, reminiscent of sCJDVV1; 1C-2C, resembling sCJDMM1-2 with predominant MM1 histotypic component; and novel histotypes 1C-2PL and 1C-2K, overall mimicking 1C in the cerebral cortex, but harboring T2 and plaque-like PrP deposits in subcortical regions (1C-2PL), and T2 and kuru plaques in the cerebellum (1C-2K). Lesion profiles of 1C, 1V, and 1C-2C are similar, but differ from 1C-2PL and 1C-2K, as the latter two groups show prominent hippocampal and nigral degeneration. We believe that the novel "C-PL" histotypes are distinct entities rather than intermediate forms between "C" and "C-K" groups, and that 1C-2PL and 1C-2K histotypes may be characterized by different T1 variants of the same size.

Toric Trifocal Intraocular Lens for Refractive Lens Exchange: A Multi-center, Multi-surgeon Large Cohort Study.

PURPOSE: To assess the outcomes of a novel toric trifocal intraocular lens (IOL) for refractive lens exchange (RLE) in a large series of eyes with corneal astigmatism. METHODS: Consecutive eyes that underwent RLE with the PanOptix Toric IOL (Alcon Laboratories, Inc) were included. Outcomes measures included postoperative distance (UDVA), 60 cm intermediate (UIVA), and 40 cm near (UNVA) uncorrected visual acuity, manifest refraction, spherical and defocus equivalent, efficacy and safety indices, and vector analyses of refractive and toric IOL accuracy. RESULTS: A total of 4,933 eyes had a median follow-up of 3 months. UDVA of 20/20 and 20/40 was obtained in 65% and 99% of eyes monocularly and 87% and 100% binocularly, respectively. UIVA at 60 cm of 20/25 and 20/40 was achieved in 70% and 99% of eyes monocularly and in 77% and 100% binocularly, respectively. UNVA at 40 cm of 20/25 and 20/40 was achieved in 85% and 96% of eyes monocularly and in 95% and 100% binocularly, respectively. A total of 67%, 89%, 97%, and 99% of eyes had a SEQ within 0.25, 0.50, 0.75, and 1.00 diopter (D) of intended target (R2 = 0.99). Postoperative refractive astigmatism of 0.50, 0.75, and 1.00 D or less was achieved in 86%, 95%, and 98% of eyes. The vector analysis correction index and index of success were 1.04 ± 0.35 and 0.41 ± 0.31 for toric IOL accuracy and 1.00 ± 0.46 and 0.36 ± 0.55 for refractive accuracy, respectively. The 3- and 12-month post-RLE excimer laser enhancement rates were 1.1% (95% CI: 0.8% to 1.4%) and 7.6% (95% CI: 6.9% to 8.3%), respectively. CONCLUSIONS: The PanOptix Toric IOL performed well for a wide range of axial lengths and corneal astigmatism in eyes that had RLE. Most patients achieved effective uncorrected binocular near, intermediate, and distance vision for daily functioning. [J Refract Surg. 2023;39(5):302-310.].