Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net.

OBJECTIVE: Here we report our preclinical, proof-of-concept testing to assess the ability of a novel device to correct mitral regurgitation. The Milwaukee Heart device aims to enable any cardiac surgeon to perform high-quality mitral valve repair using a standard annuloplasty ring with a crosshatch of microporous, monofilament suture. METHODS: Hemodynamic, echocardiographic, and videographic data were collected at baseline, following induction of mitral regurgitation, and after repair using porcine hearts in an ex vivo biosimulator model. A commercially available cardiac prosthesis assessment platform was then used to assess the hydrodynamic characteristics of the study device. RESULTS: Porcine biosimulator pressure and flow metrics exhibited successful correction of mitral regurgitation following device implantation with similar values to baseline. Hydrodynamic results yielded pressure gradients and an effective orifice area comparable to currently approved prostheses. CONCLUSIONS: The study device effectively reduced mitral valve regurgitation and improved hemodynamics in our preclinical model with similar biophysical metrics to currently approved devices. Future in vivo trials are needed to evaluate the efficacy, biocompatibility, and freedom from the most likely adverse events, such as device thrombosis, embolic events, and hemolysis.

Validation of Population Pharmacokinetic Models for Clozapine Dosage Prediction.

BACKGROUND: Clozapine is unique in its capacity to ameliorate severe schizophrenia but at high risk of toxicity. A relationship between blood concentration and clinical response and evidence for concentration-response relationships to some adverse effects justify therapeutic drug monitoring of clozapine. However, the relationship between drug dose and blood concentration is quite variable. This variability is, in part, due to inductive and inhibitory interactions varying the activity of cytochrome P450 1A2 (CYP1A2), the principal pathway for clozapine elimination. Several population pharmacokinetic models have been presented to facilitate dose selection and to identify poor adherence in individual patients. These models have faced little testing for validity in independent populations or even for persisting validity in the source population. METHODS: Therefore, we collected a large population of clozapine-treated patients (127 patients, 1048 timed plasma concentrations) in whom dosing and covariate information could be obtained with high certainty. A population pharmacokinetic model was constructed with data collected in the first 6 weeks from study enrolment (448 plasma concentrations), to estimate covariate influences and to allow alignment with previously published models. The model was tested for its performance in predicting the concentrations observed at later time intervals up to 5 years. The predictive performances of 6 published clozapine population models were then assessed in the entire population. RESULTS: The population pharmacokinetic model based on the first 6 weeks identified significant influences of sex, smoking, and cotreatment with fluvoxamine on clozapine clearance. The model built from the first 6 weeks had acceptable predictive performance in the same patient population up to the first 26 weeks using individual parameters, with a median predictive error (PE) of -0.1% to -15.9% and median absolute PE of 22.9%-27.1%. Predictive performance fell progressively with time after 26 weeks. Bayesian addition of plasma concentration observations within each prediction period improved individual predictions. Three additional observations extended acceptable predictive performance into the second 6 months of therapy. When the published models were tested with the entire data set, median PE ranged from -8% to +35% with a median absolute PE of >39% in all models. Thus, none of the tested models was successful in external validation. Bayesian addition of single patient observations improved individual predictions from all models but still without achieving acceptable performances. CONCLUSIONS: We conclude that the relationship between covariates and blood clozapine concentrations differs between populations and that relationships are not stable over time within a population. Current population models for clozapine are not capturing influential covariates.

Dual plating in the metastatic distal humerus: Benefits may outweigh the risks.

Background: Impending and complete pathologic fractures of the distal humerus are rare complications of metastatic cancer. Surgical treatment aims to quickly restore function and minimize pain. Plate and screw fixation (PSF) is a common method for addressing these lesions, but unlike in orthopaedic trauma, there are no clear guidelines for best management. While dual PSF theoretically provides better support and reduces the chance of reoperation due to tumor progression, single PSF is currently the more common choice. Materials and methods: Between March 2008 and September 2021, 35 consecutive patients who underwent PSF for distal humerus metastasis or multiple myeloma were retrospectively reviewed. The proportion of patients who developed various postoperative complications, including infection, nonunion, deep vein thrombosis, tumor progression, and radial nerve palsy, as well as those requiring reoperation, was calculated. Mann-Whitney U test, Pearson's chi-squared, and Fisher's exact test were used to investigate differences between the single and dual PSF groups with statistical significance defined as p ≤ 0.05. Results: There was no significant difference (p = 0.259) in revision rate, although 3 of 21 (14.3 %) single PSF patients required reoperation compared to 0 of 14 (0.0 %) dual PSF patients. The revisions were performed in one patient due to refracture and in two patients due to tumor progression. Although not statistically significant, a larger percentage of single PSF patients developed a postoperative complication compared to dual PSF patients [odds ratio 0.42 (95 % confidence interval 0.071 to 2.5); p = 0.431]. Single PSF did lead to shorter operative time compared to dual PSF [p < 0.001]. Conclusion: Dual PSF is non-inferior to single PSF and potentially results in fewer reoperations and postoperative complications in distal humerus pathologic lesions, although it leads to longer operative time. The current study is limited by small sample size due to the rarity of distal humerus metastatic lesions.

High-resolution single-particle imaging at 100-200 keV with the Gatan Alpine direct electron detector.

Developments in direct electron detector technology have played a pivotal role in enabling high-resolution structural studies by cryo-EM at 200 and 300 keV. Yet, theory and recent experiments indicate advantages to imaging at 100 keV, energies for which the current detectors have not been optimized. In this study, we evaluated the Gatan Alpine detector, designed for operation at 100 and 200 keV. Compared to the Gatan K3, Alpine demonstrated a significant DQE improvement at these voltages, specifically a ~4-fold improvement at Nyquist at 100 keV. In single-particle cryo-EM experiments, Alpine datasets yielded better than 2 Å resolution reconstructions of apoferritin at 120 and 200 keV on a ThermoFisher Scientific (TFS) Glacios microscope. We also achieved a ~3.2 Å resolution reconstruction for a 115 kDa asymmetric protein complex, proving its effectiveness with complex biological samples. In-depth analysis revealed that Alpine reconstructions are comparable to K3 reconstructions at 200 keV, and remarkably, reconstruction from Alpine at 120 keV on a TFS Glacios surpassed all but the 300 keV data from a TFS Titan Krios with GIF/K3. Additionally, we show Alpine's capability for high-resolution data acquisition and screening on lower-end systems by obtaining ~3 Å resolution reconstructions of apoferritin and aldolase at 100 keV and detailed 2D averages of a 55 kDa sample using a side-entry cryo holder. Overall, we show that Gatan Alpine performs well with the standard 200 keV imaging systems and may potentially capture the benefits of lower accelerating voltages, possibly bringing smaller sized particles within the scope of cryo-EM.

Unplanned Sarcoma Excisions: Understanding How They Happen.

BACKGROUND: Soft-tissue sarcomas present as a mass with nonspecific symptoms, and unplanned excisions commonly occur. The purpose of this study was to analyze the incidence of unplanned excisions performed by orthopaedic surgeons and to conduct a root cause analysis (RCA) of the steps that led to unplanned excisions in all the cases. METHODS: A retrospective case-control study was conducted. Two cohorts were identified, one including patients who underwent an unplanned excision of a soft-tissue sarcoma (n = 107) and a second cohort with patients whose entire care was performed at our sarcoma center (n = 102). A RCA was conducted with the whole sample to identify the preventable causes that led to sarcoma unplanned excisions. RESULTS: Orthopedic surgeons were the second group of physicians to perform the most unplanned excisions, only behind general surgeons. Inadequate imaging was encountered in 76.6% of the patients (n = 82, 95% confidence interval, 67.8 to 83.6). Forty-five patients (42.1%) had no imaging studies before the unplanned procedure. In the RCA, the most notable obstacles found were (1) incorrect assumption of a benign diagnosis, (2) failure to obtain the appropriate imaging study, (3) incorrectly reported imaging studies, (4) failure to order a biopsy, and (5) incorrect reporting of the biopsy. CONCLUSIONS: Despite educational efforts, unplanned excisions and the devastating consequences that sometimes follow continue to occur. Orthopaedic surgeons persist in playing a role in the unplanned procedure burden.

LC-MS/MS analysis of erythrocyte phosphatidylethanol in haematocrit-corrected whole blood versus isolated erythrocytes: Results of an inter-laboratory comparison.

Phosphatidylethanol (PEth) is a non-oxidative metabolite of alcohol (ethanol), which is a sensitive and specific indicator of historic ethanol consumption. Although PEth production from ethanol is catalysed by the ubiquitous enzyme phospholipase D, it resides mainly within the erythrocyte compartment of the blood. PEth analysis has been reported in different preparations of whole blood, representing one of the barriers of inter-laboratory comparisons. We previously reported that expressing PEth concentrations in terms of blood erythrocyte content is more sensitive than whole blood volume, and haematocrit-corrected liquid whole blood calculations of erythrocyte PEth and isolated erythrocyte PEth concentrations are comparable when assayed under identical analytical conditions. Acceptance of a clinical diagnostic assay by accreditation bodies requires proficiency testing with a third-party analytical facility. To explore different blood preparations within the same inter-laboratory program, 60 matched isolated erythrocyte or liquid whole blood specimens were tested at three laboratories. Laboratories measured PEth by liquid chromatography-tandem mass spectrometry (LC-MS/MS), two using isolated erythrocytes, while the third used liquid whole blood, which underwent haematocrit correction before comparison with isolated erythrocyte PEth concentrations. There was acceptable consensus (87%) among laboratories to detect PEth around a cut-off of 35 µg/L of erythrocytes. Each laboratory correlated well with the group average PEth concentration (R > 0.98) for each specimen above the cut-off. Differences were observed between laboratories in bias, which did not affect comparable sensitivity at the selected cut-off. This work demonstrates the feasibility of an inter-laboratory comparison for erythrocyte PEth analysis across different LC-MS/MS methodologies and different blood preparations.

Primary B cell lymphoma of the patella presenting as anterior knee pain: A case report.

Case: A 76-year-old female with a history of multiple falls on the patella presented with worsening knee pain, swelling, and reduced range of motion. Radiographs revealed tricompartmental osteoarthritis and subtle erosion of the posterior cortex of the patella that was missed by the referring orthopedist and radiologist. Her persistent pain prompted an MRI, revealing a mass later confirmed to be primary diffuse large B-cell lymphoma of the patella after biopsy and appropriate metastatic workup. Conclusion: Primary B-cell patellar lymphoma is a rarely described cause of knee pain requiring broad differential diagnosis and multidisciplinary workup in order to avoid erroneous treatment and ensure prompt oncologic treatment.

Limb Amputations in Cancer: Modern Perspectives, Outcomes, and Alternatives.

PURPOSE OF REVIEW: This review summarizes current findings regarding limb amputation within the context of cancer, especially in osteosarcomas and other bony malignancies. We seek to answer the question of how amputation is utilized in the contemporary management of cancer as well as explore current advances in limb-sparing techniques. RECENT FINDINGS: The latest research on amputation has been sparse given its extensive history and application. However, new research has shown that rotationplasty, osseointegration, targeted muscle reinnervation (TMR), and regenerative peripheral nerve interfaces (RPNI) can provide patients with better functional outcomes than traditional amputation. While limb-sparing surgeries are the mainstay for managing musculoskeletal malignancies, limb amputation is useful as a palliative technique or as a primary treatment modality for more complex cancers. Currently, rotationplasty and osseointegration have been valuable limb-sparing techniques with osseointegration continuing to develop in recent years. TMR and RPNI have also been of interest in the modern management of patients requiring full or partial amputations, allowing for better control over myoelectric prostheses.

Remote patient monitoring for COVID-19 patients: comparisons and framework for reporting.

BACKGROUND: COVID-19 has challenged health services throughout the world in terms of hospital capacity and put staff and vulnerable populations at risk of infection. In the face of these challenges, many health providers have implemented remote patient monitoring (RPM) of COVID-19 patients in their own homes. However systematic reviews of the literature on these implementations have revealed wide variations in how RPM is implemented; along with variations in particulars of RPM reported on, making comparison and evaluation difficult. A review of reported items is warranted to develop a framework of key items to enhance reporting consistency. The aims of this review of remote monitoring for COVID-19 patients are twofold: (1) to facilitate comparison between RPM implementations by tabulating information and values under common domains. (2) to develop a reporting framework to enhance reporting consistency. METHOD: A review of the literature for RPM for COVID-19 patients was conducted following PRISMA guidelines. The Medline database was searched for articles published between 2020 to February 2023 and studies reporting on items with sufficient detail to compare one with another were included. Relevant data was extracted and synthesized by the lead author. Quality appraisal was not conducted as the the articles considered were evaluated as informational reports of clinical implementations rather than as studies designed to answer a research question. RESULTS: From 305 studies retrieved, 23 studies were included in the review: fourteen from the US, two from the UK and one each from Africa, Ireland, China, the Netherlands, Belgium, Australia and Italy. Sixteen generally reported items were identified, shown with the percentage of studies reporting in brackets: Reporting Period (82%), Rationale (100%), Patients (100%), Medical Team (91%) Provider / Infrastructure (91%), Communications Platform (100%), Patient Equipment (100%), Training (48%), Markers (96%), Frequency of prompt / Input (96%),Thresholds (82%), Discharge (61%), Enrolled (96%), Alerts/Escalated (78%), Patient acceptance (43%), and Patient Adherence (52%). Whilst some studies reported on patient training and acceptance, just one reported on staff training and none on staff acceptance. CONCLUSIONS: Variations in reported items were found. Pending the establishment of a robust set of reporting guidelines, we propose a reporting framework consisting of eighteen reporting items under the following four domains: Context, Technology, Process and Metrics.

Supporting the right ventricle in postcardiotomy renal dysfunction: A case series.

Postcardiotomy RV dysfunction is an under-recognized cause of acute kidney injury (AKI). Insertion of a percutaneous right ventricular assist device (RVAD) reduces central venous hypertension and congestive nephropathy by augmenting cardiac output. In selected patients, percutaneous RVAD insertion may improve renal function and obviate the need for long-term dialysis.

Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Transplantation Outcomes with Donor Hearts after Circulatory Death.

BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).

Maximum speed exposures in Australian rules football: do methods matter?

This study compared weekly near-to-maximum speed exposure data when determined via different methods and criteria. Forty-seven professional Australian rules football (AF) players undertook pre-season sprint assessments (PSSA) via 3 × 50 m maximal efforts using 10 Hz GPS over two consecutive seasons. The same technology was used continually during the in-season to identify maximum speeds attained in training and matches. Weekly near-to-maximal speed (MS) exposure counts were aggregated for speeds ≥80%, ≥85%, ≥90% and ≥95% of their individual maximum for both determination approaches. Weekly near-to-MS exposures was lower (p < 0.0001) when determined from in-season monitoring for ≥80% (-1.26; CI: -1.58 to -0.93), ≥85% (-0.78; CI: -0.97 to -0.59), ≥90% (-0.42; CI: -0.53 to -0.32), and ≥95% (-0.09; CI: -0.12 to -0.06) versus PSSA, with no effect of playing position (P ≥ 0.161). Although ≥80% and ≥85% near-to-maximum speed exposure data was meaningfully influenced by the determination method, the effect was somewhat trivial at higher speed criteria (≥90% and ≥95%) often considered important for performance gains and injury risk reduction purposes. Maximum speed determination methods therefore may be used interchangeably, and discrete sprint assessments may not be necessary for this purpose.

Building cardiac surgical programs in lower-middle income countries.

Objectives: Medical care in low-income countries is often limited by inadequate resources, treatment facilities, and the necessary infrastructure for healthcare delivery. We hypothesized that the development of an independently functioning, internationally supported Kenyan cardiac surgical training program could address these issues through targeted investment. Methods: A review was conducted of the programmatic structure and clinical outcomes from January 2008 to October 2021 at Tenwek Hospital, Bomet, Kenya. Program development phases included (1) cardiovascular care provided by 1 full-time US board-certified cardiothoracic surgeon; (2) short-term volunteer surgical teams from the United States and Canada; and (3) development of a cardiothoracic residency program based on the Society of Thoracic Surgeons training curriculum. Patient demographics and outcomes were analyzed throughout each phase of program development. Results: A total of 817 cardiac procedures were performed during the study period, including 236 congenital (28.8%) and 581 adult (71.1%) procedures. Endemic rheumatic valvular heart disease predominated (581 patients, 62.3%). Local surgical team case volume grew over the study period, overtaking visiting team volume in 2019. Perioperative mortality was 2.1% and consistent between the visiting teams and the locally trained teams. Surgical training via a 3-year cardiothoracic residency is now in its fourth year, with the 2 graduates now retained as full-time teaching staff. Conclusions: Global health partnerships have the potential to address unmet needs in cardiac care within low- and middle-income countries. These data support the concept that acceptable clinical outcomes and consistent growth in volume can be achieved during the transition toward fully independent cardiac surgical care.

Intractable Bleeding After Revision Hip Arthroplasty Because of Angiosarcoma: A Report of 2 Cases.

CASE: Two cases of revision total hip arthroplasty (THA) for pseudotumor and infection with persistent postoperative bleeding because of angiosarcoma are presented. After surgery, both patients' health deteriorated because of hypovolemic shock despite transfusion, pressors, embolization, and prothrombotics. Diagnosis was obscure and delayed despite extensive imaging. Standard and computed tomography angiogram were nondiagnostic and did not localize the tumors or bleeding. Repeat surgeries and biopsies requiring special staining ultimately revealed epithelioid angiosarcoma. CONCLUSION: A diagnosis of angiosarcoma was etiologic for persistent postoperative bleeding after revision THA and should be considered in such cases.

The history of resection prosthesis.

INTRODUCTION: The purpose of this historical review is to highlight the progression and development of prosthetic reconstruction with a focus on the modular distal femur with hinged total knee arthroplasty. METHOD: Scientific literature was searched for descriptions of endoprosthetic reconstruction of the extremities to provide a thorough overview of the subject, focusing the research on the evolution of limb salvage of the distal femur. RESULTS: After the first works of Gluck and Giordano, with ivory and metal and the pioneer shoulder prosthesis by Pean in the late 1890s, a great advancement was brought by reconstructions performed for injured soldiers of the Great War. By the 1940s, replacement of all the main joints had been attempted, and documented. DISCUSSION: Walldius in the 1950s developed a fully constrained hinge knee, offering for the first time a consistent and replicable method of substituting the joint. In 1953, Shiers' prosthesis allowed for good flexion and extension. Stanmore and GUEPAR group prosthesis in the 1960s were the first to have a different right and left side model. The rotating hinge was developed in 1978 by Walker, with the innovative concept of six degrees of freedom. Between 1979 and 1982, Kotz developed the modular segmental replacement that, added to a fixed hinge knee, permitted the revolutionary creation of the modern distal femur replacement. CONCLUSION: The study of the materials and mechanical solutions that was brought to the modern distal femur resection prosthesis is a good example of a virtuous multidisciplinary teamwork between orthopaedic surgeons, anatomists, and biomechanical engineers.

Reduced Morbidity and Mortality Associated With Minimally Invasive Single-vessel Coronary Artery Bypass Compared With Conventional Sternotomy.

OBJECTIVE: We aimed to describe the safety and clinical benefits of minimally invasive, nonsternotomy coronary artery bypass grafting (MICABG) using data from The Society of Thoracic Surgeons (STS) National Database. BACKGROUND: MICABG has gained popularity, owing to expected lower perioperative morbidity and shorter recovery. Despite this, concerns remain regarding anastomotic quality and the validity of proposed perioperative benefits. METHODS: We queried the STS National Database for all patients who underwent single-vessel coronary artery bypass grafting (CABG) from January 2014 to December 2016 to compare outcomes of MICABG with conventional CABG. Patients who underwent concomitant or emergent procedures were excluded. Propensity-weighted cohorts were compared by operative approach with adjustment for variability across institutions. RESULTS: Of 12,406 eligible patients, 2688 (21.7%) underwent MICABG, and 9818 (78.3%) underwent conventional CABG. Propensity weighting produced excellent balance in patient characteristics, including completeness of revascularization, body mass index, and STS predictive risk scores. MICABG was associated with significant reduction of in-hospital mortality [odds ratio (OR)=0.32, absolute reduction (AR)=0.91%, P <0.0001]; 30-day mortality (OR=0.51, AR=0.88%, P =0.001), duration of ventilation (8.62 vs 12.6 hours, P <0.0001), prolonged hospitalization (OR=0.77, AR=1.6, P =0.043), deep wound infection (OR=0.33, AR=0.68, P <0.004), postoperative transfusions (OR=0.52, AR=7.7%, P <0.0001), and STS composite morbidity (OR=0.72, AR=1.19%, P =0.008). Subgroup analysis of only off-pump left internal mammary artery-left anterior descending CABG showed similar findings. Major adverse cardiac events and graft occlusion did not differ between groups. CONCLUSIONS: MICABG is associated with lower mortality and perioperative morbidity compared with conventional sternotomy CABG. MICABG may have a role in treating single-vessel disease.