Modern approaches to therapeutic oligonucleotide manufacturing.

Therapeutic oligonucleotides are a powerful drug modality with the potential to treat many diseases. The rapidly growing number of therapies that have been approved and that are in advanced clinical trials will place unprecedented demands on our capacity to manufacture oligonucleotides at scale. Existing methods based on solid-phase phosphoramidite chemistry are limited by their scalability and sustainability, and new approaches are urgently needed to deliver the multiton quantities of oligonucleotides that are required for therapeutic applications. The chemistry community has risen to the challenge by rethinking strategies for oligonucleotide production. Advances in chemical synthesis, biocatalysis, and process engineering technologies are leading to increasingly efficient and selective routes to oligonucleotide sequences. We review these developments, along with remaining challenges and opportunities for innovations that will allow the sustainable manufacture of diverse oligonucleotide products.

Assessment of Primary Healthcare Providers' Knowledge and Practices in Addressing Asymptomatic Hyperuricemia and Gout in the Asir Region of Saudi Arabia.

Introduction and aim Gout, the most common form of inflammatory arthritis, arises from hyperuricemia, a condition where elevated levels of uric acid lead to the deposition of monosodium urate (MSU) crystals in the joints. Nevertheless, it's important to note that not all cases of hyperuricemia result in gout. Methodology This cross-sectional study was conducted in the Asir region of Saudi Arabia, targeting primary healthcare physicians (PHPs) specializing in family medicine and general practice. The study utilized a modified electronic questionnaire, inspired by similar studies and aligned with recent guidelines, to assess PHPs' knowledge and practices concerning asymptomatic hyperuricemia (AH) and gout. The questionnaire encompassed the PHPs' demographic data and their knowledge and practices for AH and gout management. Results Out of 201 participating PHPs, the majority were male (68.2%), predominantly aged 25-34 years (73.1%), and practicing as general practitioners (61.2%). A significant proportion of PHPs had less than five years of experience (63.7%). In terms of education, 36.8% attended continuing medical education (CME) on AH or gout, and 66.7% were aware of the related management guidelines. The study revealed that the total knowledge score among PHPs averaged 5.18 out of seven, indicating a moderate level of knowledge. However, their practice level was moderate, with a mean practice score of 6.75 out of 12. The study also found no significant differences in knowledge scores based on gender, age, or years of experience, but significant variations were noted based on medical specialty. Conclusion There is a moderate level of knowledge and practice among PHPs in managing AH and gout in the Asir region. Despite adequate knowledge levels, there appears to be a gap in implementing this knowledge into practice, particularly in long-term management strategies. The findings emphasize the need for ongoing medical education and specialized training programs to bridge these gaps. The study provides a valuable framework for identifying and addressing similar challenges in other regions and medical practices.

Detection of SARS-CoV-2 in Environment: Current Surveillance and Effective Data Management of COVID-19.

Since diagnostic laboratories handle large COVID-19 samples, researchers have established laboratory-based assays and developed biosensor prototypes. Both share the same purpose; to ascertain the occurrence of air and surface contaminations by the SARS-CoV-2 virus. However, the biosensors further utilize internet-of-things (IoT) technology to monitor COVID-19 virus contamination, specifically in the diagnostic laboratory setting. The IoT-capable biosensors have great potential to monitor for possible virus contamination. Numerous studies have been done on COVID-19 virus air and surface contamination in the hospital setting. Through reviews, there are abundant reports on the viral transmission of SARS-CoV-2 through droplet infections, person-to-person close contact and fecal-oral transmission. However, studies on environmental conditions need to be better reported. Therefore, this review covers the detection of SARS-CoV-2 in airborne and wastewater samples using biosensors with comprehensive studies in methods and techniques of sampling and sensing (2020 until 2023). Furthermore, the review exposes sensing cases in public health settings. Then, the integration of data management together with biosensors is well explained. Last, the review ended with challenges to having a practical COVID-19 biosensor applied for environmental surveillance samples.

Renal Function Parameters and Serum Sodium Enhance Prediction of Wait-List Outcomes in Pediatric Liver Transplantation.

BACKGROUND AND AIMS: Reliance on exception points to prioritize children for liver transplantation (LT) stems from concerns that the Pediatric End-Stage Liver Disease (PELD) score underestimates mortality. Renal dysfunction and serum sodium disturbances are negative prognosticators in adult LT candidates and various pediatric populations, but are not accounted for in PELD. We retrospectively evaluated the effect of these parameters in predicting 90-day wait-list death/deterioration among pediatric patients (<12 years) listed for isolated LT in the United States between February 2002 and June 2018. APPROACH AND RESULTS: Among 4,765 patients, 2,303 (49.3%) were transplanted, and 231 (4.8%) died or deteriorated beyond transplantability within 90 days of listing. Estimated glomerular filtration rate (eGFR) (hazard ratio [HR] 1.09 per 5-unit decrease, 95% confidence interval [CI] 1.06-1.10) and dialysis (HR 7.24, 95% CI 3.57-14.66) were univariate predictors of 90-day death/deterioration (P < 0.001). The long-term benefit of LT persisted in patients with renal dysfunction, with LT as a time-dependent covariate conferring a 2.4-fold and 17-fold improvement in late survival among those with mild and moderate-to-severe dysfunction, respectively. Adjusting for PELD, sodium was a significant nonlinear predictor of outcome, with 90-day death/deterioration risk increased at both extremes of sodium (HR 1.20 per 1-unit decrease below 137 mmol/L, 95% CI 1.16-1.23; HR per 1-unit increase above 137 mmol/L 1.13, 95% CI 1.10-1.17, P < 0.001). A multivariable model incorporating PELD, eGFR, dialysis, and sodium demonstrated improved performance and superior calibration in predicting wait-list outcomes relative to the PELD score. CONCLUSIONS: Listing eGFR, dialysis, and serum sodium are potent, independent predictors of 90-day death/deterioration in pediatric LT candidates, capturing risk not accounted for by PELD. Incorporation of these variables into organ allocation systems may highlight patient subsets with previously underappreciated risk, augment ability of PELD to prioritize patients for transplantation, and ultimately mitigate reliance on nonstandard exceptions.

Temozolomide Treatment Induces lncRNA MALAT1 in an NF-κB and p53 Codependent Manner in Glioblastoma.

Alkylating chemotherapy is a central component of the management of glioblastoma (GBM). Among the factors that regulate the response to alkylation damage, NF-κB acts to both promote and block cytotoxicity. In this study, we used genome-wide expression analysis in U87 GBM to identify NF-κB-dependent factors altered in response to temozolomide and found the long noncoding RNA (lncRNA) MALAT1 as one of the most significantly upregulated. In addition, we demonstrated that MALAT1 expression was coregulated by p50 (p105) and p53 via novel κB- and p53-binding sites in the proximal MALAT1 coding region. Temozolomide treatment inhibited p50 recruitment to its cognate element as a function of Ser329 phosphorylation while concomitantly increasing p53 recruitment. Moreover, luciferase reporter studies demonstrated that both κB and p53 cis-elements were required for efficient transactivation in response to temozolomide. Depletion of MALAT1 sensitized patient-derived GBM cells to temozolomide cytotoxicity, and in vivo delivery of nanoparticle-encapsulated anti-MALAT1 siRNA increased the efficacy of temozolomide in mice bearing intracranial GBM xenografts. Despite these observations, in situ hybridization of GBM specimens and analysis of publicly available datasets revealed that MALAT1 expression within GBM tissue was not prognostic of overall survival. Together, these findings support MALAT1 as a target for chemosensitization of GBM and identify p50 and p52 as primary regulators of this ncRNA. SIGNIFICANCE: These findings identify NF-κB and p53 as regulators of the lncRNA MALAT1 and suggest MALAT1 as a potential target for the chemosensitization of GBM.

Risk of conventional cardiac surgery among patients with severe left ventricular dysfunction in the era of mechanical circulatory support.

BACKGROUND: Despite suggestions that severe left ventricle dysfunction may warrant selection of durable mechanical circulatory support over conventional surgery, comparative studies are lacking due to incomplete characterization of patients at highest risk after conventional surgery. We sought to define subsets of patients with severe left ventricle dysfunction who are at greatest mortality risk following conventional cardiac surgery. METHODS: We studied 892 patients aged ≥ 18 years who underwent conventional coronary or valve surgery from 1993 to 2014, with preoperative ejection fraction ≤ 25%. Exclusions were transcatheter interventions, major concomitant procedures, active endocarditis, and prior/concurrent durable mechanical circulatory support use. Logistic and Cox regression identified determinants of early and late mortality. RESULTS: Median age was 70 years (interquartile range, 62-76 years), 46% (n = 411) had New York Heart Association (NYHA) functional class IV symptoms, and 16% (n = 142) had undergone prior surgery. Operative mortality was 7.5%. NYHA functional class IV (odds ratio [OR], 1.88; P = .033), prior cardiac surgery (OR, 2.13; P = .017), peripheral vascular disease (OR, 2.55; P = .001), emergency status (OR, 2.68; P = .024), and intra-aortic balloon pump use (OR, 4.95; P < .001) independently predicted operative death. Risk imparted by presence of both NYHA functional class IV symptoms and prior surgery was additive, with a 4-fold increase in early mortality risk (OR, 3.95; P = .003). Prior surgery increased the hazard of late death by 60% (P < .001). In patients without prior surgery, late mortality was greatest in those aged ≥ 70 years (hazard ratio, 1.86; P < .001), especially if NYHA functional class IV symptoms were concurrently present (hazard ratio, 2.25; P < .001). Surgery type (coronary artery bypass graft surgery, aortic valve surgery, or mitral valve surgery) did not predict long-term outcome. CONCLUSIONS: In patients referred for conventional surgery with an ejection fraction ≤ 25%, prior cardiac surgery, and/or NYHA functional class IV symptoms-particularly in those aged ≥ 70 years-confer significant and sustained survival disadvantages. Such high-risk subsets may benefit from durable mechanical circulatory support consideration.

High prevalence and functional effects of serum antineuronal antibodies in patients with gastrointestinal disorders.

BACKGROUND: Antineuronal antibodies can be associated with both gastrointestinal (GI) and brain disorders. For example, antibodies against the potassium channel subunit dipeptidyl-peptidase-like protein-6 (DPPX) bind to neurons in the central nervous system (CNS) and myenteric plexus and cause encephalitis, commonly preceded by severe unspecific GI symptoms. We therefore investigated the prevalence of antineuronal antibodies indicative of treatable autoimmune CNS etiologies in GI patients. METHODS: Serum samples of 107 patients (Crohn's disease n = 42, ulcerative colitis n = 16, irritable bowel syndrome n = 13, others n = 36) and 44 healthy controls were screened for anti-DPPX and further antineuronal antibodies using immunofluorescence on rat brain and intestine and cell-based assays. Functional effects of high-titer reactive sera were assessed in organ bath and Ussing chamber experiments and compared to non-reactive patient sera. KEY RESULTS: Twenty-one of 107 patients (19.6%) had antibodies against the enteric nervous system, and 22 (20.6%) had anti-CNS antibodies, thus significantly exceeding frequencies in healthy controls (4.5% each). Screening on cell-based assays excluded established antienteric antibodies. Antibody-positive sera were not associated with motility effects in organ bath experiments. However, they induced significant, tetrodotoxin (TTX)-insensitive secretion in Ussing chambers compared to antibody-negative sera. CONCLUSIONS & INFERENCES: Antineuronal antibodies were significantly more frequent in GI patients and associated with functional effects on bowel secretion. Future studies will determine whether such antibodies indicate patients who might benefit from additional antibody-directed therapies. However, well-characterized encephalitis-related autoantibodies such as against DPPX were not detected, underlining their rarity in routine cohorts.

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

[Benign recurring aseptic meningitis. What requires our attention?]. / Benigne rekurrierende aseptische Meningitis. Worauf muss man achten?

Benign recurrent aseptic meningitis (BRAM) or Mollaret's meningitis is a rare disease characterized by recurrent episodes of aseptic meningitis followed by spontaneous recovery. Disease courses over several years have been reported. In most cases, BRAM is caused by HSV-2, less frequently by other viruses or autoimmune diseases. In up to 10 %, the aetiology remains unclear. We present a case of idiopathic BRAM and discuss clinical findings, diagnosis and therapeutic options of this rare illness.

Decoy Receptor DcR1 Is Induced in a p50/Bcl3-Dependent Manner and Attenuates the Efficacy of Temozolomide.

Temozolomide is used widely to treat malignant glioma, but the overall response to this agent is generally poor. Resistance to DNA-damaging drugs such as temozolomide has been related to the induction of antiapoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB-binding sequence (κB-site) was identified in the proximal promoter and was demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53(+/+) glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy.

Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.

BACKGROUND: Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. METHODS AND RESULTS: Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-ß2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-ß signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/ß-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-ß2 increased ß-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-ß2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. CONCLUSIONS: These data support a new disease framework whereby activation of TGF-ß2, bone morphogenetic protein 4, Wnt/ß-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.

Do differences in early hemodynamic performance of current generation biologic aortic valves predict outcomes 1 year following surgery?

OBJECTIVE: Small early postoperative hemodynamic differences were noted in a randomized comparison of 3 current-generation bioprosthetic aortic valves. Whether these differences persist and influence clinical outcomes 1 year following implantation is unknown. METHODS: Three hundred adults with severe aortic stenosis undergoing valve replacement were randomized to receive the Epic (St Jude, St Paul, Minn) (n = 99), Magna (Edwards LifeSciences Inc, Irvine, Calif) (n = 100), or Mitroflow (Sorin Biomedica Spa, Saluggio, Italy) (n = 101) bioprostheses. Hemodynamic valve performance was examined by echocardiography at 1 year, and clinical outcomes were assessed in 241 patients (79 Epic, 77 Magna, and 85 Mitroflow; P = .437). RESULTS: Mean age was 75 ± 8 years and 164 were men (68%). Between dismissal and 1 year there were 9 deaths (3.7%) (Epic: 3.7%, Magna: 5.0%, and Mitroflow: 2.3%; P = .654), 6 episodes of heart failure (2.5%) (Epic: 1.3%, Magna: 1.3%, and Mitroflow: 5.8%; P = .265), 27 instances of atrial fibrillation/flutter (11.2%) (Epic: 8.1%, Magna: 11.0%, and Mitroflow: 7.9%; P = .577) and no strokes/transient ischemic attacks. One-year echocardiography demonstrated small hemodynamic differences between Epic, Magna, and Mitroflow bioprostheses in mean gradient (15.2 ± 5.5, 12.3 ± 4.3, and 16.2 ± 5.7 mm Hg, respectively; P < .001) and indexed aortic valve area (0.93 ± 0.28, 1.04 ± 0.28, and 0.96 ± -0.26 cm(2)/m(2), respectively; P = .015). Several early trends persisted when stratifying data by echocardiographic annulus diameter, universal annulus size, and implant size, particularly with annular size ≥23 mm. Overall left ventricular mass index regression between dismissal and 1 year was -16.5 ± 28.1 g/m(2), and was similar among groups (P = .262). There were no aortic valve reoperations. CONCLUSIONS: Despite midterm persistence of small hemodynamic differences amongst current-generation porcine and pericardial aortic valves, our prospective randomized comparison reveals that clinical outcomes and mass regression are equivalent between devices at 1 year. These encouraging trends must continue to be assessed during longitudinal follow-up.

The prognostic impact of concomitant coronary artery bypass grafting during aortic valve surgery: implications for revascularization in the transcatheter era.

OBJECTIVE: Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). METHODS: We studied 1308 consecutive patients with significant CAD (≥50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. RESULTS: Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG (P = .007). Adjusting for older age (hazard ratio [HR], 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). CONCLUSIONS: In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.

Untreated aortic valve stenosis identified at the time of coronary artery bypass grafting: thresholds associated with adverse prognosis.

OBJECTIVES: Aortic valve replacement (AVR) for severe aortic valve stenosis (AS) is a Class I indication at the time of coronary artery bypass grafting (CABG). Management of less-than-severe AS in patients undergoing CABG is uncertain however, because the thresholds at which untreated AS impacts long-term outcome are unclear. METHODS: We identified 312 patients who underwent isolated CABG between 1993 and 2006 with mild or moderate AS [aortic valve area (AVA) 1-2 cm(2)], and matched them to patients undergoing CABG alone during the same period with similar characteristics but without AS (AVA >2 cm(2)). Long-term survival after CABG and its determinants were analysed using Cox proportional hazards models with AVR as a time-dependent covariate. RESULTS: Late survival was lower in patients with untreated moderate AS (12 years 23 ± 5.1%) versus mild (42 ± 3.8%) or no AS (38 ± 3.3%) (P = 0.01). Adjusting for age, ejection fraction, heart failure, creatinine, diabetes, peripheral vascular disease (PVD) and interval AVR, moderate AS independently predicted higher mortality [hazard rate (HR) 2.01, 95% confidence interval (CI) 1.49-2.73; P < 0.001]; whereas incremental risk was insignificant for patients with mild AS (HR 1.09, 95% CI 0.85-1.66; P = 0.33). Further stratification showed that highest late postoperative mortality occurred with an AVA of 1-1.25 cm(2) (adjusted HR 2.45, 95% CI 1.57-3.82; P < 0.001), while risk was intermediate with an AVA of 1.25-1.5 cm(2) (HR 1.83, 95% CI 1.28-2.61; P = 0.001). CONCLUSIONS: Untreated moderate AS is an independent determinant of excess late mortality following isolated CABG, and mortality risk increases with decreasing AVA. Those with moderate-to-severe AS (AVA 1-1.25 cm(2)) have more than 2-fold greater long-term mortality compared with those without AS. These data define AS severity thresholds for clinical trials aimed at defining whether valve intervention might mitigate this risk.

Risk assessment methods for cardiac surgery and intervention.

Surgical risk models estimate operative outcomes while controlling for heterogeneity in 'case mix' within and between institutions. In cardiac surgery, risk models are used for patient counselling, surgical decision-making, clinical research, quality assurance and improvement, and financial reimbursement. Importantly, risk models are only as good as the databases from which they are derived; physicians and investigators should, therefore, be aware of shortcomings of clinical and administrative databases used for modelling risk estimates. The most frequently modelled outcome in cardiac surgery is 30-day mortality. However, results of randomized trials to compare conventional surgery versus transcatheter aortic valve implantation (TAVI) indicate attrition of surgical patients at 2-4 months postoperatively, suggesting that 3-month survival or mortality might be an appropriate procedural end point worth modelling. Risk models are increasingly used to identify patients who might be better-suited for TAVI. However, the appropriateness of available statistical models in this application is controversial, particularly given the tendency of risk models to misestimate operative mortality in high-risk patient subsets. Incorporation of new risk factors (such as previous mediastinal radiation, liver failure, and frailty) in future surgical or interventional risk-prediction tools might enhance model performance, and thereby optimize patient selection for TAVI.

Left ventricular dysfunction after mitral valve repair--the fallacy of "normal" preoperative myocardial function.

OBJECTIVE: A proportion of patients experience a decrease in left ventricular (LV) ejection fraction (EF) after mitral valve repair; however, predictors and long-term consequences remain unclear. METHODS: A study of 1705 patients with severe, degenerative mitral valve regurgitation and normal preoperative EF (>60%) undergoing mitral valve repair from 1993 to 2012 was performed. Multivariate logistic regression and Cox proportional hazards models were used to determine the predictors of early postoperative LV dysfunction (EF < 50%) and long-term survival, respectively. RESULTS: Postoperative outcomes were comparable between patients; however, those with an EF of <50% (n = 314, 18.4%) had significantly greater enlargement in systolic dimension (left ventricular end-systolic diameter, -0.6 vs 4.3 mm; P < .001) and decrease in right ventricular systolic pressure (-2.7 vs -7.8 mm Hg; P < .001) immediately after repair. On longitudinal follow-up, early LV impairment persisted, with EF recovering to preoperative levels (>60%) in only one third of patients with postrepair EF <50% versus two thirds of those with an EF of ≥ 50% (P < .001). The overall survival at 5, 10, and 15 years of follow-up was 95%, 85%, and 70.8%, respectively. Although early postoperative EF < 50% was not a significant determinant of late survival, when adjusting for older age (hazard ratio [HR], 1.09), hypertension (HR, 1.38), New York Heart Association class III or IV (HR, 1.71), and preoperative atrial fibrillation (HR, 2.33), postoperative EF < 40% conferred a 70% increase in the hazard of late death (HR, 1.74; 95% confidence interval, 1.03-2.92; P = .037). A preoperative right ventricular systolic pressure >49 mm Hg and left ventricular end-systolic diameter >36 mm were independently associated with a 4.4- and 6.5-fold increased risk of developing a postoperative EF < 40% (P < .001, for both). CONCLUSIONS: De novo postoperative LV dysfunction is not uncommon in patients with "normal" preoperative EF undergoing mitral valve repair. LV dysfunction can persist, impairing recovery of LV size, function, and survival. The consideration of mitral repair before the onset of excessive LV dilation or pulmonary hypertension, even in those with preserved EF, seems warranted.

Rituximab for non-Hodgkin's lymphoma: a story of rapid success in translation.

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Assessment of coronary artery disease risk in 5463 patients undergoing cardiac surgery: when is preoperative coronary angiography necessary?

OBJECTIVES: We sought to critically analyze the routine use of conventional coronary angiography (CCA) before noncoronary cardiac surgery and to assess clinical prediction models that might allow more selective use of CCA in this setting. METHODS: We studied 5463 patients undergoing aortic valve surgery, mitral valve surgery, or septal myectomy with or without coronary artery bypass grafting from 2001 to 2010. Preoperative CCAs were evaluated for the presence of significant coronary artery disease (CAD). Random forests and logistic regression methods were used to determine the predictors of significant (≥50%) coronary stenosis. RESULTS: Preoperative CCA was performed in 4711 patients (86%). Two thirds of those with angina, previous myocardial infarction, or percutaneous coronary intervention had significant CAD found on CCA, versus one third of patients free of these risk factors (P < .001). Among 3019 patients without angina, previous myocardial infarction or percutaneous coronary intervention, older age, male gender, diabetes, and peripheral vascular disease independently predicted significant CAD (P < .001 for all; C-index = 0.74). Specifically, a multivariate model with these variables identified 10% (301 of 3019) of patients as having a low (≤10%) probability of coronary stenosis, of whom fewer than 5% had significant CAD and fewer than 1% had left main or triple-vessel coronary disease. CONCLUSIONS: In the absence of angina, previous myocardial infarction, or percutaneous coronary intervention, preoperative CCA identified significant CAD in only one third of patients. Our clinical prediction models could enhance the identification of patients at low risk of significant CAD for whom CCA might potentially be avoided before cardiac surgery. This strategy may improve the efficiency of cardiac surgical care delivery by diminishing procedure-related morbidity and offering significant cost savings.

Minimally invasive heart valve surgery: how and why in 2012.

Cardiac surgical procedures via traditional sternotomy are safe and effective operations performed by cardiothoracic surgeons worldwide. However, postoperative limitations in upper extremity activity during bone healing are seen as undesirable by some. Percutaneous catheter-based attempts to emulate the outcomes of traditional cardiac surgical procedures have largely fallen short of established standards of efficacy and durability. The field of minimally invasive heart valve surgery thus developed out of a need to offer smaller, better-tolerated incisions to patients while maintaining high-quality clinical outcomes. These operations are safe and effective when performed by proficient surgical teams, allowing patients to resume normal activities more rapidly. We explore current evidence supporting the practice of minimally invasive heart valve surgery in 2012 and analyze the clinical impact of these nascent surgical platforms.

Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection.

Acute type A aortic dissection is a lethal condition requiring emergency surgery. It has diverse presentations, and the diagnosis can be missed or delayed. Once diagnosed, decisions with regard to initial management, transfer, appropriateness of surgery, timing of operation, and intervention for malperfusion complications are necessary. The goals of surgery are to save life by prevention of pericardial tamponade or intra-pericardial aortic rupture, to resect the primary entry tear, to correct or prevent any malperfusion and aortic valve regurgitation, and if possible to prevent late dissection-related complications in the proximal and downstream aorta. No randomized trials of treatment or techniques have ever been performed, and novel therapies-particularly with regard to extent of surgery-are being devised and implemented, but their role needs to be defined. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement. By highlighting difficulties and controversies in diagnosis, patient selection, and surgical therapy, our over-arching goal should be to enfranchise more patients for treatment and improve surgical outcomes.