Beneficial effects of endoventricular circular patch plasty in patients with left ventricular systolic dysfunction and left ventricular dyskinetic or akinetic apical segment

Background  Available data on the efficiency of endoventricular circular patch plasty (EVCPP) especially from Asian Indians are limited. The objective of the present investigation was to evaluate the efficacy of endoventricular circular patch plasty along with coronary artery bypass grafting (CABG). Methods  Patients having ischemic left ventricular (LV) systolic dysfunction [LV ejection fraction (LVEF)≤25%] with left ventricular dyskinetic or akinetic apical segement [as depicted by two dimensional (2D) echocardiography] were enrolled in the study. They were evaluated for 2D echocardiography and color Doppler parameters as well as functional capacity before surgery and after one, three and six months of surgery. Results  39 patients (35 males; average age 59 years) were enrolled in the study. There was significant (P<0.05) increase in LV contractility measured in terms of LVEF with absolute rise of 8–14 digits from presurgery levels during time course of the study. EVCPP performed in addition to CABG produced significant reduction in LV end diastolic diameter (5–5.5 mm) and LV end systolic diameter (4.5–8.5 mm) at short-and intermediate-term following surgery. EVCPP plus CABG also produced significant improvement in functional capacity as a significant decrease in New York Heart Association class for heart failure was observed at all three stages of follow-up after surgery. Conclusion  EVCPP carried out along with CABG produces significant improvement in LV contractility, in reverting LV remodeling and functional status in Indian patients with LV systolic dysfunction and LV dyskinetic or akinetic apical segment at shor-term as well as intermediate-term following surgery.     

Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings

Background  

Despite wide promotion, clinical practice guidelines have had limited effect in changing physician behavior. Effective implementation strategies to date have included: multifaceted interventions involving audit and feedback, local consensus processes, marketing; reminder systems, either manual or computerized; and interactive educational meetings. In addition, there is now growing evidence that contextual factors affecting implementation must be addressed such as organizational support (leadership procedures and resources) for the change and strategies to implement and maintain new systems.     

Changes in interocular axial length after pediatric cataract surgery.

PURPOSE: To explore the hypothesis that preoperative interocular axial length difference changes after pediatric cataract intraocular lens implantation surgery to meet the measurement of the fellow eye. METHODS: Retrospective chart review. Eyes with traumatic and secondary cataract, lens subluxation, or postoperative glaucoma were excluded. In bilateral cataract cases, only right eye data were included. In addition, eyes were included only if axial length data for both eyes were available before surgery and at follow-up equal to or greater than the age at surgery. RESULTS: Forty-seven eyes fit the inclusion criteria. Average age at surgery and follow-up was 2.2 +/- 2.2 and 5.6 +/- 2.9 years, respectively. Three groups were formed based on the preoperative interocular axial length difference: < -0.2, group 1; >or= -0.2, and 0.2, group 3. Average age at surgery between these three groups was not significantly different (p = 0.82), nor was age at follow-up between the groups (p = 0.66). The change in interocular axial length difference (postoperative interocular axial length difference minus preoperative interocular axial length difference) was significant between the three groups (0.3, 0.2, -0.4 mm, respectively; p = 0.02). The average rate of axial length growth was significantly different between three groups (3.7, 2.4, 2.5 mm, respectively; p = 0.03). CONCLUSIONS: Eyes with a shorter axial length than the fellow eye showed postoperative rate of axial growth that exceeded the growth rate of eyes with a longer interocular axial length. These growth rates resulted in a postoperative trend of intraocular axial length difference toward zero.     

The Relationship Between Gray Matter Morphometry and Neuropsychological Performance in a Large Sample of Cognitively Healthy Adults

Voxel-based morphometry (VBM) was used to examine the relationship between gray matter (GM) volume and performance on two commonly used clinical neuropsychological measures of frontal lobe or executive function, the Trail Making Test part B (TrailsB) and the Controlled Oral Word Association Test (COWAT) in 221 cognitively healthy adults between the ages of 18 and 84. We hypothesized that these measures would be associated with GM volume in the dorsolateral frontal lobes. Voxel-based multiple regression was used to correlate cognitive function with modulated GM probability maps while controlling for age, education, gender, and total intracranial volume. A relationship with TrailsB was found in bilateral lateral inferior frontal gyri and left basal ganglia. A relationship with COWAT was found in the left lateral inferior and middle frontal gyri. Lesion studies have long implicated the importance of these regions for executive function. The present results confirm and extend those prior findings to healthy adults.     

Measurement of myocardial fractional flow reserve is a cost-effective way to identify coronary artery lesions of indeterminate severity that warrant revascularisation

BACKGROUND: The RADI pressure wire may be used in stenotic coronary arteries to calculate myocardial fractional flow reserve (FFR(myo)), the ratio between distal hyperaemic coronary pressure and aortic pressure. A ratio less than 0.75 categorizes lesions of haemodynamic significance for which percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be warranted. We undertook this study to evaluate the cost implications of performing these measurements. METHODS: We recorded FFR(myo) using RADI wires in 32 coronary artery lesions of between 30 and 60% diameter stenosis in 31 patients and assessed how this information changed our management. RESULTS: We followed our original "management plan" in only eight patients. PCI or CABG was performed in eight whose lesions were characterised by a FFR(myo) value of 0.76 or less. Myocardial perfusion imaging (MPI) was done in only one of nine for whom this had seemed to be appropriate. Two-thirds of those for whom PCI had appeared to be warranted were treated conservatively and only one quarter of the original "surgical" group underwent CABG. CONCLUSION: Although RADI pressure wires are an additional expense, it is appropriate to use them to assess coronary stenotic lesions of indeterminate severity. When we took into account the savings that arose from changes in management, the additional cost of measuring FFR(myo) was around dollar 580 per study.     

The ontogeny of serum GH binding protein in man: a possible indicator of hepatic GH receptor development

Experiments in rabbits suggest that a serum GH binding protein (GH-BP) probably is derived largely from hepatic membrane bound GH receptors. Human serum contains a specific GH binding protein which can be easily measured by incubation with [125I] hGH and separation of [125I] hGH-BP complexes from free [125I] hGH by gel filtration through an Ultrogel AcA 44 minicolumn. In each assay GH-BP activity of a reference (normal young adult) serum is similarly run and the results are expressed as a percentage of the activity of the unknown serum divided by the GH-BP activity of the reference serum after correction for the expected inhibition of GH binding resulting from the GH content of the unknown serum. The mean relative specific GH binding protein (RSGH-BP) of cord serum from 11 premature infants was only 3.2 +/- 1.4% (SE) and of cord serum from 17 full term infants was 14.9 +/- 2.5%. During the first two decades of life there was a progressive rise of RSGH-BP with considerable individual variation. The mean serum RSGH-BP of 13 such subjects was 54.5 +/- 6.2%. More uniform RSGH-BP results were obtained in serum from 15 young adults, 91.7 +/- 7.4%. Lower RSGH-BP 77.2 +/- 5.4% was found in serum from 12 healthy older adults (age 60 to 70 years). The low levels of RSGH-BP in fetal serum are consistent with the reported low concentrations of GH receptors in sheep and rat fetal liver membranes. We suggest the measurement of GH-BP activity provides a simple, noninvasive measure of the ontogeny of GH receptors of human beings.     

Prevalence of renal artery stenosis requiring revascularization in patients initially referred for coronary angiography.

To evaluate the prevalence of clinically significant renal artery stenosis (RAS) in patients referred for coronary angiography, we analyzed data on 2,439 consecutive patients. Patients underwent selective renal angiography in conjunction with coronary angiography if refractory hypertension (blood pressure > 140/90 on two drugs) or flash pulmonary edema was present. A total of 1,089 renal arteries of 534 patients were evaluated. Twelve percent (137/1,089) of the renal arteries in 19% (101/534) of patients had > 70% diameter stenosis in at least one vessel. Bilateral renal artery stenosis was present in 26% (26/101) of patients. One hundred and thirty-two of the 137 vessels underwent stent revascularization due to clinical renovascular hypertension. Acute clinical success (< 20% diameter stenosis without death or urgent surgery) was 98% (99/101). Due to high prevalence and effective available treatment, we recommend routine screening for RAS in all patients with refractory hypertension referred for coronary angiography.     

A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike

The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR^−/−mice, IFNAR^−/−-hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2–specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.

In December 2019, a novel coronavirus disease (COVID-19) was first identified in Wuhan City, Hubei Province, People’s Republic of China. The causative agent was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On 11 March 2020 the World Health Organization (WHO) declared COVID-19 a global pandemic (1–3). It spread rapidly within China and swept into at least 200 countries within 3 mo. Symptoms are primarily pneumonia, as with two other important human coronaviruses (CoVs), SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV (1–3). As of 1 February 2021, more than 102,399,513 cases had been reported worldwide, with 2,217,005 deaths (∼2.2% mortality). There is an urgent need to develop a safe and efficacious vaccine to protect the populace from this new virus. Globally, more than 300 SARS-CoV-2 vaccine candidates are in preclinical development (4–6) and at least 30 vaccine candidates have entered human clinical trials (4, 5, 7, 8). Among them, vaccines based on messenger RNA (mRNA), inactivated virus, and adenovirus vectors (Ad5-nCoV and ChAdOx1) are now in phase III clinical trials. Excitingly, preliminary results indicate that these vaccines are highly efficacious, reaching 90 to 95% effectiveness against SARS-CoV-2 infection in some cases. The durability of the protection conferred by these vaccine candidates is unknown. Although these vaccine candidates are highly promising, exploration of other vaccine platforms is needed.The CoV spike (S) protein is the main target for neutralizing antibodies that inhibit infection and prevent disease. As such, the S protein is the primary focus for CoV vaccine development (9, 10). The CoV S protein is a class I fusion protein trimer that is incorporated into virions as they bud into the endoplasmic reticulum–Golgi intermediate compartment. For SARS-CoV-2, S is cleaved into S1 and S2 subunits by furin before the virion is released. The S1 subunit contains the receptor-binding domain (RBD) that attaches to the hACE2 receptor on the surface of a target cell. The S2 subunit is further cleaved by TMPRSS2 (or cathepsin L/B) and possesses the membrane-fusing activity (9, 11, 12). Both S and its RBD have been shown to be immunogenic for many CoVs (13–15). The native S in the virion is in its “prefusion” form. Upon triggering, the prefusion S (preS) undergoes significant conformational changes to insert its fusion peptide into the target cell membrane and bring the virion and cell membranes together, arriving at its postfusion S form as it causes the membranes to fuse. For paramyxoviruses, pneumoviruses, and HIV, it has been shown that prefusion forms of glycoprotein are more potent in inducing neutralizing antibodies than their postfusion forms (16–20). Currently, whether the SARS-CoV-2 preS protein is more immunogenic than the postfusion S protein is unknown.Live attenuated measles virus (MeV) vaccine has been one of the safest and most efficient human vaccines and has been used in children since the 1960s (21, 22). Worldwide MeV vaccination campaigns have been very successful in controlling measles. MeV is an enveloped nonsegmented negative-sense RNA virus that belongs to the genus Morbillivirus within the Paramyxoviridae family. MeV is an excellent vector to deliver vaccines for human pathogens primarily because of its high safety, efficacy, and long-lived immunity (22, 23). MeV has previously been shown to be a highly efficacious vaccine vector for many viral diseases such as HIV (24, 25), SARS-CoV-1 (26, 27), MERS-CoV (28, 29), respiratory syncytial virus (30), hepatitis B and C viruses (31), influenza virus (30, 32), chikungunya virus (CHIKV) (33), and flaviviruses (Zika virus, dengue virus, West Nile virus, and yellow fever virus) (34–36). Recent human clinical trials have demonstrated that an recombinant MeV (rMeV)-based CHIKV vaccine is safe and highly immunogenic in healthy adults, even in the presence of preexisting anti-MeV vector immunity (33).In this study, we developed a series of rMeV-based vaccine candidates expressing different forms of the SARS-CoV-2 S protein and evaluated them in cotton rats, IFNAR^−/−mice, IFNAR^−/−-hCD46 mice, and golden Syrian hamsters. We found that all SARS-CoV-2 S antigens are highly expressed by the MeV vector. Among these vaccine candidates, rMeV expressing stabilized preS (rMeV-preS) and full-length S (rMeV-S) proteins were the most potent in triggering SARS-CoV-2–specific antibodies. Animals immunized with rMeV-preS induced the highest level of neutralizing antibodies that were higher than convalescent sera of patients recovered from COVID-19, and the highest Th1-biased T cell immune response. Furthermore, hamsters immunized with rMeV-preS provided complete protection against SARS-CoV-2 challenge and lung pathology.     

Generation of CMV-specific T lymphocytes using protein-spanning pools of pp65-derived overlapping pentadecapeptides for adoptive immunotherapy

Cell-mediated immunity is essential for control of human cytomegalovirus (HCMV) infection. We used a pool of 138 synthetic overlapping pentadecapeptides overspanning the entire pp65 protein to generate polyclonal CMV-specific T-cell lines from 12 CMV-seropositive donors inheriting different HLA genotypes. Autologous monocyte-derived dendritic cells (DCs) pulsed with this complete pool consistently induced highly specific T cells that selectively recognized 1-3 pentadecapeptides identified by secondary responses to a mapping grid of pentadecapeptide subpools with single overlaps. Responses against peptide-loaded targets sharing single HLA class I or II alleles identified the restricting HLA alleles. HLA-A*0201+ donors consistently responded to pentadecapeptides containing HLA-A*0201-binding epitope(aa495-503)NLVPMVATV. T-cell lines from other donors contained high frequencies of CD4 and/or CD8 T cells selectively reactive against peptides presented by other HLA alleles, including both known epitopes such as (aa341-350)QYDPVAALF (HLA-A*2402) as well as unreported epitopes such as (aa267-275)HERNGFTVL (HLA-B*4001 and B*4002) and (aa513-523)FFWDANDIYRI (HLA-DRB1*1301). These T cells consistently lysed CMV-infected target cells. Thus, this approach fosters expansion and selection of HLA-restricted CMV-pp65-reactive T-cell lines of high specificity that also lyse CMV-infected targets, and from a functional and regulatory perspective, may have advantages for generating virus-specific T cells for adoptive immunotherapy.