Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear. OBJECTIVE: The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials. METHODS: Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I2 statistic. RESULTS: In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12-52), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p<0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p<0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6-15), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01). CONCLUSION: PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by >40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.

Bilateral Anteriorly Displaced Microspherophakia in a Female Child With Marfanoid Habitus.

Microspherophakia is a rare congenital anomaly characterized by an abnormally small and spherical crystalline lens, which can be associated with several systemic syndromes. We present an extremely rare case of bilateral anteriorly displaced microspherophakia in a female child with Marfanoid habitus. The patient displayed phenotypic features resembling Marfan syndrome, including tall stature, muscle hypotonia, dolichostenomelia, and increased arm span than body length. However, unlike Marfan syndrome, Marfanoid habitus is not associated with mutations in the fibrillin-1 gene. The association between microspherophakia and Marfanoid habitus is a unique presentation that has not been reported in the literature. This case report aims to increase awareness of microspherophakia as a possible ocular association of Marfanoid habitus.

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic.

Understanding the molecular evolution of the SARS-CoV-2 virus as it continues to spread in communities around the globe is important for mitigation and future pandemic preparedness. Three-dimensional structures of SARS-CoV-2 proteins and those of other coronavirusess archived in the Protein Data Bank were used to analyze viral proteome evolution during the first 6 months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48 000 viral isolates revealed how each one of 29 viral proteins have undergone amino acid changes. Catalytic residues in active sites and binding residues in protein-protein interfaces showed modest, but significant, numbers of substitutions, highlighting the mutational robustness of the viral proteome. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for potential drug discovery targets and the four structural proteins that comprise the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and protein-protein and protein-nucleic acid interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

Treating Vertebral Compression Fractures: Establishing the Appropriate Diagnosis, Preoperative Considerations, Treatment Techniques, Postoperative Follow-Up and General Guidelines for the Treatment of Patients With Symptomatic Vertebral Compression Fractures.

Vertebral compression fractures (VCFs) result from either trauma or a pathologic process that weakens the bone by conditions such as osteoporosis or tumor. The incidence of VCFs has been rising over the last few decades in accordance with the aging population. These fractures can result in severe pain, physical limitation and disability, as well as increased morbidity and mortality. Patients with VCFs are optimally treated by accurate and early diagnosis and treatment. An effective method to treat these fractures is percutaneous vertebral augmentation, which is a set of minimally invasive procedures that stabilizes osseous fractures, provides immediate pain relief, and improves quality of life. Vertebral augmentation procedures include vertebroplasty, kyphoplasty, and vertebral augmentation with implants. Each of these techniques is described in general terms in this article. The ideal candidate for vertebral augmentation is a patient with a symptomatic fracture seen on cross-sectional imaging in which nonsurgical management has failed and has positive signs on physical examination with no absolute contraindication. This procedure should be done with the appropriate equipment and personnel in a facility designed for this purpose. After the procedure, the patient should undergo the appropriate follow-up to ensure optimal recovery. Additionally, it is essential that the patient receives appropriate therapy for the underlying disorder that predisposed them to the vertebral fracture.

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic.

Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and functional interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

Haemoperitoneum after an endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of a pancreatic lesion in a peritoneal dialysis patient.

Haemoperitoneum was observed in a peritoneal dialysis (PD) patient after undergoing endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). EUS-FNA was performed to evaluate a pancreatic cyst seen on a prekidney transplant evaluation abdominal CT scan. Haemoperitoneum cleared with a PD exchange. In this case report, we discuss aetiologies for bleeding risks in patients with chronic kidney disease and focus on haemoperitoneum in patients receiving PD. We will also explore treatment options to minimise bleeding associated with an abdominal procedure such as EUS-FNA.

Successful use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) on a pancreatic lesion in a peritoneal dialysis patient without interrupting treatment.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), a well-established minimally invasive gastrointestinal procedure, has been used to diagnose and stage cancers of the pancreas. We describe the successful use of EUS-FNA in a peritoneal dialysis (PD) patient to evaluate a pancreatic cyst. The patient continued on PD immediately after the procedure without using hemodialysis. The patient did not experience any complication such as infection, bleeding, or peritoneal fluid leakage.

Intravenous Dexmedetomidine Has Synergistic Effect on Subarachnoid Block with Hyperbaric Bupivacaine.

Objective To assess the effect of intravenous dexmedetomidine on subarachnoid anesthesia with the help of hyperbaric bupivacaine when administered as a bolus or as an infusion. Materials and methods This randomized control trial was conducted at the Department of Anesthesia, Nishtar Hospital, Multan, Pakistan, from January 2017 to December 2018. Seventy patients were enrolled in the study. Patients were segregated into three groups. At the T10 level, a sensory blockade was noted. The motor blockade was also periodically measured until a modified Bromage score of three was achieved. The depth of sedation was measured with the help of the Ramsay Sedation Scale score. Oxygen saturation and other factors were also measured and recorded. Nausea, vomiting, diarrhea, and pruritus were the adverse effects noted during the study. To check and compare the statistical differences among the variables from different groups, the Chi-square test and analysis of variance test were performed. A probability (p) value of <.05 was considered statistically significant. Results The duration of the sensory blockade was shortest in the control group receiving only bupivacaine (Group B) and longest in the group receiving bupivacaine plus dexmedetomidine as a single bolus (Group BDexB; p: <.001). The time of complete sensory and motor recovery was longest in Group BDexB and shortest in Group B. The difference was statistically significant (p: <.001). The Ramsay score was >2 (i.e., 3 or 4) in five patients from Group B, 19 from Group BDexB, and 17 from the group receiving intrathecal bupivacaine plus dexmedetomidine as an infusion (Group BDexI). Between these groups, a statistically significant difference was found (p: <.001). Conclusions Intravenous administration of dexmedetomidine as either a bolus or infusion prolonged the duration of the sensory and motor blockade.

A facile hydrothermal approach for catalytic and optical behavior of tin oxide- graphene (SnO2/G) nanocomposite.

A cost-effective, facile hydrothermal approach was made for the synthesis of SnO2/graphene (Gr) nano-composites. XRD diffraction spectra clearly confirmed the presence of tetragonal crystal system of SnO2 which was maintaining its structure in both pure and composite materials' matrix. The stretching and bending vibrations of the functional groups were analyzed using FTIR analysis. FESEM images illustrated the surface morphology and the texture of the synthesized sample. HRTEM images confirmed the deposition of SnO2 nanoparticles over the surface of graphene nano-sheets. Raman Spectroscopic analysis was carried out to confirm the in-plane blending of SnO2 and graphene inside the composite matrix. The photocatalytic performance of the synthesized sample under UV irradiation using methylene blue dye was observed. Incorporation of grapheme into the SnO2 sample had increased the photocatalytic activity compared with the pure SnO2 sample. The electrochemical property of the synthesized sample was evaluated.

The link between chronic thromboembolic pulmonary hypertension and sarcoidosis: association or visual masquerade?

Chronic thromboembolic pulmonary hypertension (CTEPH) and sarcoidosis are recognized causes of pulmonary hypertension according to the World Health Organization classification scheme. This case series describes seven patients with sarcoidosis with a mean age of 61 who developed pulmonary hypertension. They were found to have CTEPH, diagnosed by either CT pulmonary angiography or a lung ventilation perfusion scan. They all underwent confirmatory right heart catheterization showing elevated mean pulmonary artery pressures (mean of 42 mmHg - normal less than 25 mmHg). Sarcoidosis has been previously shown to be associated with increased rates of venous thromboembolic disease. In these cases, patients with sarcoidosis later developed CTEPH and this may be another mechanism in which sarcoidosis can lead to pulmonary hypertension. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 352-355).

Coronary artery anatomy and apical sparing in apical ballooning syndrome: implications for diagnosis and aetiology.

BACKGROUND: Apical ballooning syndrome (ABS) is characterised by transient regional systolic dysfunction involving the left ventricular apex and mid-myocardial segments. The absence of obstructive coronary disease is required in some diagnostic criteria. Some investigators have suggested that a long "wrap-around" left anterior descending (LAD) artery may explain the pattern of regional wall motion abnormalities. METHODS AND RESULTS: We reviewed the coronary angiograms and ventriculograms findings in a prospective ABS cohort of 46 patients (mean age 63+/-13, female 96%). Normal smooth coronary arteries were observed in 54%, with 30% having minor irregularities. Moderate or severe coronary artery lesions were identified in 7 (15%) patients, including 4 with moderate LAD disease. The extent of the LAD artery around the left ventricular apex to the diaphragmatic surface of the heart was scored. This score was compared to 60 consecutive gender-matched control patients without ABS and no observed difference between the two groups (p=0.62). 42% had sparing of LV apical akinesis which was independent of the LAD extent. CONCLUSION: Moderate or severe coronary artery stenosis may co-exist in a small proportion of patients with ABS. Exclusion of these patients will underestimate the true incidence of ABS. The prevalence of "wrap-around" LAD is similar in ABS and non-ABS patients. Apical sparing in ABS is more consistent with aetiological hypotheses implicating LV stunning due to acutely elevated LV wall stress, rather than single or multi-vessel coronary spasm.