Harnessing Aromatic-Histidine Interactions through Synergistic Backbone Extension and Side Chain Modification.

Peptide engineering efforts have delivered drugs for diverse human diseases. Side chain alteration is among the most common approaches to designing new peptides for specific applications. The peptide backbone can be modified as well, but this strategy has received relatively little attention. Here we show that new and favorable contacts between a His side chain on a target protein and an aromatic side chain on a synthetic peptide ligand can be engineered by rational and coordinated side chain modification and backbone extension. Side chain modification alone was unsuccessful. Binding measurements, high-resolution structural studies and pharmacological outcomes all support the synergy between backbone and side chain modification in engineered ligands of the parathyroid hormone receptor-1, which is targeted by osteoporosis drugs. These results should motivate other structure-based designs featuring coordinated side chain modification and backbone extension to enhance the engagement of peptide ligands with target proteins.

The Fried Frailty Phenotype in Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: Frailty is an increasingly recognized marker of poor surgical outcomes in cardiac surgery. Frailty first was described in the seminal "Fried" paper, which constitutes the longest-standing and most well-recognized definition. This study aimed to assess the impact of the Fried and modified Fried frailty classifications on patient outcomes following cardiac surgery. METHODS: The PUBMED, MEDLINE, and EMBASE databases were searched from January 2000 until August 2021 for studies evaluating postoperative outcomes using the Fried or modified Fried frailty indexes in open cardiac surgical procedures. Primary outcomes were one-year survival and postoperative quality of life. Secondary outcomes included postoperative complications, intensive care unit (ICU) length of stay (LOS), total hospital LOS, and institutional discharge. RESULTS: Eight eligible studies were identified. Meta-analysis identified that frailty was associated with an increased risk of one-year mortality (Risk Ratio [RR]:2.23;95% confidence interval [CI]1.17 -4.23), postoperative complications (RR 1.78;95% CI 1.27 - 2.50), ICU LOS (Mean difference [MD] 21.2 hours;95% CI 8.42 - 33.94), hospital LOS (MD 3.29 days; 95% CI 2.19 - 4.94), and institutional discharge (RR 3.29;95% CI 2.19 - 4.94). A narrative review of quality of life suggested an improvement following surgery, with frail patients demonstrating a greater improvement from baseline over non-frail patients. CONCLUSIONS: Frailty is associated with a higher degree of surgical morbidity, and frail patients are twice as likely to experience mortality within one-year post-operatively. Despite this, quality of life also improves dramatically in frail patients. Frailty, in itself, does not constitute a contraindication to cardiac surgery.

Metastatic giant cell tumour of bone: a narrative review of management options and approaches.

Giant cell tumour of bone (GCTB) is a locally aggressive bone neoplasm with a rare tendency to metastasise, most commonly to the lungs. The management of metastatic GCTB (metGCTB) is controversial due to its unpredictable behaviour. Asymptomatic patients should be monitored radiologically and undergo treatment only when disease progression occurs. Surgery is recommended for resectable metGCTB. Denosumab, a monoclonal antibody which inhibits receptor activator of nuclear factor-κB ligand, is recommended for unresectable metGCTB with evidence from phase II trials demonstrating its safety and efficacy. Relapse after denosumab withdrawal may occur and prolonged treatment may be associated with serious adverse events, thus further research is warranted to inform a maintenance regimen with reduced dosing and frequency. Combined denosumab and bisphosphonate therapy has the potential to achieve sustained disease control or remission in unresectable metGCTB without requiring long-term treatment and should be evaluated in prospective trials. Various novel agents have demonstrated in vitro and anecdotal efficacy and warrant further evaluation.

Slow gait speed is associated with worse postoperative outcomes in cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Frailty is associated with poorer outcomes in cardiac surgery, but the heterogeneity in frailty assessment tools makes it difficult to ascertain its true impact in cardiac surgery. Slow gait speed is a simple, validated, and reliable marker of frailty. We performed a systematic review and meta-analysis to examine the effect of slow gait speed on postoperative cardiac surgical patients. METHODS: PubMED, MEDLINE, and EMBASE databases were searched from January 2000 to August 2021 for studies comparing slow gait speed and "normal" gait speed. Primary outcome was in-hospital mortality. Secondary outcomes were composite mortality and major morbidity, AKI, stroke, deep sternal wound infection, prolonged ventilation, discharge to a healthcare facility, and ICU length of stay. RESULTS: There were seven eligible studies with 36,697 patients. Slow gait speed was associated with increased likelihood of in-hospital mortality (risk ratio [RR]: 2.32; 95% confidence interval [CI]: 1.87-2.87). Additionally, they were more likely to suffer from composite mortality and major morbidity (RR: 1.52; 95% CI: 1.38-1.66), AKI (RR: 2.81; 95% CI: 1.44-5.49), deep sternal wound infection (RR: 1.77; 95% CI: 1.59-1.98), prolonged ventilation >24 h (RR: 1.97; 95% CI: 1.48-2.63), reoperation (RR: 1.38; 95% CI: 1.05-1.82), institutional discharge (RR: 2.08; 95% CI: 1.61-2.69), and longer ICU length of stay (MD: 21.69; 95% CI: 17.32-26.05). CONCLUSION: Slow gait speed is associated with poorer outcomes in cardiac surgery. Frail patients are twofold more likely to die during hospital admission than nonfrail counterparts and are at an increased risk of developing various perioperative complications.

First genetic assessment of brackish water polychaete Tylorrhynchus heterochaetus: mitochondrial COI sequences reveal strong genetic differentiation and population expansion in samples collected from southeast China and north Vietnam.

Tylorrhynchus heterochaetus is a widespread benthic polychaete worm found in coastal brackish waters of the west Pacific. It has high ecological and economic value as a biomarker of water quality and as a high-quality feed in aquaculture and fisheries and is considered a delicacy in some areas of Asia. However, it has experienced a marked reduction in recent years due to overexploitation as well as changes in the environment and climate. Here, to comprehensively understand its genetic background and thus provide insights for better conservation and utilization of this species, we assessed the genetic variability and demographic history of T. heterochaetus individuals sampled from eight locations along the coasts of southeast China and north Vietnam based on mitochondrial cytochrome c oxidase I ( COI) sequences. We observed high haplotype diversity ( Hd), with an average of 0.926, but relatively low nucleotide diversity ( π), with a mean of 0.032 across all samples. A total of 94 polymorphic sites and 85 haplotypes were identified among 320 individuals. The pairwise genetic distances among haplotypes ranged from 0.001 to 0.067, with the high intraspecific divergence possibly reflecting geographic isolation and gene pool fragmentation. Significant genetic structures were revealed among the studied locations; specifically, the eight locations could be treated as six genetically different populations based on pairwise Φ ST results (0.026-0.951, P<0.01). A significant pattern of isolation-by-distance was detected between the genetic and geographic distances ( r=0.873, P=0.001). Three geographic lineages were defined based on phylogenetic tree and network analyses of COI haplotypes. AMOVA results indicated that genetic variations mainly occurred among the three lineages (89.96%). Tests of neutrality and mismatch distribution suggested that T. heterochaetus underwent recent population expansion. These results provide the first report on the genetic status of T. heterochaetus and will be valuable for the management of genetic resources and better understanding of the ecology and evolution in this species.