Understanding 'value' in the context of community-based interventions for people affected by dementia: A concept analysis.

AIM: This study aimed to conduct a concept analysis of value in the context of community-based interventions for people affected by dementia. BACKGROUND: Concepts of value play a critical role in shaping the delivery and distribution of community-based health interventions through related concepts. However, the use and meaning of 'value' is rarely clarified limiting the term's utility in practice and research. Increasing need for community healthcare and scarce public resources means developing understanding of value in community-based interventions for people affected by dementia is timely, and may support more informed approaches to exploring, explaining and delivering value. DESIGN: Evolutionary Concept Analysis was used to systematically determine the characteristics of value. DATA SOURCES: Peer-reviewed and grey literature databases were searched between April and July 2021, with 32 pieces of literature from different disciplines included in the final sample. No limits were set for the years of literature retrieved. METHODS: Literature was thematically analysed for information on the antecedents, attributes and consequences of value. RESULTS AND DISCUSSION: The analysis uncovered a need and/or desire to understand the experience of people affected by or that affect interventions; and to demonstrate, prove/disprove the (best) quality and nature of results of interventions as antecedents of value. Attributes of value were stakeholder/person centred, measurable, time and context dependent and multidimensional. Consequences of the concept included shared decision-making, valuation of interventions and internal/external investment and development of interventions. CONCLUSION: Through concept analysis value can now be better understood and applied. The development of a conceptual model to illustrate the constituent elements and relationships of the concept adds transparency to where, why and how concepts of value are enabled that supports future concept development. PATIENT AND PUBLIC CONTRIBUTION: No patient or public contribution.

Exploring Language Development Support for Foster Children: A Scoping Review of Interventions for Foster Care Families.

PURPOSE: Children in foster care are at an increased risk for language delays and disorders, and foster parents can play a significant role in preventing delays in early language development. This scoping review explored empirical studies that included foster parent training programs for families with foster children under the age of 5 years. METHOD: Using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews), multiple databases were searched, and resulting article titles and abstracts were screened for inclusion in the review. Each study that met inclusion criteria was then coded for the training methods used to teach foster parents intervention strategies and the targeted outcomes of the intervention. RESULTS: A total of 24 studies were identified. Of the 24 studies reviewed, all included interventions focused on increasing parent-child relationships and decreasing child challenging behaviors, but few included opportunities for foster parents to practice using intervention strategies with their foster child. None of the studies focused specifically on strategies for promoting children's language development. When outcomes across the studies were reviewed, only two focused on children's language. CONCLUSIONS: The results of this review point to the need for more research on language interventions that can be implemented by foster parents. The discussion focuses on the important role speech-language pathologists can play in the prevention of early language delays or disorders in young foster children. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21714311.

Endoscopic surveillance alone is feasible and safe in type I gastric neuroendocrine neoplasms less than 10 mm in diameter.

PURPOSE: Type I gastric neuroendocrine neoplasms (g-NENs) have a low risk of metastasis and a generally favourable prognosis. Patients with small type I g-NENs (≤10 mm) frequently require no treatment, whereas those with larger polyps usually undergo resection. We evaluated the safety and outcomes of endoscopic surveillance after no initial treatment in selected patients with type I g-NENs. METHODS: Retrospective analysis of type I g-NEN patients across two European Neuroendocrine Tumour Society Centers of Excellence 2003-2019. RESULTS: Following initial assessment, 87 of 115 patients with type I g-NEN (75 with polyps ≤10 mm) received no initial treatment and underwent endoscopic surveillance. 79/87 (91%) demonstrated no clinically meaningful change in tumour size or grade over a median 62 month follow up. Only two patients developed NEN progression that required a change in management and two other patients developed gastric adenocarcinoma/high grade dysplasia; all four initially had ≥11 mm g-NENs. CONCLUSIONS: Patients with ≤10 mm type I g-NENs were unlikely to develop clinically significant tumour progression and in most cases, resection was not needed. The endoscopic surveillance interval could therefore potentially be safely increased to every 2-3 years in such patients. However, lifelong surveillance is still advocated due to the additional risk of developing gastric adenocarcinoma.

Oligometastasis to the testes from oesophageal adenocarcinoma.

Upper gastrointestinal tumours can metastasise to many viscera including the female reproductive system (Krukenberg tumour). However, spread to the male genitalia is extremely rare. We report the case of a man in his 70s who underwent oesophagogastrectomy for oesophagogastric junctional (OGJ) cancer with a complete response to neoadjuvant treatment who presented 4 months after completing treatment with a solitary testicular metastases.

New Developments in Gastric Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: Gastric neuroendocrine neoplasms (g-NENs) are a rare type of stomach cancer. The three main subtypes have different pathogeneses, biological behaviours and clinical characteristics, so they require different management strategies. This article will provide an overview of g-NENs and highlight recent advances in the field. RECENT FINDINGS: Molecular profiling has revealed differences between indolent and aggressive g-NENs, as well as a new somatic mutation responsible for some familial type I g-NENs. Novel biomarkers have been developed which will hopefully improve diagnosis, treatment, risk stratification and follow-up. Patient treatment is also changing, as evidence supports the use of less aggressive options (e.g. endoscopic surveillance or resection) in some patients with more indolent tumours. g-NEN heterogeneity poses challenges in understanding and managing this rare disease. More basic science research is needed to investigate molecular pathogenesis, and future larger clinical studies will hopefully also further improve treatment and patient outcomes.

Plasma Metabolomics Identifies Lipid and Amino Acid Markers of Weight Loss in Patients with Upper Gastrointestinal Cancer.

Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The 'omics' technologies allow us the opportunity to study the end points of many biological processes. Among these, blood-based metabolomics is a promising method to investigate the pathophysiology of human cancer cachexia and identify candidate biomarkers. In this study, we performed liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of cancer-associated weight loss. Non-selected patients undergoing surgery with curative intent for upper gastrointestinal cancer were recruited. Fasting plasma samples were taken at induction of anaesthesia. LC/MS analysis showed that 6 metabolites were highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, L-Proline, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16:1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight-stable samples (<5%weight loss) between predicted and actual weight change (r = 0.976, p = 0.0014). Overall, 40 metabolites were associated with ≥5% weight loss. This study provides biological validation of the consensus definition of cancer cachexia (Fearon et al.) and provides feasible candidate markers for further investigation in early diagnosis and the assessment of therapeutic intervention.

Effect of prophylactic ankle taping on ankle and knee biomechanics during basketball-specific tasks in females.

OBJECTIVE: The aim of this study was to investigate the effects of ankle taping on ankle and knee joint biomechanics during cutting and rebound activities in females. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Twenty semi-professional female basketball players performed a cut and rebound task under two conditions (taped and no-tape). MAIN OUTCOME MEASURES: Kinematic and ground reaction force data were collected during the deceleration phase of each movement task. RESULTS: Taping resulted in a significant reduction in peak ankle dorsiflexion, inversion and internal rotation angles and range of motion (ROM) at the ankle joint; and reduced knee ROM in the sagittal plane during the rebound task only. Taping significantly reduced peak knee flexion moment (0.29 Nm/kg, P = 0.013) and increased knee internal rotation moment (0.63 Nm/kg, P = 0.026) during the cutting task compared to control. Taping also significantly reduced the internal rotation moment (0.07 Nm/kg, P = 0.025), and medial shear forces (0.14 N/kg, P = 0.012) in the rebound task. CONCLUSION: Results of the study suggest that ankle taping restrict ankle range of movement in the rebound task only and ankle taping appears to have upstream effects on the knee, which may have injury implications.

Cancer cachexia associates with a systemic autophagy-inducing activity mimicked by cancer cell-derived IL-6 trans-signaling.

The majority of cancer patients with advanced disease experience weight loss, including loss of lean body mass. Severe weight loss is characteristic for cancer cachexia, a condition that significantly impairs functional status and survival. The underlying causes of cachexia are incompletely understood, and currently no therapeutic approach can completely reverse the condition. Autophagy coordinates lysosomal destruction of cytosolic constituents and is systemically induced by starvation. We hypothesized that starvation-mimicking signaling compounds secreted from tumor cells may cause a systemic acceleration of autophagy during cachexia. We found that IL-6 secreted by tumor cells accelerates autophagy in myotubes when complexed with soluble IL-6 receptor (trans-signaling). In lung cancer patients, were cachexia is prevalent, there was a significant correlation between elevated IL-6 expression in the tumor and poor prognosis of the patients. We found evidence for an autophagy-inducing bioactivity in serum from cancer patients and that this is clearly associated with weight loss. Importantly, the autophagy-inducing bioactivity was reduced by interference with IL-6 trans-signaling. Together, our findings suggest that IL-6 trans-signaling may be targeted in cancer cachexia.

New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss.

BACKGROUND: Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/- computerized tomography-defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype METHODS: A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform. RESULTS: Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle-specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05). CONCLUSIONS: The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro-inflammatory cytokines and the renin-angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients.

BACKGROUND: In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients. METHODS: One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time-polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), ß-dystroglycan (n = 52), and ß-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581-1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively. RESULTS: Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. ß-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008). CONCLUSIONS: The present study has identified intramuscular protein level of ß-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.

Programmed cell death 6 interacting protein (PDCD6IP) and Rabenosyn-5 (ZFYVE20) are potential urinary biomarkers for upper gastrointestinal cancer.

PURPOSE: Cancer of the upper digestive tract (uGI) is a major contributor to cancer-related death worldwide. Due to a rise in occurrence, together with poor survival rates and a lack of diagnostic or prognostic clinical assays, there is a clear need to establish molecular biomarkers. EXPERIMENTAL DESIGN: Initial assessment was performed on urine samples from 60 control and 60 uGI cancer patients using MS to establish a peak pattern or fingerprint model, which was validated by a further set of 59 samples. RESULTS: We detected 86 cluster peaks by MS above frequency and detection thresholds. Statistical testing and model building resulted in a peak profiling model of five relevant peaks with 88% overall sensitivity and 91% specificity, and overall correctness of 90%. High-resolution MS of 40 samples in the 2-10 kDa range resulted in 646 identified proteins, and pattern matching identified four of the five model peaks within significant parameters, namely programmed cell death 6 interacting protein (PDCD6IP/Alix/AIP1), Rabenosyn-5 (ZFYVE20), protein S100A8, and protein S100A9, of which the first two were validated by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE: We demonstrate that MS analysis of human urine can identify lead biomarker candidates in uGI cancers, which makes this technique potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.

Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI Cancer Cachexia.

PURPOSE: Skeletal muscle wasting and weight loss are characteristic features of cancer cachexia and contribute to impaired function, increased morbidity, and poor tolerance of chemotherapy. This study used a novel technique to measure habitual myofibrillar protein synthesis in patients with cancer compared with healthy controls. EXPERIMENTAL DESIGN: An oral heavy water (87.5 g deuterium oxide) tracer was administered as a single dose. Serum samples were taken over the subsequent week followed by a quadriceps muscle biopsy. Deuterium enrichment was measured in body water, serum alanine, and alanine in the myofibrillar component of muscle using gas chromatography-pyrolysis-isotope ratio mass spectrometry and the protein synthesis rate calculated from the rate of tracer incorporation. Net change in muscle mass over the preceding 3 months was calculated from serial CT scans and allowed estimation of protein breakdown. RESULTS: Seven healthy volunteers, 6 weight-stable, and 7 weight-losing (≥5% weight loss) patients undergoing surgery for upper gastrointestinal cancer were recruited. Serial CT scans were available in 10 patients, who lost skeletal muscle mass preoperatively at a rate of 5.6%/100 days. Myofibrillar protein fractional synthetic rate was 0.058%, 0.061%, and 0.073%/hour in controls, weight-stable, and weight-losing patients, respectively. Weight-losing patients had higher synthetic rates than controls (P = 0.03). CONCLUSION: Contrary to previous studies, there was no evidence of suppression of myofibrillar protein synthesis in patients with cancer cachexia. Our finding implies a small increase in muscle breakdown may account for muscle wasting.

Clinical classification of cancer cachexia: phenotypic correlates in human skeletal muscle.

BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with a reduction in treatment tolerance, response to therapy, and duration of survival. One impediment towards the effective treatment of cachexia is a validated classification system. METHODS: 41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and/or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10%WL, LM, and LM+>2%WL. All patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, Western blots for markers of autophagy, SMAD signalling, and inflammation. FINDINGS: Compared with non-cachectic cancer patients, patients with LM or LM+>2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either >5%WL or LM+>2%WL. Compared with non-cachectic patients, SMAD3 protein levels were increased in patients with >5%WL (p = 0.022) and with >10%WL, beclin (p = 0.05) and ATG5 (p = 0.01) protein levels were increased. There were no differences in phospho-NFkB or phospho-STAT3 levels across any of the groups. CONCLUSION: Muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the diagnostic criteria for cachexia are based on weight loss alone, a measure of low muscularity alone or a combination of the two. For intervention trials where the primary end-point is a change in muscle mass or function, use of combined diagnostic criteria may allow identification of a more homogeneous patient cohort, reduce the sample size required and enhance the time scale within which trials can be conducted.

The Human Urinary Proteome Fingerprint Database UPdb.

The use of human urine as a diagnostic tool has many advantages, such as ease of sample acquisition and noninvasiveness. However, the discovery of novel biomarkers, as well as biomarker patterns, in urine is hindered mainly by a lack of comparable datasets. To fill this gap, we assembled a new urinary fingerprint database. Here, we report the establishment of a human urinary proteomic fingerprint database using urine from 200 individuals analysed by SELDI-TOF (surface enhanced laser desorption ionisation-time of flight) mass spectrometry (MS) on several chip surfaces (SEND, HP50, NP20, Q10, CM10, and IMAC30). The database currently lists 2490 unique peaks/ion species from 1172 nonredundant SELDI analyses in the mass range of 1500 to 150000. All unprocessed mass spectrometric scans are available as ".xml" data files. Additionally, 1384 peaks were included from external studies using CE (capillary electrophoresis)-MS, MALDI (matrix assisted laser desorption/ionisation), and CE-MALDI hybrids. We propose to use this platform as a global resource to share and exchange primary data derived from MS analyses in urinary research.

Muscle protein kinetics in cancer cachexia.

PURPOSE OF REVIEW: Skeletal muscle loss appears to be the most significant event in cancer cachexia and is associated with a poor outcome. The balance between mechanisms that control synthesis and degradation is fundamental when designing new therapies. This review aims to highlight the molecular mechanisms that are associated with protein kinetics. RECENT FINDINGS: The mechanisms that promote muscle synthesis have been explored in detail recently but moreover they have been the mechanisms behind degradation. Specific advances in cellular signalling molecules related to autophagy pathways including signal transducer and activators of transcription-3, activin type-2 receptor, TRAF6, and transcriptomic research have been given special attention in this review to highlight their roles in degradation and as potential targets for therapeutics. Ways to quantify muscle loss are badly needed for outcome measures; recent research using radiolabelled amino acids has also been discussed in this review. SUMMARY: Only by having an appreciation of the complex regulation of muscle protein synthesis and degradation, will potential new therapeutics be able to be developed. This review identifies known targets in molecular pathways of current interest, explores methods used to find novel genes which may be involved in muscle kinetics and also highlights ways in which muscle kinetics may be measured to assess the efficacy of such interventions.

Intrahepatic choledochoscopy during trans-cystic common bile duct exploration; technique, feasibility and value.

BACKGROUND: Transcystic laparoscopic common bile duct exploration (TC-LCBDE) is advantageous for exploring the bile duct. Choledochoscopy, however, may be quite challenging to perform transcystically because the cystic duct is usually narrow, duct anatomy may be unfavorable, and not all stones are amenable to transcystic extraction. Convention suggests that it is technically very difficult to visualize the intrahepatic bile ducts with transcystic choledochoscopy, due to the angle of insertion of the cystic into the common bile duct (CBD). However, we have performed intrahepatic choledochoscopy successfully, moving the choledochoscope from the CBD into the common hepatic duct by using what we have termed a "wiper blade maneuver". The purpose of this study was to confirm how often this was possible. METHODS: A search of a prospectively collected database of patients undergoing routine intraoperative cholangiography (IOC) and laparoscopic CBD exploration under the care of a single consultant surgeon was performed. RESULTS: A total of 592 LCBDEs were performed between September 1992 and January 2011; 325 were transcystic explorations. Of these, 72.5 % were female and 56 % were admitted acutely. Exploration and duct clearance was performed by blind Dormia basket trawling in 63 %. The choledochoscope was utilized in 120 cases (37 %). The 3-mm choledochoscope was used in 66 (55 %) and the 5-mm scope in 54 (45 %). Intrahepatic choledochoscopy was performed in 49 patients (40.8 %). Length of surgery was 40-350 min (median 90 min; standard deviation 49 min). CONCLUSIONS: It is technically challenging to perform intrahepatic choledochoscopy with a 3-mm choledochoscope due to its narrow gauge. The more rigid 5-mm scope is thus preferred, but is limited in TCE because its effective use depends on the presence of a dilated cystic duct. Despite the technical limitations of both caliber scopes, we have demonstrated that intrahepatic choledochoscopy during TCE is possible, with each, in 40 % of cases.

Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies.

PURPOSE: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies. EXPERIMENTAL DESIGN: Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post-resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12). RESULTS: Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow-up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation. CONCLUSIONS: Metabolic and protein turnover-related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity.