Cognitive, psychological and social factors associated with older adults' mobility: a scoping review of self-report and performance-based measures.

Although many factors have been associated with mobility among older adults, there is paucity of research that explores the complexity of factors that influence mobility. This review aims to synthesise the available evidence for factors comprising the cognitive, psychological, and social mobility determinants and their associations with mobility self-reported and performance-based outcomes in older adults (60 years). We followed Arksey and O'Malley's five stages of a scoping review and searched PubMed, EMBASE, PsychINFO, Web of Science, AgeLine, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Sociological Abstract databases. Reviewers in pairs independently conducted title, abstract, full-text screening and data extraction. We reported associations by analyses rather than articles because articles reported multiple associations for factors and several mobility outcomes. Associations were categorised as significantly positive, negative, or not significant. We included 183 peer-reviewed articles published in 27 countries, most of which were cross-sectional studies and conducted among community-dwelling older adults. The 183 articles reported 630 analyses, of which 381 (60.5%) were significantly associated with mobility outcomes in the expected direction. For example, older adults with higher cognitive functioning such as better executive functioning had better mobility outcomes (e.g., faster gait speed), and those with poor psychological outcomes, such as depressive symptoms, or social outcomes such as reduced social network, had poorer mobility outcomes (e.g., slower gait speed) compared to their counterparts. Studies exploring the association between cognitive factors, personality (a psychological factor) and self-reported mobility outcomes (e.g., walking for transportation or driving), and social factors and performance-based mobility outcomes in older adults are limited. Understanding the additive relationships between cognitive, psychological, and social factors highlights the complexity of older adults' mobility across different forms of mobility, including independence, use of assistive devices, transportation, and driving.

Multiple Endocrine Neoplasia Type 1 (MEN1) 5'UTR Deletion, in MEN1 Family, Decreases Menin Expression.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic and pituitary tumors, and is due to mutations in the coding region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumors. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesized that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from five family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides -1087 and -492 upstream of the translation start site, located within the MEN1 5' untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5'UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumor BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p < 0.0001) and 16-fold (p < 0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5'UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p < 0.05) and 88% (p < 0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5'UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Reducing hospital mortality: Incremental change informed by structured mortality review is effective.

Hospital mortality rates have frequently been improved by identifying diagnostic groups with high mortality and targeting interventions to those specific groups. We found that high residual inpatient mortality persisted after targeted measures had achieved an initial reduction, and that the causes were spread across a wide range of diagnostic groups. Further interventions were put in place consisting of a structured electronic mortality form and systematised mortality scrutiny and reporting (primary intervention) accompanied by a number of quality improvement interventions arising from the mortality analysis (secondary interventions). We found that those interventions were associated with progressive improvements in mortality rates and average lengths of inpatient stay over the 5-year study period. Winter quarter mortality improvements reached a high level of statistical significance but could not be attributed to changes in any particular diagnostic groups. We conclude that progress with mortality improvements is probably best achieved by applying both code-targeted and general interventions simultaneously.

Cyclical Cushing's: how best to catch the ups and downs.

A 68-year-old man with a background of hypertension and type 2 diabetes presented with fluctuating symptoms of muscle aches and pains and tiredness. His initial work-up for the possibility of hypercortisolaemia showed a completely variable pattern, with 24-hour cortisol excretion and serum cortisol post 1 mg dexamethasone suppression test ranging from normal to significantly elevated. A series of salivary cortisol with symptom diary confirmed the cyclical nature of hypercortisolaemia, and his concomitant adrenocorticotropic hormone (ACTH) levels were elevated. An inferior petrosal sinus sampling, performed during hypercortisolaemic phase of his cycle,suggested a central source of ACTH secretion. He had unsuccessful exploration of his pituitary and was eventually treated with bilateral adrenalectomy followed by lifelong steroid replacement. His symptoms improved immediately, and he came off his oral hypoglycaemic and antihypertensive agents within 6 months following his surgery.

Fever of unknown origin in a patient initially presenting with traveller's diarrhoea.

A 17-year-old male presented with diarrhoea and malaise following his return from Kenya and Tunisia. He was managed as a case of traveller's diarrhoea. Stool cultures were negative for pathogenic bacterial growth. Two weeks later he presented with worsening lower back pain. MRI of lumbosacral spine suggested L1 osteomyelitis. CT-guided spinal aspirate grew no organisms and repeat viral serology and blood cultures (including tuberculosis screening) were negative. He was treated with a 6-week course of ceftriaxone. Back pain did not improve and a repeat MRI scan 8 weeks after his antibiotic course indicated progressive changes in L1 extending to L2 with an intradiscal abscess. Repeat CT-guided spinal aspirate grew Salmonella arizonae sensitive to cotrimoxazole and ceftriaxone. He was treated with intravenous ceftriaxone and cotrimoxazole for 12 weeks. A 4-month follow-up MRI scan showed progressive improvement of the L1/L2 discitis with resolution of intradiscal fluid.

A Follow-Up Study of the Prevalence of Valvular Heart Abnormalities in Hyperprolactinemic Patients Treated With Cabergoline.

CONTEXT: Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate. OBJECTIVE: Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used. DESIGN: Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group. SETTING: Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included. RESULTS: There were 192 patients (81 males; median age, 51 years; interquartile range [IQR], 42-62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20-377) and 232 mg (91-551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24-42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.

Proton pump inhibitor associated hypomagnasaemia - a cause for concern?

AIMS: In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. METHODS: To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. RESULTS: For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. CONCLUSION: We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Compartment syndrome: an unusual complication of influenza A infection.

This case report discusses a 43-year-old man who presented with 4-limb compartment syndrome secondary to influenza A myositis. We describe the clinical features that were present and the course of this unusual complication. We review the clinical features central to early diagnosis and treatment of compartment syndrome in order to increase awareness of this potentially life-threatening complication.

Addison's Disease Presenting with Abdominal Pain.

Primary Adrenal Insufficiency is due to bilateral destruction of the adrenal cortex and has a prevalence of approximately 40-60 per million adults.1 The commonest cause is autoimmune.1 Prompt treatment not only restores quality of life but also a normal life expectancy.2 Here we present an unusual case of primary adrenal insufficiency, which illustrates how such an important disease often provides a diagnostic conundrum.

Influence of caffeine on frequency of hypoglycemia detected by continuous interstitial glucose monitoring system in patients with long-standing type 1 diabetes.

OBJECTIVE: The aim of this study was to investigate the effect of caffeine (in doses equivalent to normal daily ingestion) on rates and severity of hypoglycemia in patients with long-standing type 1 diabetes to determine the relationship between caffeine, autonomic function, and hypoglycemia. RESEARCH DESIGN AND METHODS: Using a double-blinded randomized study, we investigated the effect of caffeine versus placebo in 19 patients with long-standing type 1 diabetes using continuous glucose sensing technology and simultaneous assessment of autonomic function using Holter monitoring. RESULTS: Caffeine reduced the duration of nocturnal hypoglycemia with a mean duration of 49 minutes (range 0-235) versus 132 (0-468) minutes (P = 0.035). The reduction in duration of nighttime hypoglycemia was due to a decline in the number of episodes of moderate hypoglycemia at the expense of mild hypoglycemic episodes (P = 0.04). There was no overall correlation between reduced heart rate variability (a marker of autonomic dysfunction) and hypoglycemic events (r(s) = 0.12, P = 0.62). CONCLUSIONS: Our results suggest that caffeine is associated with a significant reduction in nocturnal hypoglycemia. The reduction in nocturnal hypoglycemia was not linked to the concomitant rise in parasympathetic activity associated with caffeine.

Influence of caffeine on heart rate variability in patients with long-standing type 1 diabetes.

OBJECTIVE: The effect of caffeine on cardiovascular health remains controversial. Patients with long-standing type 1 diabetes are at risk of autonomic failure and sudden cardiac death. We investigated the effects of caffeine on autonomic dysfunction (as assessed by heart rate variability [HRV]) in this high-risk group and in a control population. RESEARCH DESIGN AND METHODS: Using a randomized blinded, placebo-controlled, crossover design trial, we examined 2 weeks of caffeine consumption (250 mg twice daily) on HRV in 20 type 1 diabetic patients and 10 matched healthy volunteers. RESULTS: Baseline HRV was blunted in the diabetic patients (P < 0.0005 vs. control subjects) and markedly increased by caffeine in both groups (+103% in the group with diabetes [P = 0.009] and +38% in control subjects [P = 0.002]). The caffeine-associated increase in HRV was not statistically different between the control and the type 1 diabetes groups (P = 0.16). CONCLUSIONS: Modest amounts of caffeine improved autonomic function in diabetic patients and healthy volunteers. For individuals with abnormal HRV, regular caffeine use may have the potential to reduce the risk of cardiovascular events.

Skin-related complications of insulin therapy: epidemiology and emerging management strategies.

The incidence and prevalence of all types of diabetes mellitus is increasing at an alarming rate. Modern therapy involves greater and earlier use of intensive insulin regimens in order to achieve better control of blood glucose levels and reduce the long-term risks associated with the condition. Insulin therapy is associated with important cutaneous adverse effects, which can affect insulin absorption kinetics causing glycemic excursions above and below target levels for blood glucose. Common complications of subcutaneous insulin injection include lipoatrophy and lipohypertrophy. The development of lipoatrophy may have an immunological basis, predisposed by lipolytic components of certain insulins. Repeated use of the same injection site increases the risk of lipoatrophy--with time, patients learn that these areas are relatively pain free and continue to use them. However, the absorption of insulin from lipoatrophic areas is erratic leading to frequent difficulties in achieving ideal blood glucose control. With the increasing use of modified, rapidly absorbed analog insulins (e.g. insulin lispro, insulin aspart) the incidence of lipoatrophy occurring has decreased over recent years. The likelihood of lipoatrophy can be reduced by regular rotation of injection sites but once developed, practical benefits may be obtained by insulin injection into the edge of the area, co-administration of dexamethasone with insulin, or changing the mode of insulin delivery. Lipohypertrophy is the most common cutaneous complication of insulin therapy. Newer insulins have also reduced its prevalence considerably, although its adverse effect on diabetic control is similar to lipoatrophy through impaired absorption of insulin into the systemic circulation. Experience with liposuction at these sites is limited, although good cosmetic results have been achieved. Local allergic reactions to insulin are usually erythema, pruritus, and induration. These allergic reactions are usually short-lived, and resolve spontaneously within a few weeks. Useful adjuncts to managing allergic reactions include addition of dexamethasone to the insulin injection, desensitization to insulin, or a change in delivery system utilizing insulin pump therapy or potentially inhaled insulins when these become available. The use of insulin pump therapy in managing cutaneous complications of insulin therapy is increasing, but this method itself carries risks of abscess formation and scarring. Fortunately, with improved education of patients these are relatively uncommon. Although many of the cutaneous manifestations are decreasing with the use of newer insulins, they may still influence glycemic control and increase the risk of hypoglycemia as well as have a cosmetic impact on a patient. The introduction of novel therapies and newer delivery systems is likely to reduce the cutaneous problems associated with long-term insulin use.