Surgical strategy in lithium-associated hyperparathyroidism: A population-based study.

BACKGROUND: The extent of parathyroidectomy (PTX) recommendation in patients with lithium-associated hyperparathyroidism (LAH) remains controversial. The primary objectives of this study were to analyze extent of surgery, complications, and long-term outcomes. METHODS: A population-based study, including all primary hyperparathyroidism (PHPT) patients who underwent PTX in Sweden between 2008 and 2017. Data on exhibited lithium prescriptions, morbidity, surgical approach, and outcomes were collected from relevant national registers and the Scandinavian Quality Register of Thyroid, Parathyroid, and Adrenal Surgery. Patients with lithium exposure before PTX were defined as having LAH. Descriptive summary statistics and regression models were used to evaluate differences in comorbidities, surgical approach, and outcomes between LAH and PHPT not exposed to lithium (non-LAH). RESULTS: Lithium exposure was significantly more common among PHPT (n = 202, 2.3%) than in controls (n = 416, 0.5%); OR 5.0 (95% CI 4.2-5.9). The risk of LAH correlated to the length of lithium exposure. In the LAH-group, the surgical procedures were more extensive and associated with a higher risk of postoperative bleeding, wound infections, persistent hypercalcemia, and hypocalcemia that remained after adjustment for the higher percentage of multiglandular disease. However, the cumulative risk of re-admission for PHPT was similar the first years after PTX and primarily elevated for patients with >5 years duration of lithium exposure prior to surgery. CONCLUSIONS: The findings support the perception of LAH as a complex entity. We recommend a functionally oriented approach, aimed to obtain and maintain normocalcemia for as long as possible, minimizing the risk of permanent hypoparathyroidism, and accepting some risk of recurrence.

Neuropsychiatric Comorbidity in Primary Hyperparathyroidism Before and After Parathyroidectomy: A Population Study.

BACKGROUND: Primary hyperparathyroidism (PHPT) is often accompanied by neuropsychiatric symptoms. This study aimed to map out psychiatric comorbidity as reflected by medical treatment for psychiatric symptoms. METHODS: A retrospective case-control analysis and a prospective cohort analysis of psychotropic drug utilization before and after PTX. A total of 8279 PHPT patients treated with parathyroidectomy in Sweden between July 1, 2008 and December 31, 2017 compared to a matched control cohort from the total population (n = 82,790). Information on filled prescriptions was collected from the Swedish Prescribed Drug Register (SDR). Socioeconomic data and diagnoses were added by linkage to national patient and population registers. Regression analyses were used to calculate relative drug utilization (OR) within 3 years prior to PTX and relative incidence of drug treatment (RR) within 3 years postoperatively. RESULTS: Utilization of antidepressant, anxiolytic and sleep medication was more comprehensive in PHPT patients compared with the controls prior to PTX. The most common were benzodiazepines [OR 1.40 (95% CI: 1.31-1.50)] and selective serotonin reuptake inhibitors [SSRI; OR 1.38 (95% CI: 1.30-1.47)]. Postoperatively, the excess prescription rate for anxiolytic benzodiazepines decreased within three years from a 30 to 19% excess and for benzodiazepines for sleep from 31 to 14%. No corresponding decrease in excess prescription rate was observed for SSRI. CONCLUSION: PHPT is associated with increased utilization of antidepressive medications and benzodiazepines before PTX. This study implies that psychiatric symptoms should be considered in PHPT patients and continuous medication should be reevaluated after PTX.

Increased risk for tooth extraction in primary hyperparathyroidism and hypercalcemia: a population study.

The aim of this study was to analyze dental comorbidities in untreated primary hyperparathyroidism (pHPT). Patients with pHPT subjected to parathyroidectomy (PTX) at Karolinska University Hospital, Stockholm, during 2011-2016 (n = 982) were selected from the Scandinavian Quality Register of Thyroid, Parathyroid and Adrenal surgery and compared to a general population cohort (n = 2944), matched for age and gender. Dental data was obtained from the Swedish Dental Health Registry for the 3 years prior to PTX. The incidence rate ratios (IRRs) of tooth loss by extraction, periodontal interventions, and dental visit rate were analyzed by Poisson regression models. In order to analyze the impact of disease severity, the PHPT cohort was sub-grouped based on preoperative serum levels of ionized calcium (S-Ca2+). The total number of tooth extractions, periodontal interventions, and number of visits were similar in the cohorts. PHPT patients belonging to the quartile with the highest S-Ca2+ (≥ 1.51 mmol/L) had increased risk for tooth extraction (IRR 1.85; 95% CI 1.39-2.46). Female gender independently amplified the risk (IRR 1.341, P < 0.027). This study indicates an association between pHPT and oral disorders reflected by increased tooth loss by extraction related to high S-Ca2. Increased awareness of dental comorbidity in primary hyperparathyroidism may benefit a large group of patients with a common disease through earlier detection and prevention.

Primary hyperparathyroidism: should surgery be performed on all patients? Current evidence and residual uncertainties.

Primary hyperparathyroidism (pHPT) is the third most common endocrine disease and is characterized by hypercalcaemia and elevated or inappropriately 'normal' levels of the parathyroid hormone (PTH). The main target organs of PTH are the skeletal system and the kidneys. Before the 1970s, pHPT was a rarely detected disease associated with notable morbidity and premature mortality. Introduction of biochemical screening, allowing for a wide range of indications, has contributed to the detection of the full spectrum of the disease. A new entity with an isolated elevation of PTH, normocalcaemic HP, has emerged and is currently being explored. The highest incidence of pHPT, 3-5%, is observed amongst women, and the prevalence increases with age. The female-to-male ratio is 3-4 : 1 except in younger patients where distribution is equal and known hereditary causes account for approximately 10% of the cases. In the last few decades, it has become evident that fewer patients than previously believed are truly asymptomatic. The cause of pHPT is often a benign tumour, a parathyroid adenoma, and the only definite treatment is parathyroidectomy (PTX). No medical treatment, single or combined, can achieve a curing of pHPT. Recent data indicate that PTX, despite being proven to be cost-effective compared to conservative treatment, is underutilized, especially in elderly pHPT patients. The decision of PTX should always be based on a safe diagnosis, and the potential benefits of curative treatment should not be outweighed by the risks of surgery or anaesthesia.

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy.

BACKGROUND: Primary hyperparathyroidism is often associated with non-disease-specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short-term medical treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision-making. METHODS: This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30-60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ-C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed-stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test. RESULTS: The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality-of-life parameters. The time spent on the timed-stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74-96 per cent). CONCLUSION: The method described in this study may be used to aid surgical decision-making for patients with primary hyperparathyroidism and non-disease-specific symptoms by predicting the effects of normalization of hypercalcaemia.

ANTECEDENTES: El hiperparatiroidismo primario (pHPT) a menudo se asocia con síntomas no específicos de la enfermedad. El objetivo de este estudio fue evaluar si la normalización de la hipercalcemia a corto plazo con tratamiento médico se podría usar para predecir los efectos de la paratiroidectomía y guiar la toma de decisiones quirúrgicas. MÉTODOS: Estudio observacional (ClinicalTrials.gov, registro NCT02227264) que incluyó 110 pacientes programados para paratiroidectomía (mediana de edad 62 años; 91 mujeres). Intervención: tratamiento calcimimético, cuatro semanas, 30-60 mg al día. Medidas de resultado: Un panel de pruebas para evaluar los aspectos de la calidad de vida (cuestionario de calidad de vida core 30, QLQ-C30; escala hospitalaria de ansiedad y depresión (HAD) y estado mental positivo (PSOM); función cognitiva (evaluación cognitiva de Montreal, MoCa) y fuerza muscular (Timed-Stands Test, TST). Las pruebas se realizaron cuatro veces: al inicio del estudio (basal), después de cuatro semanas de tratamiento calcimimético, a las seis semanas y seis meses después de la paratiroidectomía. Para cada prueba se determinaron los valores predictivos de los cambios durante el tratamiento calcimimético. RESULTADOS: El tratamiento con fármacos calcimiméticos determinó una normalización en los niveles de calcio y una mejoría en los parámetros de calidad de vida. El tiempo del TST se redujo significativamente. Once de los 38 participantes con una puntuación MoCa basal < 26, definida como deterioro cognitivo leve, alcanzaron puntuaciones ≥ 26 durante el uso de la medicación. Las mejoras observadas durante el tratamiento mostraron una buena correlación con el resultado postoperatorio (valores predictivos positivos 74-96%). CONCLUSIÓN: Este estudio presenta un método basado en la predicción de los efectos de la normalización de la hipercalcemia para ayudar en la toma de decisiones quirúrgicas en pacientes con pHPT y síntomas no específicos de la enfermedad.

Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.

AIMS: To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. METHODS: We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. RESULTS: Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12-week reductions in albuminuria compared with placebo: -33.2% [95% confidence interval (CI) -45.4, -18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: -23.5% (95% CI -37.6, -6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal-related adverse events were observed in any group. CONCLUSIONS: Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin-angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin-induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long-term renal and cardiovascular risk.

Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease.

AIM: To evaluate the long-term efficacy, safety and tolerability of dapagliflozin versus placebo added to usual care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). METHODS: Data were pooled from two phase III studies (NCT01031680 and NCT01042977) in high-risk patients (N = 1887) with T2DM and CVD treated with dapagliflozin (10 mg/day) or placebo. Patients completing the double-blind treatment studies (24 weeks) entered one or two sequential double-blind, long-term (LT) extensions of 28 (LT1; n = 1649) and 52 (LT2; n = 568) weeks. RESULTS: Baseline and CVD characteristics were similar in the two groups. Patients entering LT1 and LT2 on dapagliflozin maintained a greater mean reduction in glycated haemoglobin (HbA1c) versus placebo at 52 weeks [LT1, -0.58% (95% confidence interval -0.68, -0.49)] and 104 weeks [LT2, -0.35% (95% confidence interval -0.59, -0.12)]. Mean body weight and systolic blood pressure (SBP) reductions versus placebo were maintained in patients entering LT1 (52 weeks; -2.23 kg and -3.25 mmHg, respectively) and LT2 (104 weeks; -3.16 kg and -2.03 mmHg, respectively). Patients on dapagliflozin had a better three-item composite endpoint of clinical benefit (glycaemia, weight and SBP) compared with placebo at week 24 (LT1, 10.1% vs. 1.1%) and week 104 (LT2, 6.7% vs. 1.4%). Genital and urinary tract infections were more frequent with dapagliflozin than with placebo. Events of hypoglycaemia, renal impairment/failure and volume depletion were similar between groups. CONCLUSIONS: The long-term efficacy of dapagliflozin to maintain reductions in HbA1c, SBP and body weight over 2 years, together with its tolerability profile, make dapagliflozin an appropriate option in high-risk patients with T2DM and CVD.

Prevalence of temporomandibular disorder pain in Chinese adolescents compared to an age-matched Swedish population.

This study aimed to (i) assess the prevalence and perceived need for treatment of TMD pain, and its association with socio-economic factors and gender, in adolescents in Xiá¾½an, Shaanxi Province, China, and (ii) compare the prevalence and association with gender of TMD pain in Xiá¾½an to an age-matched Swedish population. We surveyed Chinese adolescents aged 15 to 19 years in Xi'an, China (n = 5524), using a questionnaire with two-stage stratified sampling and the school as the sampling unit. The study included second-year students at selected high schools. It also included an age-matched Swedish population (n = 17,015) surveyed using the same diagnostic criteria for TMD pain as that used in the Chinese sample. The survey found TMD pain in 14·8% (n = 817) of the Chinese sample and 5·1% (n = 871) of the Swedish sample (P < 0·0001). Girls had significantly more TMD pain than boys in both the Chinese (P < 0·05) and Swedish (P < 0·001) samples. TMD pain increased with age in the Chinese population. Of the Chinese adolescents with TMD pain, 47% reported that they felt a need for treatment. Rural schools, low paternal education levels, poverty, living outside the home, poor general and oral health, and dissatisfaction with teeth all showed significant positive correlations with TMD pain. Prevalence of TMD pain in Chinese adolescents was significantly higher than in the Swedish sample.

Prebiotic preferences of human lactobacilli strains in co-culture with bifidobacteria and antimicrobial activity against Clostridium difficile.

AIM: To evaluate robustness, prebiotic utilization of Lactobacillus paracasei F8 and Lactobacillus plantarum F44 in mono- and co-cultures with Bifidobacterium breve 46 and Bifidobacterium animalis sub sp. lactis 8 : 8 and antimicrobial activity of co-culture against Clostridium difficile. METHODS AND RESULTS: The two Lactobacillus strains showed a high acid and bile tolerance. Lactobacillus plantarum F44 showed maximum growth in de Man Rogosa Sharpe basal broth with glucose and lactulose compared to growth in galacto-oligosaccharides (GOS) and isomalto-oligosaccharides (IMOS). In co-culture system, the amylolytic Bif. breve 46 stimulated the growth of a nonamylolytic Lact. paracasei F8, probably by producing intermediate metabolites of starch metabolism. A higher growth of four strains Lact. paracasei F8, Lact. plantarum F44, Bif. breve 46 and Bif. animalis ssp lactis 8 : 8 with different prebiotic combinations was found in a MRSC basal broth with SS (soluble starch) + IMOS + GOS and IMOS + GOS respectively. The two Lactobacillus strains exhibited a high antimicrobial activity against four clinical Cl. difficile strains and a hypervirulent NAP1/027strain and suppressed the toxin titres possibly through the production of organic acids and heat stable antimicrobial proteins when grown on glucose and through the production of acids when grown on prebiotics. Culture supernatants from synbiotic combinations inhibited the growth of the Cl. difficile NAP1/027 strain and its toxin titres. CONCLUSION: Lactobacillus paracasei F8, Lact. plantarum F44 exhibited potential probiotic properties. Further, the two Lactobacillus and two bifidobacteria strains were compatible with each other and exhibited high growth in co-cultures in presence of prebiotics and SS and antimicrobial activity against clinical Cl. difficile strains and a hypervirulent NAPI/027 strain. SIGNIFICANCE AND IMPACT OF THE STUDY: Results are promising for the development of a multi-strain synergistic synbiotic supplement for protection against Cl. difficile infection.

Occupational engagement among community dwelling older people: A time-geographic perspective†.

How older people spend their time in different occupations could contribute to our understanding of everyday life in healthy ageing. This study adopted a time-geographic method and occupational perspective to explore the occupational engagement of community dwelling older people. The term occupational engagement encompasses what people do, where and with whom they spend their time and the perceived level of competence and meaningfulness of their time use. Nineteen volunteers born between 1932 and 1933, living alone in an urban area in northern Sweden and receiving no home care services, completed open time-geographic diaries for 5 days in May 2010. The diary data were analyzed using Daily Life software program. The study revealed the complexity and the diversity of the older people's occupational engagement and that most of their time was spent alone in their home. The older people reported they were very good at doing almost half of the occupations in which they engaged and that their occupations were primarily either very meaningful or meaningful. While some methodological limitations were identified, time-geographic studies of community dwelling older people living independently are considered to have potential to contribute to community and social planning for older people as they can provide interesting insights to older persons' time use and occupational needs.

Differences in activities of daily living (ADL) abilities of children across world regions: a validity study of the assessment of motor and process skills.

BACKGROUND: One important goal of paediatric occupational therapy services is to improve activities of daily living (ADL) abilities of children. In order to plan and evaluate the effectiveness of targeted interventions, valid assessments are critically needed. The Assessment of Motor and Process Skills (AMPS) is an internationally standardized assessment of ADL performance that has not been validated for use with children in Middle Europe. AIM: To evaluate for (i) significant differences in mean ADL motor and mean ADL process ability measures among children from Middle Europe compared with children from North America, UK/Republic of Ireland, Nordic countries, Western Europe, Australia/New Zealand and Asia; and (ii) meaningful differences between the international age-normative means of the AMPS and those for children from Middle Europe. METHOD: We analysed data of children across world regions extracted from the international AMPS database using many-facet Rasch and two-way anova analyses and by estimating contrasts to evaluate for significant group differences. RESULTS: anova analyses of data for 11 189 children ages 2-15 revealed significant effects for mean ADL motor and ADL process ability by region [F ≥ 15.32, d.f. = (6, 11 091), MSE ≥ 0.20, P < 0.001, ή(2) ≥ 0.008], and age [F ≥ 253.47, d.f. = (13, 11 091), MSE ≥ 0.20, P < 0.001, ή(2) ≥ 0.229], and a significant interaction effect for mean ADL process ability [F = 1.48, d.f. = (78, 11 091), P = 0.004, ή(2) = 0.010]. Out of 168 estimated contrasts between Middle Europe and the other world regions for mean ADL motor and ADL process ability, seven were statistically significant (4.17%), but none exceeded ±1SE from the international means. CONCLUSION: The AMPS remains free of relevant differences in mean ADL ability measures between Middle Europe and other world regions, indicating that the international age-normative mean values are likely to be applicable to children from Middle Europe. The AMPS can be used internationally to evaluate ADL performance in children and to determine if the child is eligible for occupational therapy services.

Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment.

AIM: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. METHODS: In this multicentre, randomized, parallel-group, double-blind, placebo-controlled study, patients with glycated haemoglobin (HbA1c) 7-11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end-stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end-point) was analysed using an analysis of covariance model with last observation carried forward methodology. RESULTS: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was -0.42% (95% confidence interval: -0.71 to -0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate (-0.64 vs. -0.05%) and severe (-0.95 vs. -0.50%) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end-stage renal disease on haemodialysis (-0.84 vs. -0.87%). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. CONCLUSIONS: Saxagliptin 2.5 mg once daily is a well-tolerated treatment option for patients with inadequately controlled T2DM and renal impairment.

Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis.

Unmethylated CpG motifs are often found in bacterial DNA, and exert immunostimulatory effects on hematopoietic cells. Bacteria produce severe joint inflammation in septic and reactive arthritides; bacterial DNA may be involved in this process. We injected bacterial DNA originating from Escherichia coli and Staphylococcus aureus and oligonucleotides containing CpG directly into the knee joints of mice of different strains. Arthritis was seen by histopathology within 2 hours and lasted for at least 14 days. Unmethylated CpG motifs were responsible for this induction of arthritis, as oligonucleotides containing these motifs produced the arthritis. The arthritis was characterized by an influx of monocytic, Mac-1+ cells and by a lack of T lymphocytes. Depletion of monocytes resulted in abrogation of the synovial inflammation. Tumor necrosis factor (TNF)-alpha, a cytokine produced by cells of the monocyte/macrophage lineage, is an important mediator of this disease, as expression of mRNA for TNF-alpha was evident in the inflamed joints, and the CpG-mediated inflammation was abrogated in mice genetically unable to produce this cytokine. These findings demonstrate that bacterial DNA containing unmethylated CpG motifs induces arthritis, and indicate an important pathogenic role for bacterial DNA in septic arthritis.

Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study.

OBJECTIVE: Therapeutic options are limited for diabetes patients with renal disease. This report presents 52-week results from a study assessing the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus (T2DM) and renal impairment. DESIGN: Double-blind study in patients stratified by baseline renal impairment (moderate, severe or end-stage renal disease [ESRD] on haemodialysis) randomised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline, including insulin. PATIENTS: A total of 170 adults with glycated haemoglobin (HbA(1c) ) 7-11% and creatinine clearance < 50 ml/min or ESRD were randomised and treated. MEASUREMENTS: Absolute changes in HbA(1c) and fasting plasma glucose (FPG) from baseline to week 52 were evaluated using analysis of covariance (ANCOVA) with last observation carried forward. Repeated-measures analyses were also performed. RESULTS: Adjusted mean decrease in HbA(1c) was greater with saxagliptin than placebo (difference, -0.73%, p < 0.001 [ANCOVA]). Reductions in adjusted mean HbA(1c) were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate (-0.94% vs. 0.19% respectively) or severe (-0.81% vs. -0.49%), but similar to placebo for those with ESRD (-1.13% vs. -0.99%). Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment. Saxagliptin was generally well tolerated; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events (28% and 29% respectively). CONCLUSIONS: Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment.

Prediction of cognitive response to surgery in elderly patients with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) can be associated with potentially reversible cognitive impairment, which is occasionally mistaken for natural ageing and dementia. The aim was to evaluate short-term medical normalization of hypercalcaemia in surgical decision-making for elderly patients with mild cognitive deficiency. METHODS: Patients with pHPT were included in a prospective observational study. A test panel including the Montreal Cognitive Assessment (MoCA) and validated tools for estimation of psychological status (Hospital Anxiety and Depression Scale, HADS), and muscle strength (timed-stands test, TST) was applied at baseline, after 4 weeks of calcimimetic treatment, and after parathyroidectomy. Mild cognitive impairment was defined by a MoCA score below 26. A longitudinal increase in MoCA score of at least 2 points 6 months after surgery was considered clinically meaningful. RESULTS: Of 110 patients who underwent testing, 35 aged 50 years or more were identified to have mild cognitive dysfunction, including 19 who were aged at least 70 years (median MoCA score 23, i.q.r. 21-24). Calcimimetic treatment resulted in normalization of calcium levels, and improvements in MoCA and HADS scores, and TST time. Normal MoCA scores (at least 26) were reached in 17 patients by 6 months after surgery, of whom 10 were aged 70 years or older. Long-term increase in MoCA score correlated with the decrease in ionized calcium concentration (r = -0.536, P = 0.022). Baseline calcium concentration and improvement in MoCA with calcimimetic treatment were identified as independent predictors of favourable outcome after parathyroidectomy. CONCLUSION: Medical normalization of hypercalcaemia can aid in predicting outcome after parathyroidectomy.

Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial.

AIM: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS AND PATIENTS: A total of 858 patients [age ≥ 18 years; glycated haemoglobin (HbA(1c) ) > 6.5 - 10.0%; on stable metformin doses ≥ 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < 0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < 0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (∼4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia.

The COOH-terminal ends of internal signal and signal-anchor sequences are positioned differently in the ER translocase.

Signal peptides (SPs) target proteins to the secretory pathway and are cleaved from the nascent chain once the translocase in the ER has been engaged. Signal-anchor (SA) sequences also interact transiently with the ER translocase, but are not cleaved and move laterally out of the translocase to become permanent membrane anchors. One obvious difference between SP and SA sequences is the considerably longer hydrophobic regions (h regions) of the latter. To study the interaction between SP/SA sequences and the ER translocase, we have constructed signal sequences with poly-Leu h regions ranging in length from 8 to 29 residues and have characterized their locations within the translocase using both a new assay that measures the minimum number of amino acids needed to span the distance between the COOH-terminal end of the h region and the active site of the oligosaccharyl transferase enzyme and an assay where the efficiency of signal peptidase catalyzed cleavage is measured. Our results suggest that SP and SA sequences are positioned differently in the ER translocase.