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Key Takeaways: Strategic planning for pipe renewal and replacement (R&R) is key to saving money, maintaining high‐quality service to customers, and preventing catastrophic infrastructure failures. A proactive capital improvement plan involves condition assessment, risk analysis, project prioritization, and creation of an R&R schedule, giving priority to pipes most in need. Scenario analysis using a powerful simulation model provides a systemwide forecast that is instrumental in planning, budgeting, and making the most of utility assets. [ABSTRACT FROM AUTHOR]

B Conclusion: b Our results show that a high level of the M2 macrophage marker sCD163 is a negative prognostic factor in MCL, both in the chemoimmunotherapy and the ibrutinib/lenalidomide eras. B Introduction: b The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed towards the tumor immune microenvironment, where macrophages play an important role. [Extracted from the article]

Background: Limited information is available on the genetic and environmental contributions to early AD pathology. Within a sample of cognitively unimpaired genetically identical older twins we aimed to assess 1) effects of amyloid‐ß pathology on [18F]flortaucipir (tau) binding and 2) spatial similarities in tau patterns within twin pairs. Method: To date, ten twin pairs (i.e. twenty twins) from the on‐going EMIF‐AD PreclinAD study underwent dynamic (0‐30min and 80‐100min) [18F]flortaucipir PET. Two twin pairs were concordant amyloid‐ß positive, four twin pairs concordant amyloid‐ß negative and four twin pairs amyloid‐ß discordant (i.e. one twin positive and co‐twin negative) based on [18F]flutemetamol visual read. [18F]flortaucipir binding potential (BPND) images were generated using receptor parametric mapping (reference region: cerebellar gray matter). First, we compared [18F]flortaucipir BPND in an early (entorhinal), intermediate (limbic) and late (neocortical) stage tau pathology region between amyloid‐ß positive and negative twins using generalized estimated equation correcting for twin dependency. Next, we examined spatial tau pattern similarities within twin pairs by correlating (Spearman) [18F]flortaucipir BPND across 46 ROIs from the Hammers template between each twin and their co‐twin for each true twin pair. Correlations were also performed for all non‐twin "random" pairs. Correlation coefficients within true twin pairs were compared to the correlation coefficients within random pairs, correcting for age and twin amyloid‐ß status. Results: Amyloid‐ß positive twins showed higher [18F]flortaucipir BPND in entorhinal (p=0.01) and limbic (p=0.04) regions(Table‐1). Fig‐1 shows representative [18F]flortaucipir images of an amyloid‐ß concordant positive, concordant negative and discordant pair, with regional similarities observed in amyloid‐ß concordant pairs as well as dissimilarities in amyloid‐ß discordant pairs (Fig‐1;Fig‐2). Between‐twin correlations across regional [18F]flortaucipir BPND, to assess spatial tau pattern similarities, were higher for true twin pairs (r=0.71±0.17) compared to random pairs (r=0.45±0.23) (p=0.002)(Table‐2). Conclusion: In line with previous studies, amyloid‐ß positive cognitively unimpaired twins showed higher tau deposition in early and intermediate tau stage regions. Furthermore, we observed higher spatial tau pattern similarities within true twin pairs compared to random pairs, suggesting a moderate genetic contribution to mechanisms underlying tau spread. With the upcoming larger sample we aim to further assess genetic and environmental contributions to early AD pathology. [ABSTRACT FROM AUTHOR]

Background: Tau accumulation starts during the preclinical phase of Alzheimer’s disease (AD) and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin‐pairs may give insight into genetic and environmental contributions to tau accumulation. Therefore, we assessed within‐pair similarities in 1) levels of tau and 2) spatial distribution of tau, within a sample of cognitively intact genetically identical twins. Method: Fifty‐four identical twins (27 pairs) from the EMIF‐AD PreclinAD cohort underwent dynamic dual time‐point (0‐30min and 80‐100min) [18F]flortaucipir‐PET. Binding potential (BPND) (reference region: cerebellar gray) was extracted for entorhinal (Braak‐I), temporal (Braak‐III‐IV), neocortical (Braak‐V‐VI) and global (Braak‐I‐VI) regions. Additionally, for voxel‐by‐voxel analyses, PET‐images were normalized to MNI‐space. Within twin‐pair similarities in global and regional levels of [18F]flortaucipir BPND were calculated using intra‐class correlations () and compared to correlations estimated for 20 sets of 27 random (non‐twin) pairs. To examine within‐pair similarities in [18F]flortaucipir spatial distribution, each participant’s voxel‐by‐voxel [18F]flortaucipir spatial distribution was correlated to that of every other participant (). A t‐test was performed to assess whether twin‐pairs showed higher correlation coefficients (i.e. more similar spatial distribution) compared to random pairs. Result: Demographics are summarized in. Visual inspection of [18F]flortaucipir‐PET revealed both similarities and dissimilarities within pairs (). Global [18F]flortaucipir BPND was significantly correlated within pairs (r=0.46; p=0.01). Regionally, twin‐pair correlations for [18F]flortaucipir BPND was strongest in the entorhinal region (r=0.61; p<0.01), and non‐significant in the temporal region (). The correlation coefficient observed for twin‐pairs exceeded the range of correlation coefficients observed for random pairs for the entorhinal, neocortical and global region (). Examination of within‐pair similarities in voxel‐by‐voxel [18F]flortaucipir distribution showed that the correlations were higher for twin‐pairs (mean r=0.57; SD=0.06) than for random pairs (mean r=0.38; SD=0.10) (p<0.01) (). Conclusion: Genetically identical twin‐pairs show substantial similarities in levels and spatial distribution of tau, suggesting genetic factors to play an important role. However, clear visual dissimilarities were also observed, indicating a role for non‐genetic factors as well. Unravelling mechanisms underlying within‐pair differences may aid in the development of preventive strategies for AD. [ABSTRACT FROM AUTHOR]

We examined insulin antibody formation in patients with type 1 ( T1D) or type 2 diabetes ( T2D) treated with once-daily insulin degludec ( IDeg) or insulin glargine ( IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin ( HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity ( B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event ( AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs. [ABSTRACT FROM AUTHOR]

Aims To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine ( LY IGlar) and Lantus® insulin glargine ( IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus ( T1DM or T2DM). Methods To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM ( N = 535) and T2DM ( N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response ( TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. Results No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward ( LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint ( LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. Conclusions LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes. [ABSTRACT FROM AUTHOR]

Background: Dynamic [18F]flortaucipir PET imaging allows for more accurate quantification of specific binding compared to static imaging in Alzheimer’s disease (AD). Besides, with dynamic imaging flow is taken into account, which is especially important in longitudinal studies, because disease progression or drug intervention may lead to flow changes. We aimed to compare semi‐quantitative (SUVr) and quantitative (BPND) parameters for [18F]flortaucipir PET in a longitudinal study. Method: We included subjects with subjective cognitive decline (SCD; n=38) and AD patients (n=24). All subjects underwent baseline (BL) and 2‐year follow‐up (FU) dynamic [18F]flortaucipir PET. BPND and R1 (relative cerebral blood flow) were calculated (RPM; reference region cerebellar gray). SUVr was derived 80‐100 min p.i.. (Trans)entorhinal, limbic and neocortical regions‐of‐interest (ROIs) were assessed. For each parameter %change was calculated (100*(FU‐BL)/BL). Regional SUVr was compared against respective DVR (BPND+1) using paired T‐tests. Additionally, simulations were performed to model effects of flow changes on BPND and SUVr in high, medium or low binding categories. For each category, R1 values were varied to mimic 5‐25% increase or decrease in flow. Thereafter, %bias for SUVr with respect to underlying binding and its association with respect to change in flow were evaluated. Result: In SCD, there was a significant difference between %change in DVR (2.56%) and SUVr (1.85%) in the (trans)entorhinal ROI (p<0.05) only. In AD, differences in %change were found in the limbic ROI (DVR 6.61% vs. SUVr 7.52%; p<0.05) only. R1 changes were small (+0.7% in SCD and ‐1.6% in AD). Simulations showed varying %bias in SUVr depending on underlying binding. With increasing flow a decreased bias in low binding conditions was observed, whereas in high binding conditions an increased bias was seen. DVR remained relatively stable under different flow conditions, irrespective of underlying binding. Conclusion: Compared to BPND, SUVr provided a good estimate of specific binding for [18F]flortaucipir over a two‐year follow‐up. However, simulations showed that [18F]flortaucipir SUVr is subject to variable bias in case of larger flow changes, which seemed to be depending on underlying tau load. Therefore, BPND should be preferred over SUVr, especially in the context of pharmacotherapeutic interventions that could induce significant changes in flow. [ABSTRACT FROM AUTHOR]

Aims To compare the efficacy and safety of LY2963016 insulin glargine ( LY IGlar) and the reference product ( Lantus®) insulin glargine ( IGlar) in combination with oral antihyperglycaemic medications in patients with type 2 diabetes ( T2D). Methods This phase III, randomized, double-blind, 24-week study enrolled patients with T2D who were insulin-naïve [glycated haemoglobin ( HbA1c) ≥7 and ≤11.0%] or previously on IGlar ( HbA1c ≤11%) and treated with ≥2 oral antihyperglycaemic medications. Patients were randomized to receive once-daily LY IGlar (n = 376) or IGlar (n = 380) for 24 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar, as measured by change in HbA1c from baseline to 24 weeks. Results Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met non-inferiority criteria compared with IGlar for change in HbA1c from baseline [−1.29 vs −1.34%; respectively, least-squares mean difference 0.052% (95% confidence interval −0.070 to 0.175); p > 0.05]. There were no treatment differences (p > 0.05) in fasting plasma glucose, proportion of patients reaching HbA1c <7% or insulin dose at 24 weeks. Adverse events, allergic reactions, weight change, hypoglycaemia and insulin antibodies were similar between treatment groups. Similar findings were observed in patients who were insulin-naïve or previously treated with IGlar at baseline. Conclusions Both LY IGlar and IGlar, when used in combination with oral antihyperglycaemic medications, provided effective and similar glucose control with similar safety profiles in patients with T2D. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes ( T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment. [ABSTRACT FROM AUTHOR]

Nitrogen (N) use in intensive agriculture can degrade groundwater resources. However, considerable time lags between groundwater recharge and extraction complicate source attribution and remedial responses. We construct a historic N mass balance of two agricultural regions of California to understand trends and drivers of past and present N loading to groundwater (1945-2005). Changes in groundwater N loading result from historic changes in three factors: the extent of agriculture (cropland area and livestock herd increased 120 and 800%, respectively), the intensity of agriculture (synthetic and manure waste effluent N input rates increased by 525 and 1500%, respectively), and the efficiency of agriculture (crop and milk production per unit of N input increased by 25 and 19%, respectively). The net consequence has been a greater-than-order-of-magnitude increase in nitrate (NO3-) loading over the time period, with 163 Gg N yr-1 now being leached to groundwater from approximately 1.3 million ha of farmland (not including alfalfa [Medicago sativa L.]). Meeting safe drinking water standards would require NO3- leaching reductions of over 70% from current levels through reductions in excess manure applications, which accounts for nearly half of all groundwater N loading, and through synthetic N management improvements. This represents a broad challenge given current economic and technical conditions of California farming if farm productivity is to be maintained. The findings illustrate the growing tension--characteristic of agricultural regions globally--between intensifying food, feed, fiber, and biofuel production and preserving clean water. [ABSTRACT FROM AUTHOR]

Aims Weight gain upon insulin initiation is opposite to clinical goals in diabetes management. This trial aimed to determine the impact of modest dietary intervention on weight change and examine weight change in baseline body mass index strata when initiating once-daily insulin detemir ( IDet) in overweight or obese insulin-naïve individuals with type 2 diabetes (T2D). Methods DIET (Impact of Dietary Intervention on Weight Change in Subjects With Type 2 Diabetes) was a 26-week, randomized, treat-to-target, stratified, controlled, open-label, multinational trial. Subjects were randomized 1 : 1 to either the IDet group, which received basic dietary and physical exercise advice at baseline, or the Diet+ IDet group, which had additional dietary consultations with a certified dietician (three face-to-face meetings, three phone contacts). Results Mean estimated change in body weight from baseline ± standard error ( SE) was −1.05 ± 0.23 kg for Diet+ IDet and −0.56 ± 0.23 kg for IDet alone. Estimated mean difference was 0.49 kg (95% confidence interval: −0.15; 1.13, p = 0.132). Glycaemic control, measured by haemoglobin A1c ( HbA1c) and fasting plasma glucose, improved similarly in both groups. Both groups reported variable reductions in caloric intake and overall physical activity levels. No difference in hypoglycaemia rates between groups was observed. Conclusion This study suggests that a modest dietary intervention plus basic lifestyle advice, compared with basic lifestyle advice alone, resulted in similar weight change, efficacy, safety and tolerability when initiating IDet once daily in overweight or obese insulin-naïve individuals with T2D. [ABSTRACT FROM AUTHOR]

Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2 DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2 DM. Methods Patients ( N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose ( FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52). Results HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event ( AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo. Conclusions Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2 DM patients on metformin plus sulphonylurea over 52 weeks. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims This study assessed the efficacy and safety of once-daily insulin initiation using insulin detemir (detemir) or insulin glargine (glargine) added to existing metformin in type 2 diabetes ( T2D). Methods This 26-week, multinational, randomized, treat-to-target trial involved 457 insulin-naïve adults with T2D ( HbA1c 7-9%). Detemir or glargine was added to current metformin therapy [any second oral antidiabetic drug ( OAD) discontinued] and titrated to a target fasting plasma glucose ( FPG) ≤90 mg/dl (≤5.0 mmol/l). Primary efficacy endpoint was change in HbA1c. Results Mean (s.d.) HbA1c decreased with detemir and glargine by 0.48 and 0.74%-points, respectively, to 7.48% (0.91%) and 7.13% (0.72%) [estimated between-treatment difference, 0.30 (95% CI: 0.14-0.46)]. Non-inferiority for detemir at the a priori level of 0.4%-points was not established. The proportions of patients reaching HbA1c ≤ 7% at 26 weeks were 38% and 53% (p = 0.026) with detemir and glargine, respectively. FPG decreased ∼43.2 mg/dl (∼2.4 mmol/l) in both groups [non-significant (NS)]. Treatment satisfaction was good for both insulins. Hypoglycaemia, which occurred infrequently, was observed less with detemir than glargine [rate ratio 0.73 (95% CI 0.54-0.98)]. The proportions of patients reaching HbA1c ≤ 7% without hypoglycaemia in the detemir and glargine groups were 32% and 38% ( NS), respectively. Weight decreased with detemir [−0.49 (3.3) kg] and increased with glargine [+1.0 (3.1) kg] (95% CI for difference: −2.17 to −0.89 kg). Conclusion While both detemir and glargine, when added to metformin therapy, improved glycaemic control, glargine resulted in greater reductions in HbA1c, while detemir demonstrated less weight gain and hypoglycaemia. [ABSTRACT FROM AUTHOR]

The aim of this trial was to evaluate the efficacy and safety of the combination of once-daily insulin detemir (IDet) and sitagliptin (SITA) versus SITA ± sulphonylurea (SU), both in combination with metformin (MET) in insulin-naive subjects. In a 26-week, open-label, randomized, parallel-group study in type 2 diabetes, insulin-naive subjects concomitantly treated with MET ± second oral antidiabetic drug (OAD) were randomized 1 : 1 to IDet + SITA + MET or SITA + MET ± SU. All continued with MET treatment, and those treated with SU continued if randomized to SITA + MET ± SU. Efficacy endpoints included glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), 9-point self-measured plasma glucose (SMPG), weight, body mass index (BMI). Safety endpoints included adverse events (AEs) and hypoglycaemia. Significantly higher reductions in HbA1c, FPG and SMPG were achieved with IDet + SITA + MET compared with SITA + MET ± SU. Estimated HbA1c decreased by 1.44% in the IDet + SITA + MET group versus 0.89% in SITA + MET ± SU, p < 0.001. FPG decreased by 3.7 mmol/l (66.3 mg/dl) versus 1.2 mmol/l (22.2 mg/dl), p < 0.001, respectively. Small decreases in weight and BMI were observed in both arms, with no significant differences. AEs were mild or moderate and were more common in the SITA + MET ± SU arm than in the IDet + SITA + MET arm. There was no major hypoglycaemia. Observed rates of hypoglycaemia were very low (1.3/1.7 episodes/patient year) in both arms. The subgroup treated with MET and SUs prior to the trial achieved similar results. The combination of once-daily IDet with SITA showed a clinically and significantly better improvement in glycaemic control than SITA in combination with or without SUs. Both regimens were associated with a low rate of hypoglycaemia and slight weight reduction. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM). Methods: This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages ≥ 18 and ≤ 75 years) with a BMI ≥ 27 kg/m2 and ≤ 43 kg/m2 and HbA1c ≥7.0 and ≤ 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (≥ 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints. Results: In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were −2.5, −3.7, −4.5 and −5.1 kg at Week 36 and −2.4, −4.0, −4.6 and −5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost ≥ 5 and ≥ 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were −0.40, −0.47, −0.68 and −0.71% at Week 36 and −0.30, −0.43, −0.65 and −0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group. Conclusions: After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity. [ABSTRACT FROM AUTHOR]

Abstract: Background: Few comparative studies exist of metabolic brain changes among neurodegenerative illnesses. We compared brain metabolic abnormalities in Alzheimer''s disease (AD) and in Parkinson''s disease with dementia (PDD) as measured by proton magnetic resonance spectroscopy (MRS). Methods: Twelve patients with idiopathic PDD, 22 patients with probable mild AD, and 61 healthy older controls underwent posterior cingulate MRS. Results: Patients with AD exhibited reduced N-acetyl aspartate (NAA)/creatine (Cr) (P < .05) and increased choline (Cho)/Cr (P < .05) and myo-inositol (mI)/Cr (P < .01) compared with controls. Patients with PDD exhibited reduced NAA/Cr (P < .05) and glutamate (Glu)/Cr (P < .01) compared with controls. There was reduced Glu/Cr in PDD compared with AD (P < .01). Conclusions: Patients with AD and patients with PDD exhibited distinct brain metabolic MRS profiles. Findings suggest that comparison of brain MRS profiles across dementias provides useful direction for future study. [Copyright &y& Elsevier]

Two long-term, randomized, double-blind, placebo-controlled clinical trials in insulin-using patients with type 2 diabetes, spanning a wide range of baseline glycaemic control, have shown that the addition of pramlintide, an analogue of the β-cell hormone amylin, to pre-existing insulin regimens results in reductions in HbA1c that are accompanied by weight loss. To assess whether this profile of pramlintide is observed in patients approaching, but not yet reaching, glycaemic targets, we conducted a pooled post hoc analysis of the two trials, including all patients with an entry HbA1c between 7.0 and 8.5%. Within this subset of patients, 80 were treated with placebo + insulin [baseline HbA1c 8.0 ± 0.3%, weight 87.3 ± 19.3 kg (mean ± s.d.)] and 86 with pramlintide (120 µg bid) + insulin [HbA1c 8.0 ± 0.4%, weight 92.5 ± 20.4 kg (mean ± s.d.)]. Endpoints included changes from baseline to Week 26 in HbA1c, body weight, and the event rate of severe hypoglycaemia. Adjunctive therapy with pramlintide resulted in significant reductions in both HbA1c and body weight from baseline to Week 26 (−0.43% and −2.0 kg differences from placebo, respectively, both p < 0.001). These changes were achieved without a concomitant increase in the overall rate of severe hypoglycaemic events (0.13 pramlintide vs. 0.19 placebo, events/patient year of exposure). The data from this post hoc analysis indicate that the addition of pramlintide to insulin therapy may help patients with type 2 diabetes who are approaching, but not yet reaching, glycaemic targets to achieve further reductions in HbA1c without concomitant weight gain and increased risk of severe hypoglycaemia. [ABSTRACT FROM AUTHOR]

A new method of evoked response detection, previously demonstrated in the ventricle, has been studied in the atrium at the time of routine pacemaker implant in 16 patients. The atrial evoked response was readily detectable in all patients due to excellent recovery from poststimulus polarization. In six patients, as experimental threshold-tracking pacemaker was used to automatically verify atrial capture and to generate strength-duration curves. It is concluded that this pacing technique is both simple and reliable, and that automatic atrial threshold tracking is feasible [ABSTRACT FROM AUTHOR]

Discusses the use of matched whole-blood transfusions in patients affected with pemphigus. Etiology of the condition; Symptoms that may arise during the administration of matched whole blood.

A case of 35-year-old female patient has been reported who has developed contact dermatitis on her face, hands and feet. It started after using jogging cream to prevent blisters during walking trips. Her only known allergy was to penicillin, which she had not taken recently. Patch tests showed positive reaction to jogging cream after 48 and 72 hours. Jogging cream has been reportedly containing arnica compound, which is used in physiotherapy and chemotherapy for the treatment of hemorrhage and other effects of injury. Allergy to arnica is not rare.

The glycoprotein CD47 regulates antiphagocytic activity via signal regulatory protein alpha (SIRPa). This study investigated CD47 expression on Hodgkin and Reed-Sternberg (HRS) cells in the classical Hodgkin lymphoma (cHL) tumour microenvironment and its correlation with prognosis, programmed-death (PD) immune markers, and SIRPa + leukocytes. We conducted immunohistochemistry with CD47 and SIRPa antibodies on diagnostic biopsies (tissue microarrays) from cHL patients from two cohorts (n = 178). In cohort I (n = 136) patients with high expression of CD47 on HRS cells (n = 48) had a significantly inferior event-free survival [hazard ratio (HR) = 5.57; 95% confidence interval (CI), 2.78-11.20; p < 0.001] and overall survival (OS) (HR = 8.54; 95% CI, 3.19-22.90; p < 0.001) compared with patients with low expression (n = 88). The survival results remained statistically significant in multivariable Cox regression adjusted for known prognostic factors. In cohort II (n = 42) high HRS cell CD47 expression also carried shorter event-free survival (EFS) (HR = 5.96; 95% CI, 1.20-29.59; p = 0.029) and OS (HR = 5.61; 95% CI, 0.58-54.15; p = 0.136), although it did not retain statistical significance in the multivariable analysis. Further, high CD47 expression did not correlate with SIRPa + leukocytes or PD-1, PD-L1 and PD-L2 expression. This study provides a deeper understanding of the role of CD47 in cHL during an era of emerging CD47 therapies., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoma where associations with viral hepatitis and autoimmune and inflammatory diseases (AID) have been indicated. We aimed at assessing the prevalence of viral hepatitis and AID at SMZL diagnosis and outcome by treatment in a Swedish population-based study. A total of 277 SMZL patients registered in the Swedish Lymphoma Register in 2007-2017 were included. A history of viral hepatitis was reported in five (2%) patients and AID prior to SMZL in 72/240 (30%) patients. Treatment was given up front for 207 (75%) patients. Splenectomy with or without systemic treatment was performed in 119 (57%) and was associated with statistically significantly better overall survival [hazard ratio, HR = 0·47 (95% confidence interval, CI: 0·23-0·93), P = 0·03] and progression-free survival (HR = 0·55, 95% CI: 0·35-0·86, P = 0·008) compared to non-splenectomised patients in multivariable analyses. The up-front splenectomised group was younger and generally had a lower Ann Arbor stage, but also more frequently B symptoms and high lactate dehydrogenase than the non-splenectomised group. Viral hepatitis and AID history did not affect SMZL outcome. We report high incidence of AIDs and low incidence of viral hepatitis in this population-based study of SMZL. Splenectomy up front was associated with a favourable outcome., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3 + T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1·97, 95% confidence interval (CI) 1·18-3·25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163 + cells (continuously, HR 1·51, 95% CI 1·03-2·23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3 + cells (HR 3·22, 95% CI 1·40-7·43) and CD163 + cells (HR 6·09, 95% CI 1·84-20·21), independent of sex and MIPI. When combined a higher frequency of CD163 + macrophages and PD-L1 + cells or high CD163 + macrophages and FoxP3 + regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Background: The prevalence of dyslipidaemia and the risk of cardiovascular disease are elevated in patients with type 2 diabetes. This analysis compared the effects of insulin glargine versus thiazolidinediones (TZDs) on lipid profiles., Methods: Patient-level data were pooled from two randomized clinical studies. The population included 552 men and women aged >18 years, diagnosed with type 2 diabetes for at least 6 months, on metformin and/or sulphonylurea, and with A(1C) ≥7.5% and <12.0% at screening. Lipid outcome measures included change from baseline in lipid levels [low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, triglycerides, and free fatty acids] and attainment of lipid goals for LDL-C, non-HDL-C, and triglycerides., Results: Both insulin glargine and TZDs improved lipid profiles from baseline values. Compared with TZDs, treatment with insulin glargine led to 7.9% greater reduction in LDL-C (p < 0.0003), 7.5% greater reduction in non-HDL-C (p < 0.0001), and 7.8% greater reduction in total cholesterol (p < 0.0001), whereas the HDL-C increase with TZD was 7.6% greater than that with insulin glargine (p < 0.0001). The percentage of patients attaining the lipid goals was comparable between insulin glargine and pioglitazone, but lower for rosiglitazone. Insulin glargine improved glycaemic control more than TZDs; however, insulin glargine caused more hypoglycaemia. Treatment with TZDs caused more weight gain and peripheral oedema., Conclusion: These findings suggest that the favourable effects of insulin glargine on plasma lipid profiles should be considered among the advantages of treatment with insulin glargine as they are for TZDs., (Copyright © 2011 John Wiley & Sons, Ltd.)