Significantly reduced incidence and improved survival from prostate cancer over 25 years.

BACKGROUND: Prostate cancer (PCa) was the second most frequent cancer and the fifth leading cause of cancer death among men in 2020. The aim of this study was to analyze trends in the incidence, mortality and survival of PCa in Girona, Spain, over 25 years. METHODS: Population-based study of PCa collected in the Girona Cancer Registry, 1994-2018. Age-adjusted incidence and mortality rates were calculated per 100,000 men-year. Joinpoint regression models were used for trends, calculating the annual percentage changes (APC). Observed and net survival were analyzed using Kaplan-Meier and Pohar-Perme estimations, respectively. RESULTS: A total of 9,846 cases of PCa were registered between 1994-2018. The age-adjusted incidence and mortality rates were 154.7 (95%CI: 151.7 157.8) and 38.9 (95%CI: 37.3 -40.6), respectively. An increased incidence of 6.2% was observed from 1994 to 2003 (95%CI: 4.4 -8.1), and a decrease of -2.7% (95%CI: -3.5 -;-1.9) between 2003 and 2018. Mortality APC was -2.6% (95%CI: -3.3 --2.0). Five-year observed and net survival were 72.8% (95%CI: 71.8 - 73.7) and 87.2% (95%CI: 85.9 - 88.4), respectively. Five-year net survival increased over time from 72.9% (1994-1998) to 91.3% (2014-2018). CONCLUSIONS: The analyses show a clear reduction in PCa incidence rates from 2003 on, along with an increase in overall survival when comparing the earlier period with more recent years.

A Compact Raster Lensless Microscope Based on a Microdisplay.

Lensless microscopy requires the simplest possible configuration, as it uses only a light source, the sample and an image sensor. The smallest practical microscope is demonstrated here. In contrast to standard lensless microscopy, the object is located near the lighting source. Raster optical microscopy is applied by using a single-pixel detector and a microdisplay. Maximum resolution relies on reduced LED size and the position of the sample respect the microdisplay. Contrarily to other sort of digital lensless holographic microscopes, light backpropagation is not required to reconstruct the images of the sample. In a mm-high microscope, resolutions down to 800 nm have been demonstrated even when measuring with detectors as large as 138 µm × 138 µm, with field of view given by the display size. Dedicated technology would shorten measuring time.

Pursuing the Diffraction Limit with Nano-LED Scanning Transmission Optical Microscopy.

Recent research into miniaturized illumination sources has prompted the development of alternative microscopy techniques. Although they are still being explored, emerging nano-light-emitting-diode (nano-LED) technologies show promise in approaching the optical resolution limit in a more feasible manner. This work presents the exploration of their capabilities with two different prototypes. In the first version, a resolution of less than 1 µm was shown thanks to a prototype based on an optically downscaled LED using an LED scanning transmission optical microscopy (STOM) technique. This research demonstrates how this technique can be used to improve STOM images by oversampling the acquisition. The second STOM-based microscope was fabricated with a 200 nm GaN LED. This demonstrates the possibilities for the miniaturization of on-chip-based microscopes.

Pre-contrast CT attenuation of the thyroid gland is lower in brachycephalic dogs versus non-brachycephalic dogs.

Computed tomography has been used in human medicine to evaluate the thyroid gland functional status by means of Hounsfield units (HU). Studies describing attenuation value abnormalities, other than those in thyroid neoplasia, lack in veterinary medicine. The authors have observed a subjective reduction in thyroid attenuation in some patients undergoing CT for reasons other than thyroid disease. This finding has been identified more frequently in brachycephalic breeds compared to non-brachycephalic breeds. In order to determine the thyroid gland attenuation variability on CT, a retrospective and prospective, analytical, cross-sectional study was performed. The thyroid attenuation values of 65 client-owned dogs were assessed using a 16-slice helical CT scanner. Differences in attenuation between brachycephalic and non-brachycephalic dogs were estimated by Welch's t-test. Serum TT4 and TSH levels were available in 26 patients. Statistically significant differences were observed in the pre-contrast attenuation value ranges between brachycephalic and non-brachycephalic dogs (P = .04). The pre-contrast attenuation value range for the brachycephalic group was 69.1-108 HU while being 75.8-121 HU for the non-brachycephalic group. No significant correlation was found between thyroid attenuation and serum thyroid hormone levels in our population (P > .6). All patients with hypoattenuating thyroid were brachycephalic and reported euthyroid. In conclusion, brachycephalic dogs seem to have a pre-contrast attenuation thyroid gland range lower than non-brachycephalic dogs. The present study contributes to the veterinary literature by providing a new thyroid attenuation value range for brachycephalic breeds. Additionally, hypoattenuating thyroid glands may be found in dogs with normal TT4 and TSH values.

Nano illumination microscopy: a technique based on scanning with an array of individually addressable nanoLEDs.

In lensless microscopy, spatial resolution is usually provided by the pixel density of current digital cameras, which are reaching a hard-to-surpass pixel size / resolution limit over 1 µm. As an alternative, the dependence of the resolving power can be moved from the detector to the light sources, offering a new kind of lensless microscopy setups. The use of continuously scaled-down Light-Emitting Diode (LED) arrays to scan the sample allows resolutions on order of the LED size, giving rise to compact and low-cost microscopes without mechanical scanners or optical accessories. In this paper, we present the operation principle of this new approach to lensless microscopy, with simulations that demonstrate the possibility to use it for super-resolution, as well as a first prototype. This proof-of-concept setup integrates an 8 × 8 array of LEDs, each 5 × 5 µm2 pixel size and 10 µm pitch, and an optical detector. We characterize the system using Electron-Beam Lithography (EBL) pattern. Our prototype validates the imaging principle and opens the way to improve resolution by further miniaturizing the light sources.

Effects of a polysaccharide-rich extract derived from Irish-sourced Laminaria digitata on the composition and metabolic activity of the human gut microbiota using an in vitro colonic model.

BACKGROUND: Brown seaweeds are known to be a rich source of fiber with the presence of several non-digestible polysaccharides including laminarin, fucoidan and alginate. These individual polysaccharides have previously been shown to favorably alter the gut microbiota composition and activity albeit the effect of the collective brown seaweed fiber component on the microbiota remains to be determined. METHODS: This study investigated the effect of a crude polysaccharide-rich extract obtained from Laminaria digitata (CE) and a depolymerized CE extract (DE) on the gut microbiota composition and metabolism using an in vitro fecal batch culture model though metagenomic compositional analysis using 16S rRNA FLX amplicon pyrosequencing and short-chain fatty acid (SCFA) analysis using GC-FID. RESULTS: Selective culture analysis showed no significant changes in cultured lactobacilli or bifidobacteria between the CE or DE and the cellulose-negative control at any time point measured (0, 5, 10, 24, 36, 48 h). Following metagenomic analysis, the CE and DE significantly altered the relative abundance of several families including Lachnospiraceae and genera including Streptococcus, Ruminococcus and Parabacteroides of human fecal bacterial populations in comparison to cellulose after 24 h. The concentrations of acetic acid, propionic acid, butyric acid and total SCFA were significantly higher for both the CE and DE compared to cellulose after 10, 24, 36 and 48 h fermentation (p < 0.05). Furthermore, the acetate:propionate ratio was significantly reduced (p < 0.05) for both CD and DE following 24, 36 and 48 h fermentation. CONCLUSION: The microbiota-associated metabolic and compositional changes noted provide initial indication of putative beneficial health benefits of L. digitata in vitro; however, research is needed to clarify if L. digitata-derived fiber can favorably alter the gut microbiota and confer health benefits in vivo.

A Point-of-Care Device for Molecular Diagnosis Based on CMOS SPAD Detectors with Integrated Microfluidics.

We describe the integration of techniques and technologies to develop a Point-of-Care for molecular diagnosis PoC-MD, based on a fluorescence lifetime measurement. Our PoC-MD is a low-cost, simple, fast, and easy-to-use general-purpose platform, aimed at carrying out fast diagnostics test through label detection of a variety of biomarkers. It is based on a 1-D array of 10 ultra-sensitive Single-Photon Avalanche Diode (SPAD) detectors made in a 0.18 µm High-Voltage Complementary Metal Oxide Semiconductor (HV-CMOS) technology. A custom microfluidic polydimethylsiloxane cartridge to insert the sample is straightforwardly positioned on top of the SPAD array without any alignment procedure with the SPAD array. Moreover, the proximity between the sample and the gate-operated SPAD sensor makes unnecessary any lens or optical filters to detect the fluorescence for long lifetime fluorescent dyes, such as quantum dots. Additionally, the use of a low-cost laser diode as pulsed excitation source and a Field-Programmable Gate Array (FPGA) to implement the control and processing electronics, makes the device flexible and easy to adapt to the target label molecule by only changing the laser diode. Using this device, reliable and sensitive real-time proof-of-concept fluorescence lifetime measurement of quantum dot QdotTM 605 streptavidin conjugate is demonstrated.

The effect of consuming Palmaria palmata-enriched bread on inflammatory markers, antioxidant status, lipid profile and thyroid function in a randomised placebo-controlled intervention trial in healthy adults.

PURPOSE: Palmaria palmata (P. Palmata) is reported to contain anti-inflammatory and antioxidant compounds albeit no study has investigated these effects in humans. METHODS: A randomised parallel placebo-controlled human intervention study was carried out to investigate the effect of consuming P. Palmata (5 g/day) incorporated into a bread on serum markers of inflammation [C-reactive protein (CRP); cytokine analysis] with secondary analysis investigating changes in lipids (cholesterol, triglycerides), thyroid function [thyroid-stimulating hormone (TSH)] and antioxidant status ferric reducing antioxidant power. ANCOVA with baseline values as covariates, controlling for age, BMI, sex and smoking status, was used to compare differences between treatment groups over time . In vitro studies investigated the inflammatory activity of P. Palmata extracts (hot water, cold water and ethanol extract), protein extracts and associated protein hydrolysates using a Caco-2 inflammation cell model. RESULTS: Consumption of P. Palmata-enriched bread significantly increased serum CRP (+16.1 %, P = 0.011), triglycerides (+31.9 %, P = 0.001) and TSH (+17.2 %, P = 0.017) when compared to the control group. In vitro evaluation of P. palmata extracts and protein hydrolysates identified a significant induction of IL-8 secretion by Caco-2 cells, and the hot water P. palmata extract was shown to increase adipocyte glycerol release (P < 0.05). CONCLUSION: Evidence from this human study suggests that P. palmata stimulates inflammation, increases serum triglycerides and alters thyroid function; however, these changes are not likely to impact health as changes remained within the normal clinical range. The data from the in vitro study provided indications that IL-8 may contribute to the apparent immunostimulation noted in the human study.

Cardioprotective potential of Irish macroalgae: generation of glycine betaine and dimethylsulfoniopropionate containing extracts by accelerated solvent extraction.

Accelerated solvent extraction (ASE®) was used to generate 18 macroalgal extracts from Irish seaweeds. The glycine betaine and dimethylsulfoniopriopionate content of the generated ASE® extracts were estimated using (1)H-NMR and confirmed for selected extracts using ultra performance liquid chromatography and mass spectrometry. Dimethylsulfoniopriopionate was only identified in the ASE® extract generated from Codium fragile ISCG0029. Glycine betaine was identified in the ASE® extract generated from Ulva intestinalis ISCG0356 using (1)H-NMR. Mass spectrometry analysis found that the seaweed species Cytoseira nodicaulis ISCG0070, Cytoseira tamariscofolia ISCG0283, and Polysiphonia lanosa ISCG0462 also had a glycine betaine content that ranged from 1.39 ng/ml to 105.11 ng/ml. Generated ASE® macroalgal extracts have potential for use as functional food ingredients in food products.

Inclusion of Palmaria palmata (red seaweed) in Atlantic salmon diets: effects on the quality, shelf-life parameters and sensory properties of fresh and cooked salmon fillets.

BACKGROUND: The use of Palmaria palmata (PP) as a natural ingredient in farmed Atlantic salmon diets was investigated. The effect of salmon diet supplementation with P. palmata (0, 5, 10 and 15%) or synthetic astaxanthin (positive control, PC) for 16 weeks pre-slaughter on quality indices of fresh salmon fillets was examined. The susceptibility of salmon fillets/homogenates to oxidative stress conditions was also measured. RESULTS: In salmon fillets stored in modified atmosphere packs (60% N2 /40% CO2 ) for up to 15 days at 4 °C, P. palmata increased surface -a* (greenness) and b* (yellowness) values in a dose-dependent manner, resulting in a final yellow/orange flesh colour. In general, the dietary addition of P. palmata had no effect on pH, lipid oxidation (fresh, cooked and fillet homogenates) and microbiological status. 'Eating quality' sensory descriptors (texture, odour and oxidation flavour) in cooked salmon fillets were not influenced by dietary P. palmata. Salmon fed 5% PP showed increased overall acceptability compared with those fed PC and 0% PP. CONCLUSION: Dietary P. palmata was ineffective at providing red coloration in salmon fillets, but pigment deposition enhanced fillets with a yellow/orange colour. Carotenoids from P. palmata may prove to be a natural pigment alternative to canthaxanthin in salmon feeds.

The role of albuminuria in the follow-up of HIV-infected pediatric patients.

BACKGROUND: In HIV-infected adults, elevated albumin has been associated with increased inflammatory activity, HIV-related nephropathy, and type 2 diabetes. Data on albuminuria in HIV-infected children are very scarce, and guidelines do not include routine determination of urinary albumin/creatinine ratio in this population. METHODS: We performed a cross-sectional study in a cohort of HIV-infected pediatric patients. Urinary protein/creatinine and albumin/creatinine ratios and hematuria were determined from at least three morning urine samples, and glomerular filtration rate (GFR) was estimated from creatinine levels. Persistent renal damage was defined according to the presence of at least two sequentially abnormal values in one of the parameters. The relationship between renal damage, HIV-related variables, and metabolic comorbidities (dyslipidemia, fat redistribution, glucose intolerance, hypertension) was investigated. RESULTS: Symptom-free renal damage was observed in 13 of 68 patients (19.1%) and mainly consisted of persistent proteinuria (17.6%); glomerular proteinuria was twice as prevalent as tubular proteinuria. GFR were normal in all cases. No relationship between renal markers and HIV-related variables or metabolic comorbidities was observed. CONCLUSIONS: Mild proteinuria affected approximately one fifth of patients in our cohort. The determination of albuminuria allowed the differentiation between glomerular and tubular proteinuria, although no relationship with metabolic comorbidities was observed.

A randomised clinical trial to evaluate the effects of Plantago ovata husk in Parkinson patients: changes in levodopa pharmacokinetics and biochemical parameters.

BACKGROUND: Plantago ovata husk therapy could be used in patients with Parkinson disease to reduce the symptoms of gastrointestinal disorders, but it is important to know whether this compound modifies levodopa pharmacokinetics. The maintenance of constant plasma concentrations of levodopa abolishes the clinical fluctuations in parkinsonian patients. The aim of this randomised clinical trial was to establish the influence of the fiber Plantago ovata husk in the pharmacokinetics of levodopa when administered to Parkinson patients well controlled by their oral medication. METHODS: To evaluate the effects of this fiber on several biochemical parameters. 18 volunteers participated in the study and received alternatively two treatments (Plantago ovata husk or placebo) with their usual levodopa/carbidopa oral dose. On days 0 (initial situation), 14 and 35 of the study, blood samples were taken to assess levodopa pharmacokinetics and to determine biochemical parameters. RESULTS: Levodopa Cmax was very similar in the initial situation (603.2 ng/ml) and after placebo administration (612.0 ng/ml), being slightly lower (547.8 ng/ml) when Plantago ovata husk was given. AUC was very similar in the three groups: initial situation.- 62.87 µg.min/ml, fiber treatment.- 64.47 µg.min/ml and placebo treatment.- 65.10 µg.min/ml. Fiber reduced significantly the number of peaks observed in the levodopa concentrations, maintaining concentrations more stable. No significant differences were found in total cholesterol, LDL-cholesterol and triglycerides with the administration of Plantago ovata husk. CONCLUSIONS: Plantago ovata husk administration caused a smoothing and homogenization of levodopa absorption, providing more stable concentrations and final higher levels, resulting in a great benefit for patients. TRIAL REGISTRATION: EudraCT2006-000491-33.

Prospective Randomized Controlled Clinical Trial of the Long-Term Effects of Omeprazole on Healthy Dogs.

The use of omeprazole as a preventive treatment for gastrointestinal ulcers in veterinary medicine has been questioned during previous years. The aim of the present study is to assess the long-term effect of omeprazole on cobalamin and serum gastrin levels in healthy dogs. Eighteen healthy dogs were included: 10 in the control group and 8 in the omeprazole group. Three samples were collected: before starting the treatment (T0), 30 days after the start of treatment (T1), and at 60 days (T2). The mean cobalamin value (ng/L) in the control group was 481.4 (±293.70) at T0, 481.4 (±170.21) at T1, and 513.2 (±174.50) at T2. In the omeprazole group, the values were 424.62 (±161.57) at T0, 454.5 (±160.96) at T1, and 414.87 (±127.90) at T2. No statistically significant changes were detected in cobalamin levels between the three-time period in both study groups. These results agree with previous findings in felines but contrast with human medicine studies. The median gastrin values (pg/mL) in the control group were 62.45 [30.17-218.75] at T0, 76.06 [30.67-199.87] at T1, and 63.02 [35.81-176.06] at T2. The median gastrin value in the omeprazole group was 67.59 [55.96-101.60] at T0, 191.77 [75.31-1901.77] at T1, and 128.16 [43.62-1066.46] at T2. Statistically significant differences were detected (p = 0.008), indicating an increase in gastrin levels after initiating treatment with omeprazole. In conclusion, the increased levels of gastrin observed in this population underscore the importance of conducting a comprehensive clinical assessment to identify potential gastrointestinal disorders, particularly in consideration of the usage of omeprazole as a preventive treatment.

Integrated Health and Social Home Care Services in Catalonia: Professionals' Perception of its Implementation, Barriers, and Facilitators.

Introduction: This study aimed to assess the implementation of integrated social and health home care services (HCS) offered by the Government of Catalonia, and to identify the main barriers and facilitators of integrated HCS. Methods: Analysis of the degree of implementation of integrated social and health HCS perceived by social care services (SCS) and primary health care centers (PHCs) between December 2020 and June 2021 in two phases. First, the perception of integration by social workers within SCS and PHCs was assessed using a screening questionnaire. Then, SCS in counties with the highest integration scores received a customized questionnaire for an in-depth assessment. Results: A total of 105 (100%) SCS and 94 (25%) PHCs answered the screening questionnaire, and 48 (45.7%) SCS received a customized questionnaire. The most frequent barrier identified was the lack of shared protocols, with the most frequent facilitator being the recognition of the importance of integrated HCS. Conclusions: Our study showed that the degree of implementation of integrated health and social HCS offered by the Government of Catalonia was perceived as low. The identified barriers and facilitators can be used to facilitate such implementation. Further studies should include professionals other than social workers in PHC assessments.

Influence of the Nature of Aminoalcohol on ZnO Films Formed by Sol-Gel Methods.

Here we present comparative studies of: (i) the formation of ZnO thin films via the sol-gel method using zinc acetate dihydrate (ZAD), 2-methoxyethanol (ME) as solvent, and the aminoalcohols (AA): ethanolamine, (S)-(+)-2-amino-1-propanol, (S)-(+)-2-amino-3-methyl-1-butanol, 2-aminophenol, and aminobenzyl alcohol, and (ii) elemental analyses, infrared spectroscopy, X-ray diffraction, scanning electron microscopy, absorption and emission spectra of films obtained after deposition by drop coating on glass surface, and thermal treatments at 300, 400, 500 and 600 °C. The results obtained provide conclusive evidences of the influence of the AA used (aliphatic vs. aromatic) on the ink stability (prior to deposition), and on the composition, structures, morphologies, and properties of films after calcination, in particular, those due to the different substituents, H, Me, or iPr, and to the presence or the absence of a -CH2 unit. Aliphatic films, more stable and purer than aromatic ones, contained the ZnO wurtzite form for all annealing temperatures, while the cubic sphalerite (zinc-blende) form was also detected after using aromatic AAs. Films having frayed fibers or quartered layers or uniform yarns evolved to "neuron-like" patterns. UV and photoluminescence studies revealed that these AAs also affect the optical band gap, the structural defects, and photo-optical properties of the films.

Excess mortality among older adults institutionalized in long-term care facilities during the COVID-19 pandemic: a population-based analysis in Catalonia.

Objectives: To assess excess mortality among older adults institutionalized in nursing homes within the successive waves of the COVID-19 pandemic in Catalonia (north-east Spain). Design: Observational, retrospective analysis of population-based central healthcare registries. Setting and participants: Individuals aged >65 years admitted in any nursing home in Catalonia between January 1, 2015, and April 1, 2022. Methods: Deaths reported during the pre-pandemic period (2015-2019) were used to build a reference model for mortality trends (a Poisson model, due to the event counting nature of the variable "mortality"), adjusted by age, sex, and clinical complexity, defined according to the adjusted morbidity groups. Excess mortality was estimated by comparing the observed and model-based expected mortality during the pandemic period (2020-2022). Besides the crude excess mortality, we estimated the standardized mortality rate (SMR) as the ratio of weekly deaths' number observed to the expected deaths' number over the same period. Results: The analysis included 175,497 older adults institutionalized (mean 262 days, SD 132), yielding a total of 394,134 person-years: 288,948 person-years within the reference period (2015-2019) and 105,186 within the COVID-19 period (2020-2022). Excess number of deaths in this population was 5,403 in the first wave and 1,313, 111, -182, 498, and 329 in the successive waves. The first wave on March 2020 showed the highest SMR (2.50; 95% CI 2.45-2.56). The corresponding SMR for the 2nd to 6th waves were 1.31 (1.27-1.34), 1.03 (1.00-1.07), 0.93 (0.89-0.97), 1.13 (1.10-1.17), and 1.07 (1.04-1.09). The number of excess deaths following the first wave ranged from 1,313 (2nd wave) to -182 (4th wave). Excess mortality showed similar trends for men and women. Older adults and those with higher comorbidity burden account for higher number of deaths, albeit lower SMRs. Conclusion: Excess mortality analysis suggest a higher death toll of the COVID-19 crisis in nursing homes than in other settings. Although crude mortality rates were far higher among older adults and those at higher health risk, younger individuals showed persistently higher SMR, indicating an important death toll of the COVID-19 in these groups of people.

Mechanical Disruption of the Inner Limiting Membrane In Vivo Enhances Targeting to the Inner Retina.

Purpose: To evaluate the effects of mechanical disruption of the inner limiting membrane (ILM) on the ability to target interventions to the inner neurosensory retina in a rodent model. Our study used an animal model to gain insight into the normal physiology of the ILM and advances our understanding of the effects of mechanical ILM removal on the viral transduction of retinal ganglion cells and retinal ganglion cell transplantation. Methods: The ILM in the in vivo rat eye was disrupted using mechanical forces applied to the vitreoretinal interface. Immunohistology and electron microscopy were used to verify the removal of the ILM in retina flatmounts and sections. To assess the degree to which ILM disruption enhanced transvitreal access to the retina, in vivo studies involving intravitreal injections of adeno-associated virus (AAV) to transduce retinal ganglion cells (RGCs) and ex vivo studies involving co-culture of human stem cell-derived RGCs (hRGCs) on retinal explants were performed. RGC transduction efficiency and transplanted hRGC integration with retinal explants were evaluated by immunohistology of the retinas. Results: Mechanical disruption of the ILM in the rodent eye was sufficient to remove the ILM from targeted retinal areas while preserving the underlying retinal nerve fiber layer and RGCs. Removal of the ILM enhanced the transduction efficiency of intravitreally delivered AAV threefold (1380.0 ± 290.1 vs. 442.0 ± 249.3 cells/mm2; N = 6; P = 0.034). Removal of the ILM was also sufficient to promote integration of transplanted RGCs within the inner retina. Conclusions: The ILM is a barrier to transvitreally delivered agents including viral vectors and cells. Mechanical removal of the ILM is sufficient to enhance access to the inner retina, improve viral transduction efficiencies of RGCs, and enhance cellular integration of transplanted RGCs with the retina.

Time trends and survival of marginal zone lymphoma over 25 years in Girona, Spain (1994-2018).

OBJECTIVE: To analyze the incidence, incidence trends, and survival of marginal zone lymphomas (MZLs) in Girona and to describe these indicators based on the location in the case of extranodal MZLs. METHODS: Population-based study of MZL collected in the Girona Cancer Registry, 1994-2018. Sociodemographic data, tumor location, and stage were obtained from clinical records. Crude (CR) and age-adjusted (ASRE ) incidence rates expressed per 100,000 person-years (p-y) were calculated. Joinpoint regression models were used for the trend analysis according to the MZL group. Five-year observed and net survival were analyzed. RESULTS: A total of 472 MZLs were included, 44 (9.3%) were nodal, 288 (61.0%) extranodal, 122 (25.9%) splenic, and the rest (n = 18) MZL, NOS. The CR for the MZL was 2.89 × 100,000 p-y (95% CI: 2.63-3.15), the ASRE was 3.26 × 100,000 p-y (95% CI: 2.97-3.57), and the annual percentage change (APC) was 1.6 (95% CI: 0.5-2.7). The ASRE for nodal MZL was 0.30 × 100,000 p-y (95% CI: 0.22-0.41) and showed an APC of 2.9% (95% CI: -16.4-26.6). For extranodal MZL, the ASRE was 1.98 × 100,000 p-y (95% CI: 1.76-2.23) and the APC was -0.4 (95% CI: -2.0-1.2). The most frequent locations of this type of MZL were the gastric (35.4%), skin (13.2%), and respiratory system (11.8%). The ASRE of the splenic MZL was 0.85 (95% CI: 0.71-1.02) with an APC of 12.8 (95% CI: 2.5-24.0). The 5-year net survival of MZL was 82.1% (95% CI: 76.3-86.5). CONCLUSIONS: This study reveals differences in the incidence and trend of the incidence of MZL according to the subgroup, showing a significant increase in the overall MZL mainly due to splenic MZL type.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial.

BACKGROUND: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. METHODS: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 µg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. FINDINGS: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. INTERPRETATION: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. FUNDING: Minoryx Therapeutics.