Genetic Characterization of Kidney Failure of Unknown Etiology in Spain: Findings From the GENSEN Study.

RATIONALE & OBJECTIVE: Chronic kidney disease of unknown etiology (CKDUE) is one of the main global causes of kidney failure. Genetic studies may identify an etiology in these patients, but few studies have implemented genetic testing of CKDUE in a population-based series of patients, which was the focus of the GENSEN Study. STUDY DESIGN: Case series. SETTINGS & PARTICIPANTS: 818 patients aged≤45 years at 51 Spanish centers with CKDUE, and either an estimated glomerular filtration rate of<15mL/min/1.73m2 or treatment with maintenance dialysis or transplantation. OBSERVATIONS: Genetic testing for 529 genes associated with inherited nephropathies using high-throughput sequencing (HTS). Pathogenic and/or likely pathogenic (P/LP) gene variants concordant with the inheritance pattern were detected in 203 patients (24.8%). Variants in type IV collagen genes were the most frequent (COL4A5, COL4A4, COL4A3; 35% of total gene variants), followed by NPHP1, PAX2, UMOD, MUC1, and INF2 (7.3%, 5.9%, 2.5%, 2.5%, and 2.5%, respectively). Overall, 87 novel variants classified as P/LP were identified. The top 5 most common previously undiagnosed diseases were Alport syndrome spectrum (35% of total positive reports), genetic podocytopathies (19%), nephronophthisis (11%), autosomal dominant tubulointerstitial kidney disease (7%), and congenital anomalies of the kidney and urinary tract (CAKUT, 5%). A family history of kidney disease was reported by 191 participants (23.3%) and by 65 of 203 patients (32.0%) with P/LP variants. LIMITATIONS: Missing data, and selection bias resulting from voluntary enrollment. CONCLUSIONS: Genomic testing with HTS identified a genetic cause of kidney disease in approximately one quarter of young patients with CKDUE and advanced kidney disease. These findings suggest that genetic studies are a potentially useful tool for the evaluation of people with CKDUE. PLAIN-LANGUAGE SUMMARY: The cause of kidney disease is unknown for 1 in 5 patients requiring kidney replacement therapy, reflecting possible prior missed treatment opportunities. We assessed the diagnostic utility of genetic testing in children and adults aged≤45 years with either an estimated glomerular filtration rate of<15mL/min/1.73m2 or treatment with maintenance dialysis or transplantation. Genetic testing identified the cause of kidney disease in approximately 1 in 4 patients without a previously known cause of kidney disease, suggesting that genetic studies are a potentially useful tool for the evaluation of these patients.

Description of a new method to calculate the equator of the crystalline lens using AS-OCT images: Accuracy in non-dilated measurements.

OBJECTIVE: To establish a methodology for objectively estimating the Lens Equatorial Plane (LEP) from clinical images, comparing LEP with dilated versus non-dilated pupils. METHODS: A cohort of 91 eyes from 60 patients undergoing preoperative assessments for cataract surgery was evaluated. Anterior Segment Optical Coherence Tomography (AS-OCT) images were analysed under conditions of pharmacologically induced pupil dilation versus a non-dilated pupil. Geometrical parameters, including LEP, intersection diameter (ID), lens thickness (LT), anterior and posterior lens thickness were automatically calculated by applying standard image processing techniques to clinical AS-OCT images. RESULTS: Significant differences in lens parameters, including LEP, were observed between dilated and non-dilated conditions (all p < 0.001). A strong linear correlation was found across all geometrical variables under both conditions (r[LEP] = 0.64, r[ID] = 0.78, r[LT] = 0.99, all p < 0.001); enabling reliable correction of these differences. CONCLUSION: The study introduces an objective methodology for LEP calculation, emphasising the need to consider the eye's physiological state during preoperative measurements. Incorporating LEP into future intraocular lens (IOL) power calculation formulas and replacing the habitual effective lens position may potentially improve the accuracy of IOL power estimation and thus postoperative visual outcomes.

Erdafitinib in the Treatment of Metastatic Urothelial Carcinoma.

A Hispanic man, aged 42 years, was diagnosed with stage IV metastatic urothelial bladder cancer (MUBC) with nonregional lymphadenopathies and lung, bone, and skin involvement. He received first-line treatment with gemcitabine and cisplatin for 6 cycles, achieving a partial response (PR). Next, he received immunotherapy maintenance with avelumab for 4 months until disease progression. A next-generation sequencing test of paraffin-embedded tumor tissue identified a fibroblast growth factor receptor 3 (FGFR3) S249C missense mutation.

Metastatic Renal Cell Carcinoma With Sarcomatoid Features.

A previously healthy woman, aged 38 years, presented with a 3-month history of fatigue, dyspnea on exertion, significant weight loss, and severe left flank pain; her symptoms restricted any work activities. Laboratory test results were notable for hypercalcemia (corrected serum calcium, 12.8 mg/dL), anemia (9.3 g/dL), and lactate dehydrogenase elevation (>1.5 times the upper limit of normal). A CT scan revealed a 14-cm left renal mass and multiple lung and mediastinal lymph node metastases. A surgical open biopsy was performed; histopathological analysis concluded clear cell renal carcinoma (RCC) with 30% sarcomatoid features. The patient was diagnosed with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) poor-risk metastatic RCC with sarcomatoid features. She started first-line systemic treatment.

Hand-Foot Skin Reaction Secondary to Sunitinib in a Patient With Metastatic Clear Cell Renal Cell Carcinoma.

A man, age 45 years, was diagnosed with intermediate-risk stage IV clear cell renal carcinoma (lung and lymph node metastases). He was prescribed first-line systemic treatment with sunitinib (Sutent) 50 mg per day (each cycle: 4 weeks on, 2 weeks off). Upon day 22 of his second sunitinib cycle, he came to the oncology clinic complaining of difficulty walking due to bilateral sole pain. He described initial tingling sensations, which then became burning and painful, with symmetrical erythema and edema of the soles, without blisters. These turned into painful plaques with yellowish discoloration and hyperkeratosis on pressure-bearing areas. He denied fever or other symptoms. The pain limited his instrumental activities of daily living, but not his self-care activities of daily living. Total body skin examination disclosed hyperkeratotic plaques on the undersurface of the great toes and heels of both feet, predominantly at sites of pressure; no blisters, crusts, ulcers, or fissures were found. No relevant findings were found upon physical examination of his hands, mucosae, and scalp. A diagnosis of grade 2 hand-foot skin reaction (HFSR) was made.

The Role of Postmastectomy Radiotherapy in Locally Advanced Breast Cancer After Pathological Complete Response to Neoadjuvant Chemotherapy.

The Case A previously healthy woman, aged 32 years, presented to the oncology clinic with a 6-month history of left-breast tumor, mastalgia, and swollen axillary nodes. Physical examination was relevant for a 6-cm palpable mass in the upper outer quadrant of the left breast and an ipsilateral 2-cm, nonfixed axillary lymph node. Mammography showed a 1-cm mass in the upper outer quadrant, a 5.2-cm mass in the lower outer quadrant, and enlarged pathologic lymph nodes (BI-RADS category 5 disease). Breast ultrasound revealed 3 axillary lymph nodes with cortical thickening and loss of normal morphology (the largest with a 2.6-cm length in the long axis) (Figure 1A-B). The breast´s core biopsy revealed a grade 3 apocrine invasive carcinoma with lymphovascular invasion; immunohistochemistry testing showed HER2-negative, hormone receptor-negative disease (estrogen receptor, 0%; progesterone receptor, 0%; HER2-negative, Ki67, 50%) (Figure 2A-B). A fine-needle aspiration biopsy of the axillary lymph nodes showed invasive breast carcinoma as well. Bone scintigraphy and a chest/abdomen CT scan ruled out metastatic disease. Upon initial diagnosis, clinical stage was deemed as cT3N1M0 (American Joint Committee on Cancer 8th edition: anatomic stage IIIA, clinical prognostic stage IIIC). After a multidisciplinary tumor board discussion, the patient underwent neoadjuvant chemotherapy with weekly paclitaxel, followed by 4 cycles of dose-dense doxorubicin plus cyclophosphamide. After completing neoadjuvant treatment, clinical examination was relevant for a residual 1-cm palpable left breast mass and no palpable axillary nodes. Mammography and breast ultrasound showed a 77% partial response in the primary tumors, and axillary nodes with normal morphology and size (Figure 1C-D). Due to multicentric tumor disease, breast-conserving surgery would not confer satisfactory cosmetic results on her, and a modified radical mastectomy with intraoperative sentinel lymph node biopsy (and second-stage breast reconstruction) was planned. However, during surgery, the surgeons failed to identify the mapped lymph node, and level I-III axillary lymph node dissection was performed. The pathology report described complete pathological response: Miller and Payne criteria grade 5 response with the absence of malignant cells within the mastectomy specimen and in 24 lymph nodes (Figure 2C-E). Pathological staging after neoadjuvant treatment concluded ypT0N0M0 disease. Subsequent treatment for this patient was discussed in another tumor board.

Sjögren Syndrome Induced by Immune Checkpoint Inhibitors in a Patient with Advanced Renal Cell Carcinoma.

This clinical quandary details a Mexican man, aged 77 years, who presented to the oncology clinic with a sternal mass. Based on the results, the patient fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for Sjögren syndrome, thus the diagnosis triggered by immune checkpoint inhibitors was definitively established.

The effect of high-volume online haemodiafiltration on nutritional status and body composition: the ProtEin Stores prEservaTion (PESET) study.

Background: Compared with conventional haemodialysis (HD), online haemodiafiltration (OL-HDF) achieves a more efficient removal of uraemic toxins and reduces inflammation, which could favourably affect nutritional status. We evaluate the effect of OL-HDF on body composition and nutritional status in prevalent high-flux HD (HF-HD) patients. Methods: In all, 33 adults with chronic kidney disease (CKD) Stage 5 undergoing maintenance HF-HD were assigned to post-dilution OL-HDF (n = 17) or to remain on HF-HD (n = 16, control group) for 12 months. The primary outcome was the change in lean tissue mass (LTM), intracellular water (ICW) and body cell mass (BCM) assessed by multifrequency bioimpedance spectroscopy (BIS) at baseline and 4, 8 and 12 months. The rate of change in these parameters was estimated with linear mixed-effects models. Results: Compared with OL-HDF, patients assigned to HF-HD experienced a gradual reduction in LTM, ICW and BCM. These differences reached statistical significance at Month 12, with a relative difference of 7.31 kg [95% confidence interval (CI) 2.50-12.11; P = 0.003], 2.32 L (95% CI 0.63-4.01; P = 0.008) and 5.20 kg (95% CI 1.74-8.66; P = 0.004) for LTM, ICW and BCM, respectively. The normalized protein appearance increased in the OL-HDF group compared with the HF-HD group [0.26 g/kg/day (95% CI 0.05-0.47); P = 0.002], with a relative reduction in high-sensitive C-reactive protein [-13.31 mg/dL (95% CI -24.63 to -1.98); P = 0.02] at Month 12. Conclusions: OL-HDF for 1 year compared with HF-HD preserved muscle mass, increased protein intake and reduced the inflammatory state related to uraemia and dialysis, supporting the hypothesis that high convection volume can benefit nutritional status and prevent protein-energy wasting in HD patients.

Ultrastructural characterization of normal Merkel cells in the dog.

BACKGROUND: Involvement of Merkel cells (MKs) in different cutaneous diseases as well as in the growth, differentiation and homeostasis of the skin has been previously documented. HYPOTHESIS/OBJECTIVES: The aim was to assess the ultrastructural features of MKs in canine skin, including morphometrics, highlighting their similarities with and differences from those described for other mammals. ANIMALS: Hard palate, nasal planum, lower lip and whisker pad samples were taken from two healthy young dogs destined for academic purposes. METHODS: Ultrathin sections of samples fixed in osmium tetroxide and embedded in Epon 812 resin were stained with uranyl acetate and lead citrate and examined using a JEOL JEM 2010 transmission electron microscope. RESULTS: Ultrastructural characteristics included the following: (i) arrangement in clusters in the basal layer of the epidermis, oral mucosa and external follicular root sheath; (ii) inconstant link with nerve terminal; (iii) oval (10.27 ± 1.64 µm major axis) cell shape with large lobulated nuclei (5.98 ± 1.16 µm major axis); (iv) spine-like and thick cytoplasmic processes interdigitating with surrounding keratinocytes; (v) presence of desmosomes in the cell body or at the base of spine-like processes attaching to neighbouring keratinocytes; and (vi) cytoplasm containing loosely arranged intermediate filaments (10.04 ± 1.17 nm) and numerous dense-core granules (100.1 ± 17.12 nm) arranged in the basal portion of the cytoplasm. CONCLUSIONS AND CLINICAL IMPORTANCE: This study provides the first complete description of the ultrastructural characteristics of MKs in the dog, enhancing our knowledge of the skin structure in this species and providing a basis for future physiological and pathological studies of the role of these cells in normal and damaged canine tissues.

Sensitive Detection of an Erbium Isotope in an Atomic Beam Using Cavity Ring-Down Spectroscopy.

We have applied cavity ring-down spectroscopy (CRDS) to the study of the 166Er isotope in an atomic beam. These measurements were realized with an external cavity diode laser tuned to the 400.9 nm atomic transition of erbium and a customized high-finesse ring-down optical cavity under vacuum. Erbium atomic beams of different number densities were generated in a tantalum foil micro-crucible within the cavity. Absorbance values of the 166Er isotope between 3 × 10-6 and 7 × 10-5 were measured with a best-case precision on the order of 10-6, which is remarkable when considering the extreme temperatures at which the measurements were conducted, and the short detection path which is characteristic of collimated atomic beams. Number densities of erbium atoms were inferred to be between 2 × 106 and 6 × 107 cm-3. This work demonstrates for the first time the ability of studying dilute atomic beams of refractory materials with high accuracy utilizing CRDS. In these initial studies, we used erbium as a model system, but we expect to extend the proposed approach to the measurement of isotopes of uranium and plutonium for nuclear non-proliferation applications.

Biometric description of 34 589 eyes undergoing cataract surgery: sex differences.

PURPOSE: To describe gender differences in the biometric parameters of a large sample of patients with cataract. Cataract surgery has evolved from a vision restoration to a refractive procedure, and population-based studies are vital to optimize normative databases and postsurgical outcomes. SETTING: Miguel Servet University Hospital, Zaragoza, Spain. DESIGN: Retrospective single-center observational study. METHODS: The study included 34 589 eyes (20 004 patients with cataract). Biometric data were obtained from IOL Master 700 and Pentacam HR. Linear mixed models were used to account for intereye correlation. HofferQST formula was used to calculate the hypothetical distribution of intraocular lens (IOL) power (arbitrary lens; A = 119.2). RESULTS: Most biometric variables showed significant differences between sexes ( P < .0001), such as 0.53 mm shorter eyes found in females, of which 0.16 mm are explained by shorter aqueous depth. Steeper anterior keratometries (∼0.75 diopter [D]) were found in women, to end up in no difference on anterior astigmatism magnitude, but different orientation ( P < .0001). The distribution of IOL power differed between sexes ( P < .001), with the interquartile range shifting 1 D toward more powerful lenses in women and odds ratio (power >26 D) = 2.26, P < .0001 (Fisher). CONCLUSIONS: Large sample size studies provide smaller margin of error, higher power, and controlled risk of reporting false (negative or positive) findings. Highly significant differences between sexes in ocular biometry were found; this supports the idea that including sex as a parameter in IOL calculation should be explored and may improve results. In addition, the distribution of IOL powers was provided, which may be useful for manufacturers and hospital stock planning.

Osteoporosis management in patients with chronic kidney disease (ERCOS Study): A challenge in nephrological care.

Fracture risk assessment in patients with chronic kidney disease (CKD) has been included in the CKD-MBD ("Chronic Kidney Disease-Mineral and Bone Disorders") complex in international and national nephrology guidelines, suggesting for the first time the assessment of bone mineral density (BMD) if the results can influence therapeutic decision-making. However, there is very little information on actual clinical practice in this population. The main objective of the ERCOS (ERC-Osteoporosis) study is to describe the profile of patients with CKD G3-5D with osteoporosis (OP) and/or fragility fractures treated in specialized nephrology, rheumatology and internal medicine clinics in Spain. Fifteen centers participated and 162 patients (mostly women [71.2%] postmenopausal [98.3%]) with a median age of 77 years were included. Mean estimated glomerular filtration rate (eGFR) was 36 mL/min/1.73 m2 and 38% of the included patients were on dialysis. We highlight the high frequency of prevalent fragility fractures [37.7%), mainly vertebral (52.5%) and hip (24.6%)], the disproportionate history of patients with glomerular disease compared to purely nephrological series (corticosteroids) and undertreatment for fracture prevention, especially in nephrology consultations. This study is an immediate call to action with the dissemination of the new, more proactive, clinical guidelines, and underlines the need to standardize a coordinated and multidisciplinary care/therapeutic approach to these patients in an efficient way to avoid current discrepancies and therapeutic nihilism.

Integrating cognitive load theory with other theories, within and beyond educational psychology.

BACKGROUND AND AIMS: The long-standing aim of cognitive load theory (CLT) has been to generate instructional design principles that show teachers how to instruct students effectively, based on knowledge of the intricacies of human cognitive architecture. Historically, the focus of CLT has been on identifying cognitive processes related to learning and instruction. However, the theory has become more multidisciplinary over time, drawing on theoretical perspectives both within, and beyond, educational psychology. RESULTS: This Editorial presents a brief historical overview of key developments in CLT and seven key themes that are pertinent to research on CLT. These themes are as follows: Level of Expertise, Cognitive Load Measurement, Embodied Cognition, Self-Regulated Learning, Emotion Induction, Replenishment of Working Memory, and Two Subprocessors of Working Memory. Summaries of the nine empirical contributions to the special issue are presented and discussed in relation to how they provide insight into one or more of these themes. CONCLUSIONS: Understanding the variables that impact student learning and instruction has always represented the core aim of CLT. The growing multidisciplinary features of CLT should provide researchers and practitioners with more holistic perspectives of the factors that predict student learning and, in turn, guide instructional design.

Biological evolution and human cognition are analogous information processing systems.

The mechanisms that govern biological evolution and human cognition are analogous, as both follow the same principles of natural information processing systems. In this article, we describe the following five principles that provide an analogy between biological evolution and human cognition: (a) Randomness as Genesis Principle and (b) Borrowing and Reorganizing Principle, which indicate how natural information processing systems obtain information; (c) Narrow Limits of Change Principle and (d) Information Store Principle, which indicate how information is processed and stored; and (e) Environmental Organizing and Linking Principle, which indicate how stored information is used to generate actions appropriate to an environment. In human cognition, these analogs only apply to cognitive processes associated with biologically secondary knowledge, the knowledge typically taught in educational institutions. Based on these five principles, cognitive load theory researchers have provided diverse prescriptions to optimize instructional activities and materials. We conclude by discussing general instructional implications and future research directions based on this analogy.

Veterinary Education and Training on Non-Traditional Companion Animals, Exotic, Zoo, and Wild Animals: Concepts Review and Challenging Perspective on Zoological Medicine.

The role of veterinarians is becoming more significant and necessary to support the welfare and health not only of non-traditional companion animals and wildlife animals, but also of humans and the environment. The importance of the One Health/One World concept and its social impact is increasing significantly, accompanied by the notoriety of new emerging and reemerging zoonoses. This paper aims to review and anchor the main concepts and professional applications of zoological medicine, which has been extensively discussed and adapted in recent decades. In addition, we analyse the main social demands, training, and educational needs and the perception of veterinary professionals relating to this specialised veterinary discipline. Our final goal is to reinforce the use of the term zoological medicine and contribute to highlight the need to foster and underpin specific educational policies and programs on this matter in the veterinary curricula. Zoological medicine should be the appropriate and agreed-upon term in the academic language concerning the veterinary medicine of pets, wild, or zoo species, excluding traditional domestic animals, and integrating the principles of ecology and conservation, applied to both natural and artificial environments. This discipline has suffered an intense evolution covering applications in private clinics, zoos, bioparks, and wildlife. All this implies current and future challenges for the veterinary profession that can only be addressed with greater and better attention from multiple perspectives, especially the education and training of professionals to improve and specialise in their professional scope of services.

Infection due to Buteo buteo herpesvirus in a common buzzard (Buteo buteo insularum).

This study aimed to document the pathological findings observed in a common buzzard (Buteo buteo insularum) from Gran Canaria (Canary Islands, Atlantic Ocean), naturally infected with Buteo buteo herpesvirus (HV). Local authorities found the common buzzard alive, but it died after 10 days of specialized veterinary care. Postmortem investigation, including complete gross and histologic examination, immunohistochemistry, microbiology, and PCR, was performed. The animal presented necrotizing heterophilic and histiocytic bilateral conjunctivitis, stomatitis, pharyngitis, rhinitis, and sinusitis with secondary bacterial and fungal infections. Frequent eosinophilic intranuclear inclusion bodies were observed in the oral mucosa and esophagus epithelium. HV proteins and DNA were detected in tissues from this animal. The sequences obtained from the PCR product were identical to the reported sequences of Buteo buteo HV.

A deficiency screen of the 3rd chromosome for dominant modifiers of the Drosophila ER integral membrane protein, Jagunal.

The mechanism surrounding chromosome inheritance during cell division has been well documented, however, organelle inheritance during mitosis is less understood. Recently, the endoplasmic reticulum (ER) has been shown to reorganize during mitosis, dividing asymmetrically in proneuronal cells prior to cell fate selection, indicating a programmed mechanism of inheritance. ER asymmetric partitioning in proneural cells relies on the highly conserved ER integral membrane protein, Jagunal (Jagn). Knockdown of Jagn in the compound Drosophila eye displays a pleotropic rough eye phenotype in 48% of the progeny. To identify genes involved in Jagn dependent ER partitioning pathway, we performed a dominant modifier screen of the 3rd chromosome for enhancers and suppressors of this Jagn-RNAi-induced rough eye phenotype. We screened through 181 deficiency lines covering the 3L and 3R chromosomes and identified 12 suppressors and 10 enhancers of the Jagn-RNAi phenotype. Based on the functions of the genes covered by the deficiencies, we identified genes that displayed a suppression or enhancement of the Jagn-RNAi phenotype. These include Division Abnormally Delayed (Dally), a heparan sulfate proteoglycan, the γ-secretase subunit Presenilin, and the ER resident protein Sec63. Based on our understanding of the function of these targets, there is a connection between Jagn and the Notch signaling pathway. Further studies will elucidate the role of Jagn and identified interactors within the mechanisms of ER partitioning during mitosis.