Donostiako Unibertsitate Ospitalea

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.

While start‐up firms create a substantial economic impact on most economies, the failure rate of start‐up firms seems to remain high over time. Few authors have examined the influence of intellectual capital management on business performance, and when it has been examined, the focus has been on large, mature and public companies. The purpose of this study is to analyze the extent to which IC assets are associated with new firm survival and growth. Results from this study suggest that the human capital of the entrepreneur (i.e. education, business experience and level of motivation), organizational capital (i.e. firm capacity to adapt quickly to changes and the ability to implement successful strategies), and relational capital (i.e. development of productive business networks and an immediate access to critical stakeholders) are important intangible assets, which seem to be related positively to venture performance.

A population-based survey was conducted to investigate the epidemiology of and antifungal resistance in Spanish clinical strains of filamentous fungi isolated from deep tissue samples, blood cultures, and respiratory samples. The study was conducted in two different periods (October 2010 and May 2011) to analyze seasonal variations. A total of 325 strains were isolated in 29 different hospitals. The average prevalence was 0.016/1,000 inhabitants [corrected]. Strains were identified by sequencing of DNA targets and susceptibility testing by the European Committee for Antimicrobial Susceptibility Testing reference procedure. The most frequently isolated genus was Aspergillus, accounting for 86.3% of the isolates, followed by Scedosporium at 4.7%; the order Mucorales at 2.5%; Penicillium at 2.2%, and Fusarium at 1.2%. The most frequent species was Aspergillus fumigatus (48.5%), followed by A. flavus (8.4%), A. terreus (8.1%), A. tubingensis (6.8%), and A. niger (6.5%). Cryptic/sibling Aspergillus species accounted for 12% of the cases. Resistance to amphotericin B was found in 10.8% of the isolates tested, while extended-spectrum triazole resistance ranged from 10 to 12.7%, depending on the azole tested. Antifungal resistance was more common among emerging species such as those of Scedosporium and Mucorales and also among cryptic species of Aspergillus, with 40% of these isolates showing resistance to all of the antifungal compounds tested. Cryptic Aspergillus species seem to be underestimated, and their correct classification could be clinically relevant. The performance of antifungal susceptibility testing of the strains implicated in deep infections and multicentric studies is recommended to evaluate the incidence of these cryptic species in other geographic areas.

BACKGROUND: To validate a new practical Sepsis Severity Score for patients with complicated intra-abdominal infections (cIAIs) including the clinical conditions at the admission (severe sepsis/septic shock), the origin of the cIAIs, the delay in source control, the setting of acquisition and any risk factors such as age and immunosuppression. METHODS: The WISS study (WSES cIAIs Score Study) is a multicenter observational study underwent in 132 medical institutions worldwide during a four-month study period (October 2014-February 2015). Four thousand five hundred thirty-three patients with a mean age of 51.2 years (range 18-99) were enrolled in the WISS study. RESULTS: Univariate analysis has shown that all factors that were previously included in the WSES Sepsis Severity Score were highly statistically significant between those who died and those who survived (p < 0.0001). The multivariate logistic regression model was highly significant (p < 0.0001, R2 = 0.54) and showed that all these factors were independent in predicting mortality of sepsis. Receiver Operator Curve has shown that the WSES Severity Sepsis Score had an excellent prediction for mortality. A score above 5.5 was the best predictor of mortality having a sensitivity of 89.2 %, a specificity of 83.5 % and a positive likelihood ratio of 5.4. CONCLUSIONS: WSES Sepsis Severity Score for patients with complicated Intra-abdominal infections can be used on global level. It has shown high sensitivity, specificity, and likelihood ratio that may help us in making clinical decisions.

Importance: The Enhanced Recovery After Surgery (ERAS) care protocol has been shown to improve outcomes compared with traditional care in certain types of surgery. Objective: To assess the association of use of the ERAS protocols with complications in patients undergoing elective total hip arthroplasty (THA) and total knee arthroplasty (TKA). Design, Setting, and Participants: This multicenter, prospective cohort study included patients recruited from 131 centers in Spain from October 22 through December 22, 2018. All consecutive adults scheduled for elective THA or TKA were eligible for inclusion. Patients were stratified between those treated in a self-designated ERAS center (ERAS group) and those treated in a non-ERAS center (non-ERAS group). Data were analyzed from June 15 through September 15, 2019. Exposures: Total hip or knee arthroplasty and perioperative management. Sixteen individual ERAS items were assessed in all included patients, whether they were treated at a center that was part of an established ERAS protocol or not. Main Outcomes and Measures: The primary outcome was postoperative complications within 30 days after surgery. Secondary outcomes included length of stay and mortality. Results: During the 2-month recruitment period, 6146 patients were included (3580 women [58.2%]; median age, 71 [interquartile range (IQR), 63-76] years). Of these, 680 patients (11.1%) presented with postoperative complications. No differences were found in the number of patients with overall postoperative complications between ERAS and non-ERAS groups (163 [10.2%] vs 517 [11.4%]; odds ratio [OR], 0.89; 95% CI, 0.74-1.07; P = .22). Fewer patients in the ERAS group had moderate to severe complications (73 [4.6%] vs 279 [6.1%]; OR, 0.74; 95% CI, 0.56-0.96; P = .02). The median overall adherence rate with the ERAS protocol was 50.0% (IQR, 43.8%-62.5%), with the rate for ERAS facilities being 68.8% (IQR, 56.2%-81.2%) vs 50.0% (IQR, 37.5%-56.2%) at non-ERAS centers (P < .001). Among the patients with the highest and lowest quartiles of adherence to ERAS components, the patients with the highest adherence had fewer overall postoperative complications (144 [10.6%] vs 270 [13.0%]; OR, 0.80; 95% CI, 0.64-0.99; P < .001) and moderate to severe postoperative complications (59 [4.4%] vs 143 [6.9%]; OR, 0.62; 95% CI, 0.45-0.84; P < .001) and shorter median length of hospital stay (4 [IQR, 3-5] vs 5 [IQR, 4-6] days; OR, 0.97; 95% CI, 0.96-0.99; P < .001). Conclusions and Relevance: An increase in adherence to the ERAS program was associated with a decrease in postoperative complications, although only a few ERAS items were individually associated with improved outcomes.

Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

AIMS AND OBJECTIVES: To estimate the prevalence of difficult venous access in complex patients with multimorbidity and to identify associated risk factors. BACKGROUND: In highly complex patients, factors like ageing, the need for frequent use of irritant medication and multiple venous catheterisations to complete treatment could contribute to exhaustion of venous access. DESIGN: A cross-sectional study was conducted. METHODS: 'Highly complex' patients (n = 135) were recruited from March 2013-November 2013. The main study variable was the prevalence of difficult venous access, assessed using one of the following criteria: (1) a history of difficulties obtaining venous access based on more than two attempts to insert an intravenous line and (2) no visible or palpable veins. Other factors potentially associated with the risk of difficult access were also measured (age, gender and chronic illnesses). Univariate analysis was performed for each potential risk factor. Factors with p < 0·2 were then included in multivariable logistic regression analysis. Odds ratios were also calculated. RESULTS: The prevalence of difficult venous access was 59·3%. The univariate logistic regression analysis indicated that gender, a history of vascular access complications and osteoarticular disease were significantly associated with difficult venous access. The multivariable logistic regression showed that only gender was an independent risk factor and the odds ratios was 2·85. CONCLUSIONS: The prevalence of difficult venous access is high in this population. Gender (female) is the only independent risk factor associated with this. Previous history of several attempts at catheter insertion is an important criterion in the assessment of difficult venous access. RELEVANCE TO CLINICAL PRACTICE: The prevalence of difficult venous access in complex patients is 59·3%. Significant risk factors include being female and a history of complications related to vascular access.

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.

Somatostatin and octreotide both enhance closure of gastrointestinal fistulas. The present trial was undertaken to test whether early combined treatment with parenteral nutrition and octreotide 100 micrograms every 8 h by subcutaneous injection had a beneficial effect compared with parenteral nutrition plus placebo. Thirty-one patients with post-operative gastrointestinal or pancreatic fistula were randomly assigned to receive parenteral nutrition plus octreotide (14 patients) or placebo (17) within 8 days of fistula onset. The percentage reduction in output and rate of spontaneous closure within 20 days were analysed. Mean(s.d.) reduction in output was similar after octreotide and placebo at 24 h (66(43) versus 68(47) per cent, P = 0.9), 48 h (60(46) versus 57(43) per cent, P = 0.8) and 72 h (62(50) versus 66(49) per cent, P = 0.9) after starting the combined treatment. Closure within 20 days was observed in eight of 14 fistulas in patients given octreotide and in six of 17 in those receiving placebo (P = 0.4). Administration of octreotide, within 8 days of fistula onset, associated with parenteral nutrition does not significantly increase the spontaneous fistula closure rate compared with parenteral nutrition plus placebo.

The clinical spectrum of 69 episodes of metapneumovirus pediatric infection (55 episodes caused by genotype A and 14 episodes caused by genotype B) was analyzed. Diagnosis of pneumonia was more common and the illness severity index (determined on the basis of need for hospitalization, oxygen saturation <90%, and intensive care unit stay) was higher for patients with metapneumovirus genotype A infection.

BACKGROUND: Adverse events (AE) are also the cause of suffering in health professionals involved. This study was designed to identify and analyse organization-level strategies adopted in both primary care and hospitals in Spain to address the impact of serious AE on second and third victims. METHODS: A cross-sectional study was conducted in healthcare organizations assessing: safety culture; health organization crisis management plans for serious AE; actions planned to ensure transparency in communication with patients (and relatives) who experience an AE; support for second victims; and protective measures to safeguard the institution's reputation (the third victim). RESULTS: A total of 406 managers and patient safety coordinators replied to the survey. Deficient provision of support for second victims was acknowledged by 71 and 61% of the participants from hospitals and primary care respectively; these respondents reported there was no support protocol for second victims in place in their organizations. Regarding third victim initiatives, 35% of hospital and 43% of primary care professionals indicated no crisis management plan for serious AE existed in their organization, and in the case of primary care, there was no crisis committee in 34% of cases. The degree of implementation of second and third victim support interventions was perceived to be greater in hospitals (mean 14.1, SD 3.5) than in primary care (mean 11.8, SD 3.1) (p < 0.001). CONCLUSIONS: Many Spanish health organizations do not have a second and third victim support or a crisis management plan in place to respond to serious AEs.

The Spanish Guideline on the Management of Asthma, better known by its acronym in Spanish GEMA, has been available for more than 20 years. Twenty-one scientific societies or related groups both from Spain and internationally have participated in the preparation and development of the updated edition of GEMA, which in fact has been currently positioned as the reference guide on asthma in the Spanish language worldwide. Its objective is to prevent and improve the clinical situation of people with asthma by increasing the knowledge of healthcare professionals involved in their care. Its purpose is to convert scientific evidence into simple and easy-to-follow practical recommendations. Therefore, it is not a monograph that brings together all the scientific knowledge about the disease, but rather a brief document with the essentials, designed to be applied quickly in routine clinical practice. The guidelines are necessarily multidisciplinary, developed to be useful and an indispensable tool for physicians of different specialties, as well as nurses and pharmacists. Probably the most outstanding aspects of the guide are the recommendations to: establish the diagnosis of asthma using a sequential algorithm based on objective diagnostic tests; the follow-up of patients, preferably based on the strategy of achieving and maintaining control of the disease; treatment according to the level of severity of asthma, using six steps from least to greatest need of pharmaceutical drugs, and the treatment algorithm for the indication of biologics in patients with severe uncontrolled asthma based on phenotypes. And now, in addition to that, there is a novelty for easy use and follow-up through a computer application based on the chatbot-type conversational artificial intelligence (ia-GEMA). La Guía Española para el Manejo del Asma, mejor conocida por su acrónimo en español, GEMA, está a nuestra disposición desde hace más de veinte años. Veintiuna sociedades científicas o grupos relacionados, tanto de España como de otros países, han participado en la preparación y desarrollo de la edición actualizada de GEMA que, de hecho, se ha posicionado en la actualidad a nivel mundial como la guía de referencia sobre asma en lengua española. Su objetivo es prevenir y mejorar la situación clínica de las personas con asma, aumentando el conocimiento de los profesionales sanitarios involucrados en su cuidado. Su propósito es convertir la evidencia científica en recomendaciones prácticas sencillas y fáciles de seguir. Por lo tanto, no se trata de una monografía que reúna todo el conocimiento científico sobre la enfermedad, sino más bien de un documento conciso con lo esencial, diseñado para ser aplicado rápidamente en la práctica clínica de rutina. Las recomendaciones son necesariamente multidisciplinares, están desarrolladas para ser útiles y una herramienta indispensable para médicos de diferentes especialidades, así como para profesionales de enfermería y farmacia. Seguramente, los aspectos más destacados de la guía son las recomendaciones para: establecer el diagnóstico del asma utilizando un algoritmo secuencial basado en pruebas diagnósticas objetivas; el seguimiento de los pacientes, preferentemente basado en la estrategia de lograr y mantener el control de la enfermedad; el tratamiento según el nivel de gravedad del asma utilizando seis escalones, desde la menor hasta la mayor necesidad de medicamentos, y el algoritmo de tratamiento basado en fenotipos para la indicación de biológicos en pacientes con asma grave no controlada. A esto se suma ahora una novedad para su fácil uso y seguimiento a través de una aplicación informática basada en la inteligencia artificial conversacional de tipo chatbot (ia-GEMA).

PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. RESULTS: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

BACKGROUND: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS. OBJECTIVES: To evaluate the efficacy and safety of rituximab for MS treatment. DATA COLLECTION: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies. MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

The authors introduce and study a family of interconnection schemes, the Midimew networks, based on circulant graphs of degree 4. A family of such circulants is determined and shown to be optimal with respect to two distance parameters simultaneously, namely maximum distance and average distance, among all circulants of degree 4.. These graphs are regular, point-symmetric, and maximally connected, and one such optimal graph exists for any given number of nodes. The proposed interconnection schemes consist of mesh-connected networks with wrap-around links, and are isomorphic to the optimal distance circulants previously considered. Ways to construct one such network for any number of nodes are shown, their good properties to build interconnection schemes for multicomputers are examined, and some interesting particular cases are discussed. The problem of routing is also addressed, and a basic algorithm is provided which is adequate for implementing the routing policy required to convey messages, traversing shortest paths between nodes.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>

There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.

PURPOSE Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) &gt;6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy. PATIENTS AND METHODS ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824 ), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI &gt;6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1–positive populations (alpha .025 for each population). RESULTS Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1–positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; P = .041; median 13.5 v 11.3 months, respectively) or PD-L1–positive (HR, 0.86; 95% CI, 0.63 to 1.16; P = .30; median 15.2 v 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 v 30.6 months with atezolizumab v placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% v 8%, respectively). CONCLUSION ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1–positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.