An implementation and performance measurement of the progressive retry technique

This paper describes a recovery technique called progressive retry for bypassing software faults in message-passing applications. The technique is implemented as reusable modules to provide application-level software fault tolerance. The paper describes the implementation of the technique and presents results from the application of progressive retry to two telecommunications systems. the results presented show that the technique is helpful in reducing the total recovery time for message-passing applications

Cost-effectiveness of left ventricular assist devices (LVADs) for patients with advanced heart failure : analysis of the British NHS Bridge to Transplant (BTT) program

Background: A previous cost-effectiveness analysis showed that bridge to transplant (BTT) with early design left ventricular assist devices (LVADs) for advanced heart failure was more expensive than medical management while appearing less beneficial. Older LVADs were pulsatile, but current second and third generation LVADs are continuous flow pumps. This study aimed to estimate comparative cost-effectiveness of BTT with durable implantable continuous flow LVADs compared to medical management in the British NHS. Methods and results: A semi-Markov multi-state economic model was built using NHS costs data and patient data in the British NHS Blood and Transplant Database (BTDB). Quality-adjusted life years (QALYs) and incremental costs per QALY were calculated for patients receiving LVADs compared to those receiving inotrope supported medical management. LVADs cost £80,569 ($127,887) at 2011 prices and delivered greater benefit than medical management. The estimated probabilistic incremental cost-effectiveness ratio (ICER) was £53,527 ($84,963)/QALY (95%CI: £31,802–£94,853; $50,479–$150,560) (over a lifetime horizon). Estimates were sensitive to choice of comparator population, relative likelihood of receiving a heart transplant, time to transplant, and LVAD costs. Reducing the device cost by 15% decreased the ICER to £50,106 ($79,533)/QALY. Conclusions: Durable implantable continuous flow LVADs deliver greater benefits at higher costs than medical management in Britain. At the current UK threshold of £20,000 to £30,000/QALY LVADs are not cost effective but the ICER now begins to approach that of an intervention for end of life care recently recommended by the British NHS. Cost-effectiveness estimates are hampered by the lack of randomized trials

Cost-effectiveness of left ventricular assist devices (LVADs) for patients with advanced heart failure : analysis of the British NHS Bridge to Transplant (BTT) program

Background: A previous cost-effectiveness analysis showed that bridge to transplant (BTT) with early design left ventricular assist devices (LVADs) for advanced heart failure was more expensive than medical management while appearing less beneficial. Older LVADs were pulsatile, but current second and third generation LVADs are continuous flow pumps. This study aimed to estimate comparative cost-effectiveness of BTT with durable implantable continuous flow LVADs compared to medical management in the British NHS. Methods and results: A semi-Markov multi-state economic model was built using NHS costs data and patient data in the British NHS Blood and Transplant Database (BTDB). Quality-adjusted life years (QALYs) and incremental costs per QALY were calculated for patients receiving LVADs compared to those receiving inotrope supported medical management. LVADs cost £80,569 ($127,887) at 2011 prices and delivered greater benefit than medical management. The estimated probabilistic incremental cost-effectiveness ratio (ICER) was £53,527 ($84,963)/QALY (95%CI: £31,802–£94,853; $50,479–$150,560) (over a lifetime horizon). Estimates were sensitive to choice of comparator population, relative likelihood of receiving a heart transplant, time to transplant, and LVAD costs. Reducing the device cost by 15% decreased the ICER to £50,106 ($79,533)/QALY. Conclusions: Durable implantable continuous flow LVADs deliver greater benefits at higher costs than medical management in Britain. At the current UK threshold of £20,000 to £30,000/QALY LVADs are not cost effective but the ICER now begins to approach that of an intervention for end of life care recently recommended by the British NHS. Cost-effectiveness estimates are hampered by the lack of randomized trials

Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity

BACKGROUND: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. METHODS: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. RESULTS: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. CONCLUSIONS: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders"

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each) as well as hypertrophy of the clava (24%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localization and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-myristoylation was similarly affected in acbd6-deficient zebrafish and X. tropicalis models, including Fus, Marcks and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

LLM Project

DO LLMs Show the anchoring effect? An extension and a replicatio

Logging, Checkpointing and Rollback for Localized Recovery in Message Passing and Distributed Shared Memory Systems

NASAU of I Onlythesi

A certain ambiguity: a mathematical novel

While taking a class on infinity at Stanford in the late 1980s, Ravi Kapoor discovers that he is confronting the same mathematical and philosophical dilemmas that his mathematician grandfather had faced many decades earlier--and that had landed him in jail. Charged under an obscure blasphemy law in a small New Jersey town in 1919, Vijay Sahni is challenged by a skeptical judge to defend his belief that the certainty of mathematics can be extended to all human knowledge--including religion. Together, the two men discover the power--and the fallibility--of what has long been considered the pin