Health-related quality of life across disease stages in patients with amyotrophic lateral sclerosis: results from a real-world survey.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a rapid disease course, with disease severity being associated with declining health-related quality of life (HRQoL) in persons living with ALS (pALS). The main objective of this study was to assess the impact of disease progression on HRQoL across King's, Milano-Torino Staging (MiToS), and physician-judgement clinical staging. Additionally, we evaluated the impact of the disease on the HRQoL of care partners (cALS). METHODS: Data were sourced from the Adelphi ALS Disease Specific Programme (DSP)™, a cross-sectional survey of neurologists, pALS and cALS presenting in a real-world clinical setting between July 2020 and March 2021 in Europe and the United States. RESULTS: Neurologists (n = 142) provided data for 880 pALS. There were significant negative correlations between all three clinical staging systems and EuroQol (European Quality of Life) Five Dimension Five Level Scale (EQ-5D-5L) utility scores and visual analogue scale (VAS) ratings. Although not all differences were significant, 5-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) scores showed a stepwise increase in HRQoL impairment at each stage of the disease regardless of the staging system. At later stages, high levels of fatigue and substantial activity impairment were reported. As pALS disease states progressed, cALS also experienced a decline in HRQoL and increased burden. CONCLUSIONS: Across outcomes, pALS and cALS generally reported worse outcomes at later stages of the disease, highlighting an unmet need in this population for strategies to maximise QoL despite disease progression. Recognition and treatment of symptoms such as pain and fatigue may lead to improved outcomes for pALS and cALS.

Can you detect early dementia from an email? A proof of principle study of daily computer use to detect cognitive and functional decline.

OBJECTIVE: To determine whether multiple computer use behaviours can distinguish between cognitively healthy older adults and those in the early stages of cognitive decline, and to investigate whether these behaviours are associated with cognitive and functional ability. METHODS: Older adults with cognitive impairment (n = 20) and healthy controls (n = 24) completed assessments of cognitive and functional abilities and a series of semi-directed computer tasks. Computer use behaviours were captured passively using bespoke software. RESULTS: The profile of computer use behaviours was significantly different in cognitively impaired compared with cognitively healthy control participants including more frequent pauses, slower typing, and a higher proportion of mouse clicks. These behaviours were significantly associated with performance on cognitive and functional assessments, in particular, those related to memory. CONCLUSION: Unobtrusively capturing computer use behaviours offers the potential for early detection of neurodegeneration in non-clinical settings, which could enable timely interventions to ultimately improve long-term outcomes.

ICORG 10-14: NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric junction International Study (Neo-AEGIS).

BACKGROUND: Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens. METHODS: This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research. DISCUSSION: This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG). TRIAL REGISTRATION: NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.

Fc-γ Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer.

PURPOSE: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR. EXPERIMENTAL DESIGN: DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism-treatment arm interaction term. RESULTS: Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype-treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A). CONCLUSIONS: In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435-44. ©2016 AACR.

Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel.

These consensus guidelines provide recommendations for the safe handling of monoclonal antibodies. Definitive recommendations are given for the minimum safe handling requirements to protect healthcare personnel. The seven recommendations cover: (i) appropriate determinants for evaluating occupational exposure risk; (ii) occupational risk level compared with other hazardous and non-hazardous drugs; (iii) stratification of risk based on healthcare personnel factors; (iv) waste products; (v) interventions and safeguards; (vi) operational and clinical factors and (vii) handling recommendations. The seventh recommendation includes a risk assessment model and flow chart for institutions to consider and evaluate clinical and operational factors unique to individual healthcare services. These guidelines specifically evaluated monoclonal antibodies used in the Australian cancer clinical practice setting; however, the principles may be applicable to monoclonal antibodies used in non-cancer settings. The guidelines are only applicable to parenterally administered agents.

Access to anticancer drugs: many evidence-based treatments are off-label and unfunded by the Pharmaceutical Benefits Scheme.

BACKGROUND: The off-label use of a drug refers to a use outside the terms of its approval by the Therapeutic Goods Administration (TGA). It is also possible to prescribe unlicensed drugs under the TGA's special access scheme. A high rate of off-label prescribing has previously been reported in cancer. Our study aimed to document the disparity between evidence-based clinical guidelines for anticancer therapy, product approval and funding status of these agents within an academic tertiary/quaternary cancer centre. METHODS: All chemotherapy protocols approved for use in our specialist oncology centre were assessed to determine if the drugs were off-label or unlicensed for that indication based on review of their current product information. The Pharmaceutical Benefits Scheme (PBS) funding status for each protocol was subsequently assessed. RESULTS: A total of 448 protocols containing 82 different drugs across 15 tumour groups was identified. Overall, 189 (42.2%) of protocols were off-label, and three (0.7%) were unlicensed. This resulted in all 192 protocols being unfunded by the PBS. Of the 189 off-label protocols, 132 (69.9%) were based on established evidence-based treatment guidelines, and a further 39 (20.6%) was based on phase II or III clinical trial data. CONCLUSION: Over 90% of off-label protocols are supported by established treatment guidelines or published peer-reviewed research even though the medications are not approved for that particular use by the TGA. However, these off-label protocols are unfunded by the PBS; this results in a marked inequality of access to appropriate medications for cancer patients across Australia.

Synaptic plasticity of kainate receptors.

Synaptic plasticity of ionotropic glutamate receptors has been extensively studied with a particular focus on the role played by NMDA (N-methyl-D-aspartate) receptors in the induction of synaptic plasticity and the subsequent movement of AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors. The third subtype of ionotropic glutamate receptor, kainate receptors, has not been studied to the same extent, but recent evidence shows that these receptors also exhibit synaptic plasticity in response to activity. There is also a growing body of data on the mechanisms underlying kainate receptor trafficking and the proteins they interact with. This review summarizes the current state of knowledge on this topic, focusing on the evidence for the removal or insertion of functional kainate receptors in response to synaptic activity and the cellular mechanisms that underlie this regulation of neuronal kainate receptor function.

Imitation switch complexes.

The imitation switch (ISWI) family of chromatin remodelling ATPases is found in organisms ranging from yeast to mammals. ISWI ATPases assemble chromatin and slide and space nucleosomes, making the chromatin template fluid and allowing appropriate regulation of events such as transcription, DNA replication, recombination and repair. The site of action of the ATPases is determined, in part by the tissue type in which the enzyme is expressed and in part by the nature of the proteins associated with the enzyme. The ISWI complexes are generally conserved in composition and function across species. Roles in gene expression and DNA replication in heterochromatin, gene activation and repression in euchromatin, and functions related to maintaining chromosome architecture are associated with different complexes. Defects in ISWI-associated proteins may be associated with neurodegenerative disease, anencephaly, William's syndrome and melanotic tumours. Finally, the mechanism by which yeast Isw Ib influences gene transcription is discussed.

Roles for Gcn5p and Ada2p in transcription and nucleotide excision repair at the Saccharomyces cerevisiae MET16 gene.

Chromatin structure, transcription and repair of cyclobutane pyrimidine dimers at the MET16 gene of wild type, gcn5Delta and ada2Delta Saccharomyces cerevisiae cells were studied under repressing or derepressing conditions. These two components of the SAGA/ADA chromatin remodelling complexes are expendable for the basal transcription of MET16 but are mandatory for its full transcription induction. Despite their influence on transcription neither protein induces major changes in MET16 chromatin structure, but some minor ones occur. Repair at the coding region of the transcribed strand is faster than repair at non-transcribed regions in all strains and either growth condition. Moreover, the more MET16 is transcribed the faster the repair. The data show that by changing the transcription extent the rate of repair at each DNA strand is altered in a different way, confirming that repair at this locus is strongly modulated by its chromatin structure and transcription level. Deletion of GCN5 or ADA2 reduces repair at MET16. The results are discussed in light of the current understanding of Gcn5p and Ada2p functions, and they are the first to report a role for Ada2p in the nucleotide excision repair of the regulatory and transcribed regions of a gene.

Cbf1p modulates chromatin structure, transcription and repair at the Saccharomyces cerevisiae MET16 locus.

The presence of damage in the transcribed strand (TS) of active genes and its position in relation to nucleosomes influence nucleotide excision repair (NER) efficiency. We examined chromatin structure, transcription and repair at the MET16 gene of wild-type and cbf1Delta Saccharomyces cerevisiae cells under repressing or derepressing conditions. Cbf1p is a sequence-specific DNA binding protein required for MET16 chromatin remodelling. Irrespective of the level of transcription, repair at the MspI restriction fragment of MET16 exhibits periodicity in line with nucleosome positions in both strands of the regulatory region and the non-transcribed strand of the coding region. However, repair in the coding region of the TS is always faster, but exhibits periodicity only when MET16 is repressed. In general, absence of Cbf1p decreased repair in the sequences examined, although the effects were more dramatic in the Cbf1p remodelled area, with repair being reduced to the lowest levels within the nucleosome cores of this region. Our results indicate that repair at the promoter and coding regions of this lowly transcribed gene are dependent on both chromatin structure and the level of transcription. The data are discussed in light of current models relating NER and chromatin structure.

Duplex Scorpion primers in SNP analysis and FRET applications.

Scorpions are fluorogenic PCR primers with a probe element attached at the 5'-end via a PCR stopper. They are used in real-time amplicon-specific detection of PCR products in homogeneous solution. Two different formats are possible, the 'stem-loop' format and the 'duplex' format. In both cases the probing mechanism is intramolecular. We have shown that duplex Scorpions are efficient probes in real-time PCR. They give a greater fluorescent signal than stem-loop Scorpions due to the vastly increased separation between fluorophore and quencher in the active form. We have demonstrated their use in allelic discrimination at the W1282X locus of the ABCC7 gene and shown that they can be used in assays where fluorescence resonance energy transfer is required.

Presynaptic kainate receptors at hippocampal mossy fiber synapses.

Hippocampal mossy fibers, which are the axons of dentate granule cells, form powerful excitatory synapses onto the proximal dendrites of CA3 pyramidal cells. It has long been known that high-affinity binding sites for kainate, a glutamate receptor agonist, are present on mossy fibers. Here we summarize recent experiments on the role of these presynaptic kainate receptors (KARs). Application of kainate has a direct effect on the amplitude of the extracellularly recorded fiber volley, with an enhancement by low concentrations and a depression by high concentrations. These effects are mediated by KARs, because they persist in the presence of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-selective antagonist GYKI 53655, but are blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/KAR antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and the KAR antagonist SYM2081. The effects on the fiber volley are most likely caused by a depolarization of the fibers via the known ionotropic actions of KARs, because application of potassium mimics the effects. In addition to these effects on fiber excitability, low concentrations of kainate enhance transmitter release, whereas high concentrations depress transmitter release. Importantly, the synaptic release of glutamate from mossy fibers also activates these presynaptic KARs, causing an enhancement of the fiber volley and a facilitation of release that lasts for many seconds. This positive feedback contributes to the dramatic frequency facilitation that is characteristic of mossy fiber synapses. It will be interesting to determine how widespread facilitatory presynaptic KARs are at other synapses in the central nervous system.

Long-term care and nursing home coverage: are adult children substitutes for insurance policies?

Recent theoretical work suggests that in some cases, parents will forego the purchase of long-term care insurance and rely on child-provided care in old age. This paper uses data from the Asset and Health Dynamics survey and the Panel Study of Income Dynamics to examine whether the availability of children and other potential caregivers explains why so few elderly persons have long-term care insurance. In contrast to the notion that family members serve as substitutes for long-term care insurance, variables measuring the availability of informal caregivers have no statistically significant effect in models of insurance ownership and models of intentions to purchase insurance.

Reexamining the evidence of an ecological association between income inequality and health.

Several recent studies have made the provocative claim that income inequality is an important determinant of population health. The primary evidence for this hypothesis is the repeated finding--across countries and across U.S. states--that there is an association between income inequality and aggregate health outcomes. However, most of these studies examine only a single cross section of data and employ few (or even no) control variables. We examine the relationship between income inequality and aggregate health outcomes across thirty countries over a four-decade span and across forty-eight U.S. states over five decades. In large part, our findings contradict previous claims.

Synaptically released neurotransmitter fails to desensitize postsynaptic GABA(A) receptors in cerebellar cultures.

GABA concentration jump experiments performed on membrane patches predict that postsynaptic GABA(A) receptors will become desensitized following the release of the contents of a single GABA-containing synaptic vesicle. To examine this we used a single synaptic bouton stimulation technique to directly examine whether postsynaptic GABA(A) receptors in cultured cerebellar granule cells exhibit transmitter-induced desensitization. In a large number of recordings, no evidence was found for desensitization of postsynaptic GABA(A) receptors by vesicularly released transmitter. This was the case even when as many as 40 vesicles were released from a single bouton within 1.5 s. In addition, postsynaptic depolarization and application of the benzodiazepine flunitrazepam, manipulations previously shown to enhance desensitization of GABA(A) receptors, failed to unmask transmitter-induced desensitization. In contrast, a single 2- to 3-s application of a high concentration of exogenous GABA was able to depress synaptic responsiveness for up to 70 s. Furthermore, pharmacological depletion of GABA eliminated inhibitory synaptic communication, suggesting that GABA is the transmitter and the desensitization-resistant inhibitory postsynaptic currents are not mediated by a "nondesensitizing" ligand such as beta-alanine. Overall our data indicate that a specific desensitization-resistant population of GABA(A) receptors are present at postsynaptic sites on cultured cerebellar granule cells.

Presynaptic kainate receptor mediation of frequency facilitation at hippocampal mossy fiber synapses.

Inhibition of transmitter release by presynaptic receptors is widespread in the central nervous system and is typically mediated via metabotropic receptors. In contrast, very little is known about facilitatory receptors, and synaptic activation of a facilitatory autoreceptor has not been established. Here we show that activation of presynaptic kainate receptors can facilitate transmitter release from hippocampal mossy fiber synapses. Synaptic activation of these presumed ionotropic kainate receptors is very fast (<10 ms) and lasts for seconds. Thus, these presynaptic kainate receptors contribute to the short-term plasticity characteristics of mossy fiber synapses, which were previously thought to be an intrinsic property of the synapse.

In vivo chromatin remodeling by yeast ISWI homologs Isw1p and Isw2p.

Isw1p and Isw2p are budding yeast homologs of the Drosophila ISWI chromatin-remodeling ATPase. Using indirect-end-label and chromatin immunoprecipitation analysis, we show both independent and cooperative Isw1p- and Isw2p-mediated positioning of short nucleosome arrays in gene-regulatory elements at a variety of transcription units in vivo. We present evidence that both yeast ISWI complexes regulate developmental responses to starvation and that for Isw2p, recruitment by different DNA-binding proteins controls meiosis and haploid invasive growth.

Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II.

We previously identified vitamin B6 deficiency in a child presenting with seizures whose primary diagnosis was the inherited disorder hyperprolinemia type II. This is an unrecognized association, which was not explained by diet or medication. We hypothesized that pyridoxal phosphate (vitamin B6 coenzyme) was de-activated by L-Delta(1)-pyrroline-5-carboxylic acid, the major intermediate that accumulates endogenously in hyperprolinemia type II. The proposed interaction has now been investigated in vitro with high resolution 1H nuclear magnetic resonance spectroscopy and mass spectrometry at a pH of 7.4 and temperature of 310 K. Three novel adducts were identified. These were the result of a Claisen condensation (or Knoevenagel type of reaction) of the activated C-4 carbon of the pyrroline ring with the aldehyde carbon of pyridoxal phosphate. The structures of the adducts were confirmed by a combination of high performance liquid chromatography, nuclear magnetic resonance, and mass spectrometry. This interaction has not been reported before. From preliminary observations, pyrroline-5-carboxylic acid also condenses with other aromatic and aliphatic aldehydes and ketones, and this may be a previously unsuspected generic addition reaction. Pyrroline-5-carboxylic acid is thus found to be a unique endogenous vitamin antagonist. Vitamin B6 de-activation may contribute to seizures in hyperprolinemia type II, which are so far unexplained, but they may be preventable with long term vitamin B6 supplementation.

Contrasting localizations of MALS/LIN-7 PDZ proteins in brain and molecular compensation in knockout mice.

Proteins containing PDZ (postsynaptic density-95, discs large, zonula occludens) domains play a general role in recruiting receptors and enzymes to specific synaptic sites. In Caenorhabditis elegans, a complex of three PDZ proteins, LIN-2/7/10, mediates basolateral targeting of a receptor tyrosine kinase. Homologs of these LIN proteins have also been identified in higher organisms, and here we analyze the MALS/Veli (mammalian LIN-7/vertebrate homolog of LIN-7) proteins in brain. Immunohistochemical staining and in situ hybridization show that MALS occur differentially in discrete populations of neurons throughout the brain. Most neurons express only one MALS protein, although some cells contain two or even all three MALS isoforms. At the subcellular level, MALS proteins are found in both dendritic and axonal locations, suggesting that they may regulate processes at both pre- and postsynaptic sites. Targeted disruption of MALS-1 and MALS-2 does not yield a detectable phenotype, and hippocampal synaptic function and plasticity are intact in the MALS-1/2 double knockouts. Interestingly, MALS-3 protein is dramatically induced in the MALS-1/2 double knockouts, implying that dynamic changes in protein expression may play an important regulatory role for this family of synaptic PDZ proteins.