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Generalized myasthenia gravis (gMG) is a chronic autoimmune disorder that leads to muscle weakness and fatigue. Initial treatment is with pyridostigmine and corticosteroids, but if these are ineffective off-label immunosuppressants are used. There is some published evidence that rituximab, an anti-CD20 monoclonal antibody, may be effective in the treatment of gMG, although it is unlicensed for this condition.
Methods
Evidence for rituximab as a fourth-line or later immunosuppressant treatment for refractory gMG was assessed using the One Wales Medicines (OWM) process and made available in 2019. OWM provides an access route to medicines for specific patient cohorts where no licensed treatments are routinely available. A review in 2022 identified new evidence suggesting that lower dose rituximab could be an effective first-line immunosuppressant treatment for gMG. Clinicians confirmed an unmet need, so a reassessment by OWM was considered appropriate. Clinical and cost effectiveness were assessed through a literature search, budget impact analysis, and clinical expert opinion.
Results
The OWM Advisory Group assessed the evidence outlined in an evidence summary report. Clinical experts also provided the clinical context and current treatment options for patients with gMG. Overall, it was found that rituximab as a first-line treatment provided a potential improvement in patient outcomes and value for money, compared with current therapy. It was, therefore, supported for routine use in April 2023. Starting and stopping criteria for rituximab were developed in collaboration with clinical experts. All patients in Wales who meet the agreed starting criteria will now be given the option of routine treatment with rituximab.
Conclusions
The OWM process allows routine access to rituximab as a first-line immunosuppressant treatment for gMG. The OWM team are collaborating with clinicians across Wales to instigate a new systematic method for collecting and analyzing patient outcomes. These real-world data will be used to assess benefit to ensure continued access to the best treatments for Welsh patients.
We introduce and study two conditions on groups of homeomorphisms of Cantor space, namely the conditions of being vigorous and of being flawless. These concepts are dynamical in nature, and allow us to study a certain interplay between the dynamics of an action and the algebraic properties of the acting group. A group $G\leq \operatorname {Homeo}(\mathfrak {C})$ is vigorous if for any clopen set A and proper clopen subsets B and C of A, there is $\gamma \in G$ in the pointwise stabiliser of $\mathfrak {C}\backslash A$ with $B\gamma \subseteq C$. A nontrivial group $G\leq \operatorname {Homeo}(\mathfrak {C})$ is flawless if for all k and w a nontrivial freely reduced product expression on k variables (including inverse symbols), a particular subgroup $w(G)_\circ $ of the verbal subgroup $w(G)$ is the whole group. We show: 1) simple vigorous groups are either two-generated by torsion elements, or not finitely generated, 2) flawless groups are both perfect and lawless, 3) vigorous groups are simple if and only if they are flawless, and, 4) the class of vigorous simple subgroups of $\operatorname {Homeo}(\mathfrak {C})$ is fairly broad (the class is closed under various natural constructions and contains many well known groups, such as the commutator subgroups of the Higman–Thompson groups $G_{n,r}$, the Brin-Thompson groups $nV$, Röver’s group $V(\Gamma )$, and others of Nekrashevych’s ‘simple groups of dynamical origin’).
The COVID-19 pandemic highlighted the importance of the care provided by family members and close friends to older people living in long-term care (LTC) homes. Our implementation science team helped three Ontario LTC homes to implement an intervention to allow family members to enter the homes during pandemic lockdowns.
Objective
We used a variety of methods to support the implementation, and this paper reports results from an Ontario-wide survey intended to help us understand the nature of the care provided by family caregivers.
Methods
We administered a survey of essential caregivers in Ontario, and a single open-ended question yielded a substantial qualitative data set that we analysed with a coding and theming procedure that yielded 13 themes.
Findings
The 13 themes reveal deficiencies in Ontario’s LTC sector, attempts to cope with the deficiencies, and efforts to influence change and improvement.
Discussion
Our findings indicate that essential caregivers find it necessary to take on vital roles in order to shore up two significant gaps in the current system: they provide psychosocial and emotional (and sometimes even basic) care to residents, and they play a monitoring and advocacy role to compensate for the failings of the current regulatory compliance regime.
Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians.
Methods
In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance.
Results
Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12.
Conclusions
Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.
Healthcare innovations often represent important improvements in population welfare, but at what cost, and to whom? Health technology assessment (HTA) is a multidisciplinary process to inform resource allocation. HTA is conventionally anchored on health maximization as the only relevant output of health services. If we accept the proposition that health technologies can generate value outside the healthcare system, resource allocation decisions could be suboptimal from a societal perspective. Incorporating “broader value” in HTA as derived from social values and patient experience could provide a richer evaluative space for informing resource allocation decisions. This article considers how HTA is practiced and what its current context implies for adopting “broader value” to evaluating health technologies. Methodological challenges are highlighted, as is a future research agenda. Ireland serves as an example of a healthcare system that both has an explicit role for HTA and is evolving under a current program of reform to offer universal, single-tier access to public services. There are various ways in which HTA processes could move beyond health, including considering the processes of care delivery and/or expanding the evaluative space to some broader concept of well-being. Methods to facilitate the latter exist, but their adaptation to HTA is still emerging. We recommend a multi-stakeholder working group to develop and advance an international agenda for HTA that captures welfare/benefit beyond health.
The use of communities of practice (CoP) to support the application of knowledge in improved geriatric care practice is not widely understood. This case study’s aim was to gain a deeper understanding of the knowledge-to-action (KTA) processes of a CoP focused on environmental design, to improve how persons with dementia find their way around in long-term care (LTC) homes. Qualitative data were collected (key informant interviews, observations, and document review), and analysed using emergent coding. CoP members contributed extensive knowledge to the KTA process characterized by the following themes: team dynamics, employing a structured process, technology use, varied forms of knowledge, and a clear initiative. The study’s CoP effectively synthesized and translated knowledge into practical tools to inform changes in practice, programs, and policy on dementia care. More research is needed on how to involve patients and caregivers in the KTA processes, and to ensure that practical application of knowledge has financial and policy support
Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.
The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.
The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.
Individuals with schizophrenia are at higher risk of physical illnesses, which are a major contributor to their 20-year reduced life expectancy. It is currently unknown what causes the increased risk of physical illness in schizophrenia.
Aims
To link genetic data from a clinically ascertained sample of individuals with schizophrenia to anonymised National Health Service (NHS) records. To assess (a) rates of physical illness in those with schizophrenia, and (b) whether physical illness in schizophrenia is associated with genetic liability.
Method
We linked genetic data from a clinically ascertained sample of individuals with schizophrenia (Cardiff Cognition in Schizophrenia participants, n = 896) to anonymised NHS records held in the Secure Anonymised Information Linkage (SAIL) databank. Physical illnesses were defined from the General Practice Database and Patient Episode Database for Wales. Genetic liability for schizophrenia was indexed by (a) rare copy number variants (CNVs), and (b) polygenic risk scores.
Results
Individuals with schizophrenia in SAIL had increased rates of epilepsy (standardised rate ratio (SRR) = 5.34), intellectual disability (SRR = 3.11), type 2 diabetes (SRR = 2.45), congenital disorders (SRR = 1.77), ischaemic heart disease (SRR = 1.57) and smoking (SRR = 1.44) in comparison with the general SAIL population. In those with schizophrenia, carrier status for schizophrenia-associated CNVs and neurodevelopmental disorder-associated CNVs was associated with height (P = 0.015–0.017), with carriers being 7.5–7.7 cm shorter than non-carriers. We did not find evidence that the increased rates of poor physical health outcomes in schizophrenia were associated with genetic liability for the disorder.
Conclusions
This study demonstrates the value of and potential for linking genetic data from clinically ascertained research studies to anonymised health records. The increased risk for physical illness in schizophrenia is not caused by genetic liability for the disorder.
Around 30% of individuals with schizophrenia remain symptomatic and significantly impaired despite antipsychotic treatment and are considered to be treatment resistant. Clinicians are currently unable to predict which patients are at higher risk of treatment resistance.
Aims
To determine whether genetic liability for schizophrenia and/or clinical characteristics measurable at illness onset can prospectively indicate a higher risk of treatment-resistant psychosis (TRP).
Method
In 1070 individuals with schizophrenia or related psychotic disorders, schizophrenia polygenic risk scores (PRS) and large copy number variations (CNVs) were assessed for enrichment in TRP. Regression and machine-learning approaches were used to investigate the association of phenotypes related to demographics, family history, premorbid factors and illness onset with TRP.
Results
Younger age at onset (odds ratio 0.94, P = 7.79 × 10−13) and poor premorbid social adjustment (odds ratio 1.64, P = 2.41 × 10−4) increased risk of TRP in univariate regression analyses. These factors remained associated in multivariate regression analyses, which also found lower premorbid IQ (odds ratio 0.98, P = 7.76 × 10−3), younger father's age at birth (odds ratio 0.97, P = 0.015) and cannabis use (odds ratio 1.60, P = 0.025) increased the risk of TRP. Machine-learning approaches found age at onset to be the most important predictor and also identified premorbid IQ and poor social adjustment as predictors of TRP, mirroring findings from regression analyses. Genetic liability for schizophrenia was not associated with TRP.
Conclusions
People with an earlier age at onset of psychosis and poor premorbid functioning are more likely to be treatment resistant. The genetic architecture of susceptibility to schizophrenia may be distinct from that of treatment outcomes.
Rare copy number variants (CNVs) are associated with risk of neurodevelopmental disorders characterised by varying degrees of cognitive impairment, including schizophrenia, autism spectrum disorder and intellectual disability. However, the effects of many individual CNVs in carriers without neurodevelopmental disorders are not yet fully understood, and little is known about the effects of reciprocal copy number changes of known pathogenic loci.
Aims
We aimed to analyse the effect of CNV carrier status on cognitive performance and measures of occupational and social outcomes in unaffected individuals from the UK Biobank.
Method
We called CNVs in the full UK Biobank sample and analysed data from 420 247 individuals who passed CNV quality control, reported White British or Irish ancestry and were not diagnosed with neurodevelopmental disorders. We analysed 33 pathogenic CNVs, including their reciprocal deletions/duplications, for association with seven cognitive tests and four general measures of functioning: academic qualifications, occupation, household income and Townsend Deprivation Index.
Results
Most CNVs (24 out of 33) were associated with reduced performance on at least one cognitive test or measure of functioning. The changes on the cognitive tests were modest (average reduction of 0.13 s.d.) but varied markedly between CNVs. All 12 schizophrenia-associated CNVs were associated with significant impairments on measures of functioning.
Conclusions
CNVs implicated in neurodevelopmental disorders, including schizophrenia, are associated with cognitive deficits, even among unaffected individuals. These deficits may be subtle but CNV carriers have significant disadvantages in educational attainment and ability to earn income in adult life.
We empirically test separation of ownership and control (SOC) and the interaction of SOC with farmer effort on farm success using data from the U.S. Department of Agriculture's Agricultural Resource Management Survey. We use a two-stage least-squares approach with instrumental variables that proxy for participation constraints in binding incentive contracts. We find that the interaction has a significantly positive effect on success for grain farms and an insignificant effect for livestock farms. The results are consistent with hypotheses by Allen and Lueck (1998), but our model predicts that farms with SOC are likely to be more successful than farms without SOC despite exogenous uncertainty and agency costs.
Dr. Raghavan Charudattan has worked in the area of biological control of weeds with plant pathogenic fungi for nearly four decades. He has maintained his research program in this line throughout his career. The scientific discoveries and contributions that he has made have been recognized by his peers and demonstrated through his election as fellow of both the Weed Science Society of America and the American Phytopathological Society. The basic knowledge that he has contributed to our understanding of the fundamental biology of weed/pathogen interactions and his contributions in the areas of mycology, etiology, and natural products will have long-lasting effects. Equally important to the basic and applied research that he has conducted is his role as a mentor and colleague. Dr. Charudattan has contributed to the scientific development of more than 60 students, postdocs, and scientists from more than 20 countries. Dr. Charudattan has contributed to the establishment of biological control of weeds with pathogens as a permanent and highly productive area of weed control research.
Small, irregular terraces on hillslopes, or terracettes, are common landscape features throughout west central China. Despite their prevalence, there is limited understanding of the nature of these topographic features, the processes that form them, and the role humans played in their formation. We used an interdisciplinary approach to investigate the geology, ecology, and cultural history of terracette development within Jiuzhaigou National Park, Sichuan Province, China. Terracettes occur on south facing, 20° slopes at 2500 m elevation, which appears to coincide with places people historically preferred to build villages. Ethnographic interviews suggest that traditional swidden agricultural cycles removed tree roots, causing the loess sediments to lose cohesion, slump, and the terrace risers to retreat uphill over time. This evidence is supported by landslide debris at terracette faces. Archaeological analysis of terracette sites reveal remains of rammed spread soil structures, bones, stone tools, and ceramics dating from at least 2200 years before present within a distinct paleosol layer. Radiocarbon and optically stimulated luminescence dating of terracette sediments ranged in age from between 1500 and 2000 14C yr BP and between 16 and 0.30"ka, respectively. These multiple lines of evidence indicate a long history of human habitation within Jiuzhaigou National Park and taken together, suggest strong links between terracette formation and human-landuse interactions.
J. L. Schellenberg's Philosophy of Religion argues for a specific brand of sceptical religion that takes ‘Ultimism’ – the proposition that there is a metaphysically, axiologically, and soteriologically ultimate reality – to be the object to which the sceptical religionist should assent. In this article I shall argue that Ietsism – the proposition that there is merely something transcendental worth committing ourselves to religiously – is a preferable object of assent. This is for two primary reasons. First, Ietsism is far more modest than Ultimism; Ietsism, in fact, is open to the truth of Ultimism, while the converse does not hold. Second, Ietsism can fulfil the same criteria that compel Schellenberg to argue for Ultimism.
Ediacara-type fossils are found in a diverse array of preservational styles, implying that multiple taphonomic mechanisms might have been responsible for their preservational expression. For many Ediacara fossils, the “death mask” model has been invoked as the primary taphonomic pathway. The key to this preservational regime is the replication or sealing of sediments around the degrading organisms by microbially induced precipitation of authigenic pyrite, leading toward fossil preservation along bedding planes. Nama-style preservation, on the other hand, captures Ediacaran organisms as molds and three-dimensional casts within coarse-grained mass flow beds, and has been previously regarded as showing little or no evidence of a microbial preservational influence. To further understand these two seemingly distinct taphonomic pathways, we investigated the three-dimensionally preserved Ediacaran fossil Pteridinium simplex from mass flow deposits of the upper Kliphoek Member, Dabis Formation, Kuibis Subgroup, southern Namibia. Our analysis, using a combination of petrographic and micro-analytical methods, shows that Pteridinium simplex vanes are replicated with minor pyrite, but are most often represented by open voids that can be filled with secondary carbonate material; clay minerals are also found in association with the vanes, but their origin remains unresolved. The scarcity of pyrite and the development of voids are likely related to oxidative weathering and it is possible that microbial activities and authigenic pyrite may have contributed to the preservation of Pteridinium simplex; however, any microbes growing on P. simplex vanes within mass flow deposits were unlikely to have formed thick mats as envisioned in the death mask model. Differential weathering of replicating minerals and precipitation of secondary minerals greatly facilitate fossil collection and morphological characterization by allowing Pteridinium simplex vanes to be parted from the massive hosting sandstone.
Copy number variants (CNVs) are structural changes in chromosomes that result in deletions, duplications, inversions or translocations of large DNA segments. Eleven confirmed CNV loci have been identified as rare but important risk factors in schizophrenia. These CNVs are also associated with other neurodevelopmental disorders and medical/physical comorbidities. Although the penetrance of the CNVs for schizophrenia (the chance that CNV carriers will develop the disorder) is modest, the penetrance of CNVs for any early-onset developmental disorder (e.g. intellectual disability or autism) is much higher. Testing for CNVs is now affordable and being used in clinical genetics and neurodevelopmental disorders clinics. It is possible that testing will be expanded to psychiatric clinics. This article provides a clinically relevant overview of recent CNV findings in schizophrenia and related disorders.
This paper reports on the perceptions and practices of men who have frequent unprotected sex with men in a socio-legal environment defined by the 1998 decision of the Supreme Court of Canada in R. v. Cuerrier. HIV-positive people are increasingly finding themselves in court since Cuerrier, and many are trying to take account of legal reasoning in their own conduct. The judicial construction of behaviour likely to transmit HIV relies on a set of presumptions concerning individual responsibility, rational and contractual interaction, and consenting adults that raises a series of ambiguities and uncertainties among HIV-positive people attempting to implement them in everyday life. While some express support for the reasoning in Cuerrier, others struggle with practical dilemmas in sexual interaction, and a minority strand of ethical reasoning advances a “buyer beware” principle. This latter view occurs in a social environment where HIV-positive people experience strong disincentives to disclose in the face of potential rejection or discrimination once their sero-status is known. Examination of the social consequences of Cuerrier raises questions about the viability of relying on the enforcement of disclosure, through threat of criminal prosecution, as an effective method of HIV prevention, especially when most practical, day-to-day HIV prevention occurs when safer sex is practised consistently regardless of disclosure.
A number of copy number variants (CNVs) have been suggested as susceptibility factors for schizophrenia. For some of these the data remain equivocal, and the frequency in individuals with schizophrenia is uncertain.
Aims
To determine the contribution of CNVs at 15 schizophrenia-associated loci (a) using a large new data-set of patients with schizophrenia(n = 6882) and controls (n = 6316), and (b) combining our results with those from previous studies.
Method
We used Illumina microarrays to analyse our data. Analyses were restricted to 520 766 probes common to all arrays used in the different data-sets.
Results
We found higher rates in participants with schizophrenia than in controls for 13 of the 15 previously implicated CNVs. Six were nominally significantly associated (P<0.05) in this new data-set: deletions at 1q21.1, NRXN1, 15q11.2 and 22q11.2 and duplications at 16p11.2 and the Angelman/Prader–Willi Syndrome (AS/PWS) region. All eight AS/PWS duplications in patients were of maternal origin. When combined with published data, 11 of the 15 loci showed highly significant evidence for association with schizophrenia(P<4.1×10−4).
Conclusions
We strengthen the support for the majority of the previously implicated CNVs in schizophrenia. About 2.5% of patients with schizophrenia and 0.9% of controls carry a large, detectable CNV at one of these loci. Routine CNV screening may be clinically appropriate given the high rate of known deleterious mutations in the disorder and the comorbidity associated with these heritable mutations.