Vulnerable defendants in the criminal courts: a review of provision for adults and children

A report on the treatment of vulnerable defendants within the criminal courts of England and Wales. The report is in two parts: Part I is concerned with vulnerable adult defendants, and particularly those with learning disabilities; Part II is about child defendants – that is, defendants aged between 10 and 17

Disability and the criminal justice system in Zambia

Drawing on multi-method research conducted in 2013-2014, this paper considers the extent and nature of disadvantage experienced by individuals with psychosocial and intellectual disabilities (PID) who come into contact with criminal justice system in Zambia. The research was conducted as part of a wider project aiming to bring about improvements in how people with PID are dealt with by criminal justice services. The research activities included interviews with 29 individuals with PID who had experienced the criminal justice system as suspects, defendants or prisoners (‘self-advocates’). A focus group and interviews were also conducted with family members of people with PID who had criminal justice experience. The study found that people with PID in contact with criminal justice services in Zambia are disadvantaged and discriminated against routinely and systematically. Like all detainees, they experience harsh and at times brutal conditions of detention. However, because of their disabilities, such experiences can be more keenly felt: their disabilities may be exacerbated by detention or by limited or non-existent health care; and they are likely to be less resourceful than other detainees and, therefore, less able to cope with the privations of detention

Discovery of <i>Aspergillus frankstonensis</i> sp nov during environmental sampling for animal and human fungal pathogens

Invasive fungal infections (IFI) due to species in Aspergillus section Fumigati (ASF), including the Aspergillus viridinutans species complex (AVSC), are increasingly reported in humans and cats. The risk of exposure to these medically important fungi in Australia is unknown. Air and soil was sampled from the domiciles of pet cats diagnosed with these IFI and from a nature reserve in Frankston, Victoria, where Aspergillus viridinutans sensu stricto was discovered in 1954. Of 104 ASF species isolated, 61% were A. fumigatus sensu stricto, 9% were AVSC (A. felis-clade and A. frankstonensis sp. nov.) and 30% were other species (30%). Seven pathogenic ASF species known to cause disease in humans and animals (A. felis-clade, A. fischeri, A. thermomutatus, A. lentulus, A. laciniosus A. fumisynnematus, A. hiratsukae) comprised 25% of isolates overall. AVSC species were only isolated from Frankston soil where they were abundant, suggesting a particular ecological niche. Phylogenetic, morphological and metabolomic analyses of these isolates identified a new species, A. frankstonensis that is phylogenetically distinct from other AVSC species, heterothallic and produces a unique array of extrolites, including the UV spectrum characterized compounds DOLD, RAIMO and CALBO. Shared morphological and physiological characteristics with other AVSC species include slow sporulation, optimal growth at 37°C, no growth at 50°C, and viriditoxin production. Overall, the risk of environmental exposure to pathogenic species in ASF in Australia appears to be high, but there was no evidence of direct environmental exposure to AVSC species in areas where humans and cats cohabitate

Personalized rTMS for Depression: A Review

Personalized treatments are gaining momentum across all fields of medicine. Precision medicine can be applied to neuromodulatory techniques, where focused brain stimulation treatments such as repetitive transcranial magnetic stimulation (rTMS) are used to modulate brain circuits and alleviate clinical symptoms. rTMS is well-tolerated and clinically effective for treatment-resistant depression (TRD) and other neuropsychiatric disorders. However, despite its wide stimulation parameter space (location, angle, pattern, frequency, and intensity can be adjusted), rTMS is currently applied in a one-size-fits-all manner, potentially contributing to its suboptimal clinical response (~50%). In this review, we examine components of rTMS that can be optimized to account for inter-individual variability in neural function and anatomy. We discuss current treatment options for TRD, the neural mechanisms thought to underlie treatment, differences in FDA-cleared devices, targeting strategies, stimulation parameter selection, and adaptive closed-loop rTMS to improve treatment outcomes. We suggest that better understanding of the wide and modifiable parameter space of rTMS will greatly improve clinical outcome

Clinical impact of genomic testing in patients with suspected monogenic kidney disease

Purpose: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Methods: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Results: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design

Cerebral blood flow and cerebrovascular reactivity are modified by maturational stage and exercise training status during youth

New Findings: What is the central question of this study? Gonadal hormones modulate cerebrovascular function while insulin‐like growth factor 1 (IGF‐1) facilitates exercise‐mediated cerebral angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF‐1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown. What is the main finding and its importance? Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise‐induced improvements in cerebrovascular function are attainable as early as the first decade of life. Abstract: Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia ( CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) are modulated by gonadal hormone activity, while insulin‐like growth factor 1 facilitates exercise‐mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ in n = 128 adolescents characterised as endurance‐exercise trained (males: n = 30, females: n = 36) or untrained (males: n = 29, females: n = 33). Participants were further categorised as pre‐ (males: n = 35, females: n = 33) or post‐ (males: n = 24, females: n = 36) peak height velocity (PHV) to determine pubertal or ‘maturity’ status. Three‐factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Data are reported as group means (SD). Pre‐PHV youth demonstrated elevated gCBF and slower CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response times than post‐PHV counterparts (both: P ≤ 0.001). gCBF was only elevated in post‐PHV trained males when compared to untrained counterparts (634 (43) vs. 578 (46) ml min−1; P = 0.007). However, CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time was faster in pre‐ (72 (20) vs. 95 (29) s; P ≤ 0.001), but not post‐PHV (P = 0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post‐PHV youth (r2 = 0.19; P ≤ 0.001) and CV R C O 2 ${\mathrm{CV}}{{\mathrm{R}}_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ mean response time in pre‐PHV youth (r2 = 0.13; P = 0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p