Major Deficits Research Articles

Bortezomib-induced neuropathy is in part mediated by the sensitization of TRPV1 channels

TRPV1 is an ion channel that transduces noxious heat and chemical stimuli and is expressed in small fiber primary sensory neurons that represent almost half of skin nerve terminals. Tissue injury and inflammation result in the sensitization of TRPV1 and sustained activation of TRPV1 can lead to cellular toxicity though calcium influx. To identify signals that trigger TRPV1 sensitization after a 24-h exposure, we developed a phenotypic assay in mouse primary sensory neurons and performed an unbiased screen with a compound library of 480 diverse bioactive compounds. Chemotherapeutic agents, calcium ion deregulators and protein synthesis inhibitors were long-acting TRPV1 sensitizers. Amongst the strongest TRPV1 sensitizers were proteasome inhibitors, a class that includes bortezomib, a chemotherapeutic agent that causes small fiber neuropathy in 30–50% of patients. Prolonged exposure of bortezomib produced a TRPV1 sensitization that lasted several days and neurite retraction in vitro and histological and behavioral changes in male mice in vivo. TRPV1 knockout mice were protected from epidermal nerve fiber loss and a loss of sensory discrimination after bortezomib treatment. We conclude that long-term TRPV1 sensitization contributes to the development of bortezomib-induced neuropathy and the consequent loss of sensation, major deficits experienced by patients under this chemotherapeutic agent.

Contemporary diagnosis and management of congenital microtia and aural atresia : Part2: Overview of therapeutic approaches

Congenital malformations of the pinna and aural atresia can result in major aesthetic and functional deficits. Knowledge about embryologic developments and established classification systems is an essential requirement when dealing with affected patients. Early detection of deficiencies and introduction of appropriate diagnostic measures is vital to initiate adequate therapies and prevent long-term disabilities. Treatment for malformations of the pinna-if requested-is mostly surgical, infrequently an epithesis is applied. As in other surgical fields, tissue engineering will likely play acrucial role in the future. Treatment of aural stenosis and atresia aims at improvement of hearing levels and prevention of secondary complications like cholesteatoma and chronic otorrhea. Auditory rehabilitation comprises aspectrum from conventional hearing aids to invasive hearing implants, the latter being favored in recent years.

Boron deficiency responses in maize (Zea mays L.) roots

AbstractBackgroundBoron (B) is an essential micronutrient for plants. Dicot plants respond to insufficient B supply by altering root architecture and root hair growth. How root systems of rather low‐B demanding monocot species such as maize (Zea mays L.) respond to B deficiency in terra has not been experimentally resolved, yet.AimsThe study aims to investigate root responses and their physiological consequences under B deficiency during the vegetative growth of maize.MethodsB73 wild‐type (WT) maize and its root hairless rth3 mutant were grown under varying B supply conditions in soil columns and in an automated root phenotyping facility. Biomass data, root system architecture traits, the mineral elemental composition and molecular B‐deficiency responses were quantified.ResultsThough having very low leaf B concentrations, no major growth deficit, apart from chlorotic stripes on leaves, was recorded on maize root and shoot development, with or without root hairs, on B‐deficient conditions. Although leaf B concentration of the rth3 mutant is significantly lower under B‐deficient and under B‐surplus conditions compared to the WT, the rth3 mutant neither developed a larger total root length, more fine roots nor displayed a higher expression of B uptake transporters as compensatory adaptations.ConclusionsStrikingly, maize plants did neither react with an inhibited root growth nor by a compensatory root foraging behaviour to severe B‐deficient in terra growth conditions. This is rather atypical for plants. The performance and altered leaf B concentrations of rth3 mutants may be biased by secondary effects, such as an overall reduced root growth.

Abstract 18916: Myocardial Proteomic Signatures in Human Heart Failure With Preserved Ejection Fraction

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) constitutes more than half of all heart failure but has few effective therapies. Recent myocardial transcriptomics and metabolomics have revealed major differences between HFpEF and controls and HF with a reduced ejection fraction (HFrEF); however, how this translates at the protein level is unknown. Methods: Endomyocardial biopsies from patients with HFpEF, nonfailing donor controls and analyzed by data-dependent (n=10 HFpEF, n=9 non-failing controls) and data-independent (n=44 HFpEF, n=5 non-failing controls) mass-spectrometry-based proteomics. Results: The results were integrated with reported RNAseq and clinical characteristics. Proteomics data were analyzed with machine learning and gene ontology (GO) pathway analysis. Both HFpEF and HFrEF proteomes exhibited remarkable similarities, showing upregulation of cytoskeletal pathways and down regulation of oxidative phosphorylation pathways. Notably, structural ribosomal proteins and proteins associated with EIF 2 signaling were downregulated in HFpEF but not HFrEF. Integration with prior transcriptome data found a striking discrepancy between gene (up) and protein (down) expression for oxidative phosphorylation pathways in HFpEF, versus concordant reduction in HFrEF. Agnostic clustering of the HFpEF proteome identified two sub-groups, one with marked downregulation of oxidative phosphorylation and translational initiation pathways versus the other. This sub-group also had the highest proportion of HFpEF patients above the median BMI (40 kg/m 2 in our cohort). Conclusions: To our surprise, no hemodynamic and echocardiographic differences were observed between these groups. Despite marked differences in clinical presentation and pathophysiology, both HFpEF and HFrEF had very similar changes in protein abundance related to cytoskeletal and oxidative phosphorylation related pathways. Integration of proteomics, transcriptomics, and pathway analysis identifies a major deficit in protein translation in HFpEF that is not predictable based on clinical indices. These data reveal a unique proteomic HFpEF signature and identify potential proteins and pathways for therapeutic intervention.

Assessing inter-rater agreement of the intellectual disability-frailty index short form: A descriptive pilot study.

Frailty is a health concern for many adults with intellectual disability and should be measured to detect at-risk conditions, monitor disease, plan treatment, and gauge mortality. This descriptive pilot study evaluated measurement consistency (inter-rater agreement) of the Intellectual Disability-Frailty Index Short Form among multiple assessors with 20 adults (M age = 48.3 years) who had intellectual and multiple disabilities. Agreement percentages were computed for (a) non-frail, pre-frail, and frail categories derived from total index scores, and (b) each of 17 deficits listed on the form. Low average inter-rater agreement (<85%) was obtained on the index frail categories, several of the assessed deficits had acceptable inter-rater agreement (84.2-100%), while the majority of deficits were associated with moderate-to-low agreement percentages. Though research supports the Intellectual Disability-Frailty Index Short Form as a valid and practical frailty assessment instrument, our findings suggest that full-scale inter-rater agreement must be improved by adding more specificity to the form, clarifying instructions for assessors, and providing competency-based training in assessment implementation.

A chat about actinic keratosis: Examining capabilities and user experience of ChatGPT as a digital health technology in dermato‐oncology

AbstractBackgroundThe potential applications of artificial intelligence (AI) in dermatology are evolving rapidly. Chatbots are an emerging trend in healthcare that rely on large language models (LLMs) to generate answers to prompts from users. However, the factuality and user experience (UX) of such chatbots remain to be evaluated in the context of dermato‐oncology.ObjectivesTo examine the potential of Chat Generative Pretrained Transformer (ChatGPT) as a reliable source of information in the context of actinic keratosis (AK) and to evaluate clinicians' attitudes and UX with regard to the chatbot.MethodsA set of 38 clinical questions were compiled and entered as natural language queries in separate, individual conversation threads in ChatGPT (OpenAI, default GPT 3.5). Questions pertain to patient education, diagnosis, and treatment. ChatGPT's responses were presented to a panel of 7 dermatologists for rating of factual accuracy, currency of information, and completeness of the response. Attitudes towards ChatGTP were explored qualitatively and quantitatively using a validated user experience questionnaire (UEQ).ResultsChatGPT answered 12 questions (31.6%) with an accurate, current, and complete response. ChatGPT performed best for questions on patient education, including pathogenesis of AK and potential risk factors, but struggled with diagnosis and treatment. Major deficits were seen in grading AK, providing up‐to‐date treatment guidance, and asserting incorrect information with unwarranted confidence. Further, responses were considered verbose with an average word count of 198 (SD 55) and overly alarming of the risk of malignant transformation. Based on UEQ responses, the expert panel considered ChatGPT an attractive and efficient tool, scoring highest for speed of information retrieval, but deemed the chatbot inaccurate and verbose, scoring lowest for clarity.ConclusionsWhile dermatologists rated ChatGPT high in UX, the underlying LLMs that enable such chatbots require further development to guarantee accuracy and concision required in a clinical setting.

Left and right corticobasal syndrome: comparison of cognitive profiles between metabolic imaging - matched groups

BackgroundCorticobasal syndrome (CBS) is typically asymmetric. Case reports suggest that left-hemisphere CBS (lhCBS) is associated with major language impairment, and right-hemisphere CBS (rhCBS) is associated with major visuospatial deficits, but no group study has ever verified these observations. In our study, we enrolled 49 patients with CBS, classified them as lhCBS or rhCBS based on asymmetry of hypometabolism on brain FDG-PET and compared their cognitive and behavioural profiles.MethodsWe defined asymmetry of hypometabolism upon visual inspection of qualitative PET images and confirmed it through paired comparison of left- and right-hemisphere FDG uptake values. The two groups were also matched for severity of hypometabolism within the more affected and more preserved hemispheres, to unravel differences in the cognitive profiles ascribable specifically to each hemisphere’s functional specializations. All patients were assessed for memory, language, executive and visuospatial deficits, apraxia, neglect, dyscalculia, agraphia and behavioural disturbances.ResultsLhCBS (n. 26) and rhCBS (n. 23) patients did not differ for demographics, disease duration and severity of global cognitive impairment. The two cognitive profiles were largely overlapping, with two exceptions: Digit span forward was poorer in lhCBS, and visual neglect was more frequent in rhCBS.ConclusionsAfter balancing out patients for hemispheric hypometabolism, we did not confirm worse language or visuospatial deficits in, respectively, lhCBS and rhCBS. However, verbal short-term memory was more impaired in lhCBS, and spatial attention was more impaired in rhCBS. Both of these functions reflect the functional specialization of the left and right fronto-parietal pathways, i.e. of the main loci of neurodegeneration in CBS.

Long-Term Neuropsychiatric Developmental Defects after Neonatal Organophosphate Exposure: Mitigation by Synthetic Neurosteroids.

Children are much more susceptible to the neurotoxic effects of organophosphate (OP) pesticides and nerve agents than adults. OP poisoning in children leads to acute seizures and neuropsychiatric sequela, including the development of long-term disabilities and cognitive impairments. Despite these risks, there are few chronic rodent models that use pediatric OP exposure for studying neurodevelopmental consequences and interventions. Here, we investigated the protective effect of the neurosteroid ganaxolone (GX) on the long-term developmental impact of neonatal exposure to the OP compound, diisopropyl-fluorophosphate (DFP). Pediatric postnatal day-28 rats were acutely exposed to DFP, and at 3 and 10 months after exposure, they were evaluated using a series of cognitive and behavioral tests with or without the postexposure treatment of GX. Analysis of the neuropathology was performed after 10 months. DFP-exposed animals displayed significant long-term deficits in mood, anxiety, depression, and aggressive traits. In spatial and nonspatial cognitive tests, they displayed striking impairments in learning and memory. Analysis of brain sections showed significant loss of neuronal nuclei antigen(+) principal neurons, parvalbumin(+) inhibitory interneurons, and neurogenesis, along with increased astrogliosis, microglial neuroinflammation, and mossy fiber sprouting. These detrimental neuropathological changes are consistent with behavioral dysfunctions. In the neurosteroid GX-treated cohort, behavioral and cognitive deficits were significantly reduced and were associated with strong protection against long-term neuroinflammation and neurodegeneration. In conclusion, this pediatric model replicates the salient features of children exposed to OPs, and the protective outcomes from neurosteroid intervention support the viability of developing this strategy for mitigating the long-term effects of acute OP exposure in children. SIGNIFICANCE STATEMENT: An estimated 3 million organophosphate exposures occur annually worldwide, with children comprising over 30% of all victims. Our understanding of the neurodevelopmental consequences in children exposed to organophosphates is limited. Here, we investigated the long-term impact of neonatal exposure to diisopropyl-fluorophosphate in pediatric rats. Neurosteroid treatment protected against major deficits in behavior and memory and was well correlated with neuropathological changes. Overall, this pediatric model is helpful to screen novel therapies to mitigate long-term developmental deficits of organophosphate exposure.

Radiosurgery With Prior Embolization Versus Radiosurgery Alone for Intracranial Arteriovenous Malformations: A Systematic Review and Meta-Analysis.

The addition of adjuvant embolization to radiosurgery has been proposed as a means of improving treatment outcomes of intracranial arteriovenous malformations (AVMs). However, the relative efficacy and safety of radiosurgery with adjuvant embolization vs radiosurgery alone remain uncertain. Moreover, previous systematic reviews and meta-analyses have included a limited number of studies and did not consider the effects of baseline characteristics, including AVM volume, on the outcomes. This systematic review aimed to evaluate the efficacy of preradiosurgery embolization for intracranial AVMs with consideration to matching status between participants in each treatment group. A systematic review and meta-analysis were conducted by searching electronic databases, including PubMed, Scopus, and Cochrane Library, up to January 2023. All studies evaluating the utilization of preradiosurgery embolization were included. A total of 70 studies (9 matched and 71 unmatched) with a total of 12 088 patients were included. The mean age of the included patients was 32.41 years, and 48.91% of the patients were female. Preradiosurgery embolization was used for larger AVMs and patients with previous hemorrhage ( P < .01, P = .02, respectively). The obliteration rate for preradiosurgery embolization (49.44%) was lower compared with radiosurgery alone (61.42%, odds ratio = 0.56, P < .01), regardless of the matching status of the analyzed studies. Although prior embolization was associated higher rate of cyst formation ( P = .04), it lowered the odds of radiation-induced changes ( P = .04). The risks of minor and major neurological deficits, postradiosurgery hemorrhage, and mortality were comparable between groups. This study provides evidence that although preradiosurgery embolization is a suitable option to reduce the AVM size for future radiosurgical interventions, it may not be useful for same-sized AVMs eligible for radiosurgery. Utilization of preradiosurgery embolization in suitable lesions for radiosurgery may result in the added cost and burden of an endovascular procedure.

Psychiatric disorders and cardiovascular diseases: A mendelian randomization study

BackgroundPrevious researches have demonstrated a connection between psychiatric disorders and cardiovascular diseases (CVDs), but the cause-and-effect relationship is still unclear. To that goal, the mendelian randomization (MR) method was used to study the causal link between psychiatric disorders and CVDs. MethodsGenome-wide association studies (GWAS) data were collected for four CVDs, including coronary artery disease (n = 547,261), atrial fibrillation (n = 537,409), heart failure (n = 977,323) and ischemic stroke (n = 440,328). Summary data for four psychiatric disorders, including bipolar disorder (n = 51,710), major depressive disorder (n = 480,359), schizophrenia (n = 127,906) and attention deficit hyperactivity disorder (n = 55,374), came from the Psychiatric Genomics Consortium (PGC). All participants were European. The IVW method was mainly used, and the reliability of the results was increased using sensitivity analyses such as MR-Egger, Cochrane's Q test, MR-PRESSO and leave-one-out. ResultsMR revealed that the attention deficit hyperactivity disorder was linked to an increased risk of atrial fibrillation (OR, 1.085; 95% CI, 1.021–1.153; P = 0.008), heart failure (OR, 1.117; 95% CI, 1.044–1.195; P = 0.001), and ischemic stroke (OR, 1.146; 95% CI, 1.052–1.248; P = 0.002). The schizophrenia was linked to an increased risk of heart failure (OR, 1.035; 95% CI, 1.006–1.066; P = 0.017), but was found to be suggestively inverse associated with coronary artery disease (OR, 0.969; 95% CI, 0.941–0.997; P = 0.03). The major depressive disorder was associated with higher odds of coronary artery disease (OR, 1.109; 95% CI, 1.018–1.208; P = 0.018), while the bipolar disorder was linked to a reduced incidence of coronary artery disease (OR, 0.894; 95% CI, 0.831–0.961; P = 0.002) and heart failure (OR, 0.889; 95% CI, 0.829–0.955; P = 0.001). There were no clear relationships between other psychiatric disorders and CVDs. ConclusionThe results provide genetic proof of a possible causal relationship between psychiatric disorders and CVDs. These results imply that psychiatric disorders may be the cause of some CVDs, and that some abnormal mental states may increase or reduce the likelihood of CVDs, providing guidance for the CVDs prevention.

P11.56.A MODIFIED FRAILTY INDEX (MFI) AS A SURVIVAL AND FUNCTIONAL OUTCOME PREDICTOR IN OLDER PATIENTS UNDERGOING SURGERY FOR BRAIN METASTASES

Abstract BACKGROUND Surgical decision making in older patients with brain metastases (BM) is challenging. Frailty and comorbidities are often thought to limit therapeutic options as well as functional and survival outcomes. MATERIAL AND METHODS 139 consecutive patients undergoing surgery 2017-2021 for BM were analyzed retrospectively. Cut-off for age was ≥60 yrs. in accordance with the graded prognostic assessment (GPA) index. Frailty was investigated using the mFI index, a compound measure assessing comorbidities and the patients’ functional health status. RESULTS Median age was 69.0 (IQR: 63.0-74.5) yrs. 55.4% had multiple metastases. We recorded 9.4% major (CTCAE III-V) surgical and 10.1% medical complications. 7.9% of patients had major new focal neurological deficits ≥30 days. Median overall survival (mOS) was 7.8 (IQR: 5.0-10.6) months. Frailer patients lived shorter (mOS for “least-frail”/mFl 0: 13.6 [IQR: 8.6-18.6], “moderately frail”/mFl 1-2: 9.0 [IQR: 4.9-13.0] and “frailest”/mFl ≥3: 2.7 [IQR: 0.9-4.5] months; p&amp;lt;0.001). Multivariate analysis with all parameters correlating significantly with mOS in the univariate analysis (mFI, higher preop. KPS, younger age [&amp;lt;69 yrs.], female sex) revealed a higher preop. KPS to be the only independent significant survival predictor (70 vs. 80-100; HR 2.1, p&amp;lt;0.001). Frailer patients had poorer functional outcomes (patients w/ postop. KPS ≤70 vs. 80-100; mFI 0: 9/36 [25.0%], mFI 1-2: 20/65 [30.8%], mFI ≥3: 25/38 [65.8%]; p&amp;lt;0.001). Multivariate analysis with all parameters correlating significantly with better functional outcome in the univariate analysis (mFI, higher preop. KPS, younger age, female sex and single metastasis) showed that a higher preop. KPS was the strongest prognostic parameter (RR 17.2, p&amp;lt;0.001). The mFI was not an independent outcome predictor. In a ROC analysis the preoperative KPS proved a much better predictor of functional outcome than the mFI (AUC 92 vs. 71%; sensitivity/specificity optimum 80 vs. 2, resp.). mFI was not a predictor of complications (p=NS). CONCLUSION The mFI proved a strong survival and functional outcome predictor in older patients. However, this effect was no longer seen in multivariate analyses when the KPS was included as a covariate. This may suggest that surgical outcomes depend on the patients’ presurgical functional health status rather than comorbidities. The presence of comorbidities (if well treated) should therefore not deter from BM surgery in older patients.

Complete recovery of interhemispheric subdural empyema extending to cerebellar tentorium treated with antibiotics as unimodal therapy: a case report and controversial literature review

Link of Video Abstract: https://youtu.be/ep7OSDbighoBackground: Intracranial subdural empyema, although rare, represents an extreme medical and neurosurgical emergency. Multiple burr holes or a craniotomy for drainage and antibiotics are the treatment of choice. This case study aims to evaluate the complete recovery of interhemispheric subdural empyema extending to cerebellar tentorium treated with antibiotics as unimodal therapy. Case Presentation: We present a case of a 40-year-old male with severe headache, a decrease of consciousness GCS E3V1M5, generalized onset tonic-clonic seizure, right abducens palsy, and right hemiparesis. Interhemispheric subdural empyema extending to cerebellar tentorium with associated intracranial abscess was seen from brain magnetic resonance imaging (MRI). Antibiotics were administered without surgical intervention due to the patient's family rejection. The patient regained full consciousness within 1 week and complete neurological function after 4 weeks of continuous use of antibiotics. The patient was discharged, and his recovery was uneventful on subsequent follow-up. Conclusion: The use of antibiotics as monotherapy in subdural empyema is controversial, as it is widely accepted that surgery must be initiated as soon as possible in this pathology. It is indicated in small portions of cases without major neurological deficits or in particular conditions where surgery could not be performed. Still, more recent studies found it justifiable in patients with documented initial good responses. This case report highlights the complete recovery and the clinical outcome of antibiotics as monotherapy for subdural empyema.

Rural healthcare: A retrospective review of lung carcinoma demographics and screening in the northern Arizona healthcare system.

e18696 Background: In the United States, lung carcinoma is the leading cause of cancer mortality. In 2022, the National Cancer Institute estimated 236,740 new cases of lung cancer, or 12.3% of all new cancer cases, and 130,180 deaths, or 21.4% of all cancer deaths. The risk factors for lung cancer include cigarette smoking, secondhand smoke, the non-Hispanic population, air pollution, or prior radiation therapy. The fatality and common risk factors emphasize the importance of the screening guidelines. Northern Arizona is considered an area affected by downwinder syndrome which is defined as individuals exposed to radiation from the explosion of nuclear devices at the Federal Nevada Test Site with radioactive materials being disturbed by winds. Northern Arizona Healthcare (NAH) has a large population located in these affected counties and lung cancer demographics were reviewed to observe for any variation when compared to the general population. The patients were also reviewed to determine if there were any major deficits in screening guidelines. Methods: This retrospective review included patients diagnosed with lung carcinoma based on the ICD 9 and 10 codes between 2015 to 2020 in the NAH systems. The total number of charts included 559 but 184 were excluded for the following reasons: concern for lung cancer, but not confirmed, patients located not in Northern Arizona, diagnosed prior to 2015, duplicate name but same medical record number, malignancy other than lung cancer, metastatic cancer with unknown primary, and lung cancer was eventually ruled out. The total number of patients remaining in the review was 375. Demographics and lung carcinoma screening information were obtained through NAH medical records. Results: Demographics: median age of 71 with 286 of 375 patients &gt; 65; gender 53.06% males, 46.4% female; race: 88.8% Caucasian, 4.8% Hispanic, Native American 4%, African American 2.1%, Asian 0.3%; smoking history 56.8% active, 31.4% former, 10.6% never; Lung Cancer Pathology: Adenocarcinoma 49.3%, Squamous Cell 18.9%, NSCLC (other than adenocarcinoma or squamous cell) 11.78%, Small Cell 17%, undetermined 2.7%; Lung Cancer Screening: 64.50% no screening vs 7.2% who did, 28.3% were indeterminable. Conclusions: Despite Northern Arizona being considered an area affected by downwinder syndrome, a five-year review of lung carcinoma demographics did not expose any major variation when compared to the generalized population. A limitation was molecular markers were not included and a potential area of further investigation. The review did expose deficits in lung carcinoma screening. 64% of the 375 patients were not screened for lung cancer. A formal presentation was held at NAH grand rounds to raise awareness of lung carcinoma screening guidelines. For future advancement, a collaboration with IT to develop outpatient screening alerts to optimize healthcare in rural areas.

Life cycle-based parametric optimization of buildings towards climate neutrality and its implications for environmental protection

The climate crisis represents the greatest challenge to be solved by the current generation, according to the European Union. In relation to this, the building sector plays a crucial role since it is responsible for around 37% of the global CO2 emissions. To meet the internationally and nationally defined targets for climate neutrality, different strategies such as changing the energy systems or increasing energy efficiency are applied to reduce the CO2 emissions during the use phase of buildings. However, the current strategy has major deficits since essential parts of a building’s life cycle (e.g. embedded emissions of the building construction) are neglected. In addition to climate protection, environmental protection is another global and national goal which is neglected by only focusing on the CO2 emissions. Since ecosystems provide vital ecosystem services for the survival of present and future generations, environmental protection is crucial to be considered. To show the effects of these current, limited approaches, this study displays and compares different parametric optimization strategies, such as focus on the use stage and focus on the whole life cycle of buildings, using thermal building simulations. To analyze the different approaches, the assessment boundaries are extended to the whole life cycle of buildings (product, use, refurbishment, and end-of-life) and to further environmental indicators (global warming/acidification/eutrophication potential). The results show that reducing the global warming potential (GWP) (unit: CO2-eq.) not necessarily implies a reduction regarding the acidification potential (AP) and eutrophication potential (EP). In fact, in some cases, the AP and EP are higher after a CO2-eq. focused optimization process. As a result, to plan and implement buildings and cities in a climate and ecological friendly manner, the current horizon of consideration must be expanded, and a multi-criteria optimization approach needs to be implemented as demonstrated.

The intertemporal guarantee of freedom – a concept for international human rights to address states’ failure to combat climate change and its threats?

This paper analyses, if the Intertemporal Guarantee of Freedom, that was developed by the German Federal Constitutional Court (GFCC), can be used to expand the protection of human rights against the harms of climate change. The case of the Swiss Senior Women shows that there are jurisdictions, where the Intertemporal Guarantee of Freedom could be applied to improve standing and the control standard of states’ climate change action. Within international law bodies with jurisdiction over human rights treaties there are distinctive standards of protection against the harms of climate change. A major deficit within the international human rights protection against climate change lies within the focus on the positive obligations and the corresponding wide margin of appreciation granted to the states. The Intertemporal Guarantee of Freedom could provide a protection expansion in this regard, especially in the case of the European Court of Human Rights. It could also enable and legitimise present human rights concerns focused on the future actions of states following their past inaction. One considerable hurdle that is not addressed by it are procedural hurdles like the Plaumann formula applied by the European Court of Justice. The Intertemporal Guarantee of Freedom cannot solve major problems for climate change litigation like procedural hurdles. Yet, it can provide a new approach for complaints to address unambitious mitigation legislation which will lead to future human rights infringements.

The Development of Mental Health Difficulties in Young People With and Without Developmental Language Disorder: A Gene-Environment Interplay Study Using Polygenic Scores.

Young people with developmental language disorder (DLD) have poorer mental health than those without DLD. However, not all young people with DLD are equally affected; some have more mental health difficulties than others. What explains these differences remains unclear. Data from a community cohort study, the Avon Longitudinal Study of Parents and Children, were analyzed to investigate genetic and environmental influences on the development of mental health difficulties at five time points from childhood (7 years) to adolescence (16 years) in 6,387 young people (8.7% with DLD). Regression and latent class models were fitted to the data. Polygenic scores (PGSs), indices of genetic risk, for common psychiatric disorders (major depressive disorder, anxiety disorder, and attention deficit hyperactivity disorder) predicted mental health difficulties in both groups (with and without DLD). The presence of DLD, in some instances, amplified mental health difficulties for those with high genetic risk for common psychiatric disorders. Subgroups of children with similar developmental trajectories of mental health difficulties were identified. Young people with DLD were more likely than those without DLD to follow mental health subgroups characterized by consistently high levels of difficulties during development. PGSs, socioeconomic status, and the early home environment distinguished subgroups with low mental health difficulties from those characterized by high levels of difficulties, but these effects did not differ based on DLD status. These findings suggest that, for the most part, both genetic and environmental risk affect the development of mental health difficulties in a cumulative way for young people with DLD (and those without). Some analysis did, however, suggest that genetic risk for common psychiatric disorders might manifest more strongly in those with DLD compared with those without DLD. https://doi.org/10.23641/asha.22351012.

An analysis of the intersecting factors and needs that informed the experiences of young people transitioning from out of home care in the Australian states of Victoria and Western Australia

Young people transitioning from out-of-home care (often called care leavers) are globally a disadvantaged group who can be particularly vulnerable to experiences of housing instability and homelessness. This qualitative study, based on interviews with 34 care leavers in the Australian states of Victoria and Western Australia, examined their transition experiences and outcomes with a specific focus on access to stable and affordable housing. Our study reported major deficits in transition planning including a significant reliance when leaving care on specialist homelessness services to meet housing needs. Some major policy and practice reforms were identified concerning transition planning, service coordination, and extending the leaving care age to 25 years.

Operační léčba tuberkulózní spondylodiscitidy

PURPOSE OF THE STUDY The paper presents a monocentric retrospective study of patients treated surgically for spinal tuberculosis. Clinical and radiological results are analysed, early and late complications are recorded. The study aims to answer the following questions. 1. Can we use instrumentation to restore the stability and alignment in the infected spinal focus? 2. Should we always perform radical anterior resection of TBC lesions? 3. What is the prognosis of surgical treatment of TBC patients with neurological deficit manifestation? MATERIAL AND METHODS Between 2010 and 2020, a total of 12 patients were treated for spinal tuberculosis at our department, of whom 9 patients (5 men, 4 women) with the mean age of 47.3 years (range 29 to 83 years) underwent a surgery. A total of three patients were operated on before the final confirmation of the TBC and treatment with antituberculosis medication, four patients in the initial therapy phase and two patients in the continuous phase. Two patients only underwent a non-instrumented decompression surgery followed by external support fixation. In the other seven patients, always with spinal deformity, instrumentation was used (3 cases of isolated posterior decompression, transpedicular fixation, posterior fusion, 4 cases of anteroposterior instrumented reconstruction). In 2 cases a structural bone graft and in 2 cases an expandable titanium cage were used for anterior column reconstruction. RESULTS Of the total number of patients, altogether eight patients were assessed at 1 year after surgery (one 83-year-old patient died from heart failure 4 months after surgery). Of the remaining eight patients, three patients exhibited a neurological deficit and postoperative regression of the finding. The McCormick score improved from the preoperative mean score of 3.25 to 1.62 at 1 year after surgery (p < 0.001). The clinical VAS score regressed from 5.75 to 1.63 at 1 year after surgery (p < 0.001). Radiographic healing of the anterior fusion was achieved in all patients, both after decompression and instrumented surgery. The initial mean kyphosis of 20.36 degrees of the operated segment measured by the mCobb angle was corrected to 14.6 degrees postoperatively, with a subsequent slight deterioration to 14.86 degrees (p < 0.05). The greatest correction was achieved in patients who had undergone a two-stage surgery with anterior resection and AP reconstruction. DISCUSSION In our cohort, titanium instrumentation was used in seven of nine patients. One patient only manifested persistent tuberculosis with nonspecific bacterial flora superinfection. Revision surgery with anterior radical debridement and subsequent treatment with antituberculotic drugs healed the patient. There were four patients with major preoperative neurological deficit persisting more than 2 weeks before the final treatment with subsequent improvement in all cases. These patients were treated with anteroposterior reconstruction and anterior radical debridement. CONCLUSIONS No increased risk of recurrent infection associated with the use of spinal instrumentation was found in the study. Anterior radical debridement is performed in patients with manifested kyphotic deformity and spinal canal compression, followed by reconstruction with a structural bone graft or a titanium cage. The other patients are treated based on the principle of "optimal" debridement with or without the use of transpedicular instrumentation. If adequate spinal canal decompression and stability are achieved, neurological improvement can be anticipated even in case of a major neurological deficit. Key words: spine tuberculosis, tuberculous spondylitis, Pott's disease, anterior debridement, spine instrumentation.

Interview: Timothy Clinton

Interview: Timothy Clinton

Association between major discrimination and deficit accumulation in African American cancer survivors: The Detroit Research on Cancer Survivors Study.

Discrimination can adversely affect health and accelerate aging, but little is known about these relationships in cancer survivors. This study examines associations of discrimination and aging among self-identified African American survivors. A population-based sample of 2232 survivors 20-79years old at diagnosis were enrolled within 5 years of breast (n=787), colorectal (n=227), lung (n=223), or prostate (n=995) cancer between 2017 and 2022. Surveys were completed post-active therapy. A deficit accumulation index measured aging-related disease and function (score range, 0-1, where <0.20 is robust, 0.20 to <0.35 is pre-frail, and 0.35+ is frail; 0.06 is a large clinically meaningful difference). The discrimination scale assessed ever experiencing major discrimination and seven types of events (score, 0-7). Linear regression tested the association of discrimination and deficit accumulation, controlling for age, time from diagnosis, cancer type, stage and therapy, and sociodemographic variables. Survivors were an average of 62years old (SD, 9.6), 63.2% reported ever experiencing major discrimination, with an average of 2.4 (SD, 1.7) types of discrimination events. Only 24.4% had deficit accumulation scores considered robust (mean score, 0.30 [SD, 0.13]). Among those who reported ever experiencing major discrimination, survivors with four to seven types of discrimination events (vs. 0-1) had a large, clinically meaningful increase in adjusted deficits (0.062, p<.001) and this pattern was consistent across cancer types. African American cancer survivors have high deficit accumulated index scores, and experiences of major discrimination were positively associated with these deficits. Future studies are needed to understand the intersectionality between aging, discrimination, and cancer survivorship among diverse populations.