Additional Signs Research Articles

Domiciliary Carers’ Perspectives on Alcohol Use by Older Adults in Their Care: A Systematic Review and Thematic Synthesis of Qualitative Studies

As global populations continue to age, alcohol consumption rises, and we strive to age in place, it is important to have an up-to-date understanding of domiciliary carers’ perspectives on older adults’ alcohol use in their care. Therefore, a systematic review and thematic synthesis of qualitative studies of the unique challenges faced by domiciliary care workers in front line roles regarding older adults’ alcohol use was conducted (PROSPERO registration number: CRD42024516660). Eight databases were searched on 22 February 2024 for qualitative studies focusing on older adults’ (defined as aged 50 or over) alcohol consumption and domiciliary care. The Critical Appraisal Skills Programme checklist was utilised for quality appraisal. Twenty articles reporting 14 unique studies of mainly medium to low quality were included. Three overarching themes (and associated subthemes) were identified as follows: identification (alcohol problems are common, no assessment for alcohol problems, and additional overt signs of excessive alcohol use), management (to buy or not to buy that is the question, balancing rights and risks, monitor and report but do not intervene, maintaining the vicious circle, home as a barrier to accessing support and services, and more support needed from healthcare professionals), and training (lack of alcohol education). Domiciliary carers are well placed to make every contact count to target alcohol consumption but would benefit from support and resources for alcohol consumption identification and management. Clear guidance on how to manage alcohol consumption to harmoniously balance rights and risks is crucial, particularly when caring for older adults with cognitive difficulties.

Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Evidence of altered Redox Homeostasis in Trichothiodystrophy

Trichothiodystrophy (TTD) is a rare hereditary disease whose prominent feature is brittle hair. Additional clinical signs are physical and neurodevelopmental abnormalities and in about half of the cases hypersensitivity to UV radiation. Although the mutations involved in this condition have been characterized, the correlation between the molecular defects and the plethora of clinical symptoms is not well understood. Recently the presence of a redox unbalance in TTD has been suggested although not clear evidences have been reported on this aspect. Therefore, in the present study, we evaluated the redox status of fibroblasts isolated from a TTD patient. In addition, to understand the ability of TTD cells to respond to oxidative insults, the cells were challenged with H2O2 and mitochondrial O2- and mitochondrial membrane potential were measured in different oxidative conditions. In addition, NRF2/BACH protein levels were also analysed in response to H2O2. The results suggested an aberrant mitochondrial response to oxidative stimuli, an increased baseline oxidative stress status in TTD and an altered NRF2/BACH level. This study emphasises that altered redox homeostasis might play a role in TTD pathogenesis and mitochondria functionality could represent an alternative therapeutic target for this condition to improve patients clinical features.

Analysis of Echocardiography Indicators Depending on the Type of Surgical Correction of the Mitral Valve in Patients with Ischemic Heart Disease

The aim. To study the influence of echocardiography indicators on the choice of surgical intervention on the mitral valve in patients with mitral insufficiency and coronary heart disease. Materials and methods. The study included patients with mitral insufficiency who underwent myocardial revascularization and mitral valve reconstruction (plasty or replacement). The mean age of the study participants was 65.9 ± 4.0 years. The material for analysis was data from the primary medical records: medical history, clinical and instrumental examination data and protocols of operations. The division into study groups was performed retrospectively, according to the mitral valve operation performed: plasty (experimental group) or replacement (control group). Results. We identified the features of the main echocardiographic data that guide the cardiologist when choosing the tactics of surgical correction of the mitral valve. It was established that in patients of the research group, the following was reliably significant: moderate degree of mitral insufficiency (p = 0.02; χ2 = 9.38), decrease in the systolic function of the left ventricle (p = 0.001; χ2 = 10.75); it was found that calcium deposits on the fibrous ring of the mitral valve were insignificant. When analyzing the morphological changes in patients of the experimental group, we found a significantly lower frequency of anterior leaflet prolapse (p = 0.04; χ2 = 4.21) and in general the frequency of all prolapses of any type, while in the control group the frequency of all prolapses was significantly higher (p = 0.04; χ2 = 4.0). In patients of the control group, a significantly higher frequency of akinesis (p = 0.04; χ2 = 4.21) and hypokinesis zones of the posterior-inferior-lateral wall (p = 0.001; χ2 = 19.76) was established, which is an additional sign of involvement of the chordal-muscular apparatus of the mitral valve in pathological process. Conclusions. As a result of the study, echocardiographic differences in the structure of the mitral valve were established, which influenced the selection of the intervention volume. It was found that in patients of the experimental group, the early postoperative mortality and the duration of inpatient treatment were significantly higher than in patients of the control group, which indicates the imperfection of the criteria used by cardiac surgeons when choosing the tactics of surgical correction of the mitral valve in an attempt to perform organ-preserving surgery.

Pain anticipation is a new behavioural sign of minimally conscious state.

Probing cognition and consciousness in the absence of functional communication remains an extremely challenging task. In this perspective, we imagined a basic clinical procedure to explore pain anticipation at bedside. In a series of 61 patients with a disorder of consciousness, we tested the existence of a nociceptive anticipation response by pairing a somaesthetic stimulation with a noxious stimulation. We then explored how nociceptive anticipation response correlated with (i) clinical status inferred from Coma Recovery Scale-Revised scoring, (ii) with an EEG signature of stimulus anticipation-the contingent negative variation-and (iii) how nociceptive anticipation response could predict consciousness outcome at 6 months. Proportion of nociceptive anticipation response differed significantly according to the state of consciousness: nociceptive anticipation response was present in 5 of 5 emerging from minimally conscious state patients (100%), in 10 of 11 minimally conscious state plus patients (91%), but only in 8 of 17 minimally conscious state minus patients (47%), and only in 1 of 24 vegetative state/unresponsive wakefulness syndrome patients (4%) (χ 2 P < 0.0001). Nociceptive anticipation response correlated with the presence of a contingent negative variation, suggesting that patients with nociceptive anticipation response were more prone to actively expect and anticipate auditory stimuli (Fisher's exact test P = 0.05). However, nociceptive anticipation response presence did not predict consciousness recovery. Nociceptive anticipation response appears as a new additional behavioural sign that can be used to differentiate minimally conscious state from vegetative state/unresponsive wakefulness syndrome patients. As most behavioural signs of minimally conscious state, the nociceptive anticipation response seems to reveal the existence of a cortically mediated state that does not necessarily reflect residual conscious processing.

Possibilities of post-processing of multislice computed tomography results in non-invasive diagnosis of pancreatic fibrosis

To evaluate the possibilities of post-processing of multidetector computed tomography (CT) results in the non-invasive diagnosis of pancreatic fibrosis (PF). The study included 165 patients aged 57.91±13.5 years who underwent preoperative CT during surgical treatment for chronic pancreatitis and pancreatic cancer from April 2022 to February 2024. The normalized contrast ratios of pancreatic tissue in the pancreatic (NCPP) and venous (NCVP) phases, as well as the contrast ratio (CR) were measured. Pathomorphological assessment of PF performed in tissues outside neoplasm or desmoplastic reaction by the Kloppel and Maillet scale. The values of post-processing CT results were compared in groups with different degrees of PF. Mean CR values were significantly higher (p=0.001) in patients with severe PF (CR 1.16±0.65 HU) than in patients with mild PF (CR 0.78±0.31 HU). CR value significant increase (p=0.03) was found in patients with signs of inflammatory changes in the pancreas tissue (CR 1.14±0.6 HU) than in those without them (CR 0.81±0.3 HU). There were no significant differences between the values of NCPP and NCVP, and the degree of PF. The CR value increased in patients with severe degree of PF. There was a relationship between CR value increase and the radiological density of pancreatic tissue in non-contrast phase and presence of early signs of pancreatic inflammatory changes. Thus, there was a relationship between CT postprocessing results and morphological signs of PF, which can be used for pancreatic fibrosis non-invasive diagnosis and identification of additional signs of early chronic pancreatitis.

Heart Failure Knowledge Assessment and Perceived Patient Satisfaction in Heart Failure Units: A Multicenter Observational Survey.

Self-care and empowerment promotion in patients with heart failure (HF) is essential for improving their prognosis, but there is limited information concerning the patients' depth of knowledge about this pathology as well as patient satisfaction within heart failure units (HFUs). Our objective was to assess both aspects in a cohort of patients regularly followed-up HFUs. A multicenter, observational study was conducted with consecutive patients followed in 14 HFUs between June and November 2023. It was based on a cross-sectional survey comprising 23 questions related to demographics, knowledge/self-care, and the subjective assessment of perceived quality and satisfaction in HFUs. 281 patients were included (36.7% women, 74.7% aged over 65 years). 48% had hospitalizations for HF or sought emergency department services within the preceding year. The mean correct responses related to knowledge were 9.7 ± 2.3 (80.7% of the total), and 53 patients (18.9%) answered all knowledge questions correctly. 211 (79.6%) could identify potential HF decompensation with abrupt weight gain, and 196 (74.2%) recognized at least three additional signs of worsening HF. 266 patients (98.2%) were likely or very likely to recommend HFUs, and 194 (89.8%) positively appreciated the experience at the day hospital. Patients followed up in HFUs showed adequate but improvable knowledge and capacity for self-care, with a high level of satisfaction.

The role of sacro-iliac joint magnetic resonance imaging in the diagnosis of axial spondyloarthritis: focus on differential diagnosis in women.

To review the role of sacro-iliac magnetic resonance imaging (MRI) in the diagnosis of axial spondyloarthritis (AxSpA), with a focus on gender differences. The experience of the authors and the results of an informal literature review are reported. Inflammatory changes of the sacro-iliac joint are the hallmark of AxSpA. Early, non-radiographic sacroiliitis may be diagnosed with MRI through the assessment of bone marrow edema (BMO) as well as concomitant structural damage. The MRI protocol should include three necessary sequences, i.e., fat-saturated T2-weighted sequences on two orthogonal planes, T1-weighted semi-coronal sequence, and fat-suppressed T1-weighted semi-coronal sequence. Inflammatory changes comprise required signs (BMO and/or osteitis) and additional signs, including synovitis (better defined as joint space enhancement), enthesitis, and capsulitis. Structural changes consist of erosions, sclerosis, fat metaplasia, and ankylosis. Due to mechanical axial strain, inflammatory changes in the sacro-iliac joint can be found in healthy individuals, runners, and patients with nonspecific low back pain. The prevalence of BMO is higher in women during pregnancy and postpartum, even 12 months after childbirth, but the extent and distribution of MRI findings may help in the differential diagnosis. Other challenges in the MRI diagnosis of sacroiliitis are subchondral T2 hyperintensity during developmental age, periarticular sclerosis in healthy subjects, or osteitis condensans ilii, and several pathological conditions that may mimic AxSpA, some of which are more frequently found in women. The described diagnostic challenges impose a multidisciplinary approach combining imaging findings with clinical and laboratory data.

Secondary parkinsonism associated with focal brain lesions.

Focal imaging abnormalities in patients with parkinsonism suggest secondary etiology and require a distinctive clinical approach to diagnosis and treatment. We review different entities presenting as secondary parkinsonism associated with structural brain lesions, with emphasis on the clinical course and neuroimaging findings. Secondary parkinsonism may be due to vascular causes, hydrocephalus, space-occupying lesions, metabolic causes (including acquired hepatocerebral degeneration, diabetic uremic encephalopathy, basal ganglia calcifications, osmotic demyelination syndrome), hypoxic-ischaemic brain injury, intoxications (including methanol, carbon monoxide, cyanide, carbon disulfide, manganese poisoning and illicit drugs), infections and immune causes. The onset can vary from acute to chronic. Both uni-and bilateral presentations are possible. Rigidity, bradykinesia and gait abnormalities are more common than rest tremor. Coexisting other movement disorders and additional associated neurological signs may point to the underlying diagnosis. Neuroimaging studies are an essential part in the diagnostic work-up of secondary parkinsonism and may point directly to the underlying etiology. We focus primarily on magnetic resonance imaging to illustrate how structural imaging combined with neurological assessment can lead to diagnosis. It is crucial that typical imaging abnormalities are recognized within the relevant clinical context. Many forms of secondary parkinsonism are reversible with elimination of the specific cause, while some may benefit from symptomatic treatment. This heterogeneous group of acquired disorders has also helped shape our knowledge of Parkinson's disease and basal ganglia pathophysiology, while more recent findings in the field garner support for the network perspective on brain function and neurological disorders.

Neurocysticercosis and cognitive impairment among people with epilepsy in Taenia solium endemic regions of rural southern Tanzania: A hospital-based cross-sectional study in mental health clinics of selected sites in Tanzania

BackgroundEpilepsy poses a significant public health problem in many parts of the world. The majority of people with epilepsy (PWE) are from low-income and middle-income countries (LMICs). Taenia solium neurocysticercosis (NCC) is estimated to cause 30% of preventable epilepsy in PWE in areas of T. solium endemicity. This study was conducted to assess the prevalence of NCC in PWE, evaluate the presence of cognitive impairment in PWE and assess potentially contributing factors. MethodsPWE were recruited within a mental health clinic-based cross-sectional study in rural Southern Tanzania. PWE underwent a detailed neurological examination, including mental state, and a blood sample was collected for T. solium cysticercosis (CC) serology testing. Patients who were serologically positive for CC and those detected to have prominent neurological deficits apart from epilepsy were invited to receive a cerebral computed tomography (CT) examination. ResultsOut of the 223 people with epilepsy (PWE) recruited, 221 underwent clinical examination. Among these, 26 (11.8 %) had cognitive impairment, and 2 had neurological signs or symptoms without cognitive impairment. Twenty-five of the 223 PWE (11.2 %) tested positive for CC, of which 4 had cognitive impairment. One hundred and ninety-eight (88.8 %) tested negative for CC, of which 22 had cognitive impairment. A total of 36 participants underwent CT scans, with 18 testing positive and 18 testing negative for CC. Of the 36 who had CT scans, 8 (22.2 %) were diagnosed with NCC; 7 were CC positive, and 1 was CC negative; only the latter had cognitive impairment. Multivariate logistic regression confirmed that cognitive impairment in PWE was 8.62 times higher for Kongwa participants than Chunya, with a statistically significant association (95 % CI: 1.75, 156; p = 0.037). Additionally, having and education was associated with a 91 % reduction in the odds of cognitive impairment (OR = 0.09) compared to no education, which was also statistically significant (95 % CI: 0.01, 0.33; p = 0.002). There was no association between cognitive impairment and NCC. ConclusionOur study found a 22.2 % prevalence of NCC among PWE. Cognitive impairment was present in 11.8 % of PWE but was not significantly associated with NCC. Socioeconomic and educational factors may play a larger role in cognitive impairment among PWE.

Set-Identified Structural Vector Autoregressions and the Effects of a 100 Basis Point Monetary Policy Shock

Abstract I estimate impulse responses to a 100 basis point US monetary policy shock using setidentified structural vector autoregressions. Identified sets for these responses may be unbounded when the identifying restrictions admit zero impact response of the federal funds rate following a standard-deviation shock. Such a zero response is always admissible when there are fewer sign and zero restrictions than endogenous variables. This is the case under existing restrictions on the systematic component of monetary policy, which consequently yield uninformative identified sets. Additional sign and narrative restrictions yield informative identified sets and imply smaller output responses than some previous estimates.

The Motor Optimality Score-Revised Improves Early Detection of Unilateral Cerebral Palsy in Infants with Perinatal Cerebral Stroke.

Neonatal cerebral stroke includes a range of focal and multifocal ischemic and hemorrhagic brain lesions, occurring in about one of 3000 live births. More than 50% of children with neonatal stroke develop adverse outcomes, mainly unilateral cerebral palsy. Asymmetries in segmental movements at three months have been proven to be an early sign of CP in infants with unilateral brain damage. Recognition of additional early signs could enhance prognostic assessment and enable an early and targeted intervention. The aim of the study was to assess early signs of CP in infants with arterial cerebral stroke through the General Movements Assessment and the Motor Optimality Score-Revised (MOS-R). Twenty-four infants born at term (12 females and 12 males) diagnosed with ACS, and 24 healthy infants (16 females and 8 males) were assessed. The GMs (fidgety movements) and MOS-R were assessed from videos recorded at 11-14 weeks of post-term age. Cognitive and motor outcomes were assessed at 24 months using the Griffiths III developmental quotient and Amiel-Tison neurological examination. The gross motor function classification system expanded and revised (GMFCS-E&R) was adopted to categorize CP. Among infants with ACS, 21 (87.5%) developed unilateral CP. Most of them showed non-disabling CP (14 had GMFCS-E&R grade 1 [66.6%], 6 grade 2 [28.6%], and 1 grade 5 [4.8%]). Fidgety movements (FMs) were absent in 17 (70.8%), sporadic in 4 (16.7%) infants, and normal in 3 (12.5%). Segmental movement asymmetry was found in 22/24 (91.7%). According to the MOS-R, motor items (kicking, mouth movements), postural patterns (midline centered head, finger posture variability), and movement character (monotonous and stiff) were statistically different among infants with ACS and healthy infants. The MOS-R median global score was lower in the group with ACS compared to the control group (6 vs 26; p < 0.01). FMs, segmental movement asymmetry, and MOS-R global score were significantly correlated with abnormal outcome. MOS-R global scores less than or equal to 13 had 100% specificity and sensitivity in predicting GMFCS-E&R grade ≥ 2 CP in infants with ACS. The rate of CP was high among infants with ACS, but in most cases it showed low GMFCS-E&R grades. The study highlighted a significant correlation between MOS-R, together with absent FMs and unilateral CP in infants with ACS. Moreover, the MOS-R showed high sensitivity and specificity in the prediction of CP. Combined assessment of FMs and MOS-R could help to better identify infants at high risk of developing UCP in a population of infants with ACS. Early identification of precocious signs of unilateral CP is fundamental to providing an early individualized intervention.

The "Hypointense Focal Brain" on susceptibility-weighted imaging as a sign of venous congestion in cranial dural arteriovenous fistulas.

Cranial dural arteriovenous fistulas (dAVFs) are complex neurovascular malformations accounting for approximately 10%-15% of all intracranial arteriovenous malformations. The objective is to investigate the utility of susceptibility-weighted imaging (SWI) in identifying "hypointense focal brain" as an additional helpful sign of venous congestion in cranial dAVFs. A retrospective review of patients diagnosed with cranial dAVFs between January 2015 and June 2023 was conducted, and SWI was used to identify the "hypointense focal brain" sign within the venous drainage region of the dAVF. The "hypointense focal brain" on SWI was identified as a low-intensity signal within the venous drainage region, indicative of venous congestion. The presence of this imaging sign was assessed by two neuroradiologists and signal intensity measurements were performed to support the presence of the sign. The study included six patients with cranial dAVFs exhibiting cortical venous retrograde drainage and the "hypointense focal brain" on SWI. Follow-up imaging post-treatment revealed resolution or improvement of the hypointense signal, confirming its association with venous congestion. Signal intensity measurements further supported the presence of this imaging sign in pre-treatment scans. The study's findings demonstrate the presence of a reversible "hypointense focal brain" sign on SWI in patients with cranial dAVFs and CVR, which can be useful as an additional imaging sign for venous congestion.

A scoping review of unexpected weight loss and cancer: risk, guidelines, and recommendations for follow-up in primary care.

Cancer diagnoses often begin with consultations with general practitioners (GPs), but the nonspecific nature of symptoms can lead to delayed diagnosis. Unexpected weight loss (UWL) is a common nonspecific symptom linked to undiagnosed cancer, yet guidelines for its diagnostic assessment in general practice lack consistency. To synthesise evidence on the association between UWL and cancer diagnosis, and to review clinical guidelines and recommendations for assessing patients with UWL. Systematic search and analysis of studies conducted in primary care. Four databases searched for peer-reviewed literature from 2012 to 2023. Two reviewers conducted all the steps. A narrative review was conducted detailing the evidence for UWL as a risk factor for undiagnosed cancer, existing clinical guidance, and recommended diagnostic approach. We included 25 studies involving 916,092 patients; 92% provided strong evidence of an association between UWL and undiagnosed cancer. The National Institute for Health Care and Excellence Cancer Guideline in the UK was frequently cited. General suggestions encompassed regular weight monitoring, family history, risk factor evaluation, additional signs and symptoms, and a comprehensive physical examination. Commonly recommended pathology tests included C-reactive protein, complete blood count, alkaline phosphatase, and thyroid-stimulating hormone. Immunochemical faecal occult blood test, abdominal ultrasound, and chest X-ray were also prevalent. One large cohort study provided age, sex, and differential diagnosis-specific recommendations. This evidence review informs recommendations for investigating patients with UWL and will contribute to a computer decision support tool implementation in primary care, enhancing UWL assessment and potentially facilitating earlier cancer diagnosis.

Trauma-associated vascular injuries and the vascular surgical/interventional options for vascular reconstruction

The aim of this work is to illustrate the diversity of vascular injuries in terms of vascular segments or body regions, accident mechanisms and specific patient constellations. A representative case collection was compiled based on current and relevant scientific references in PubMed, own clinical experiences, vascular surgical and novel image-guided interventional options. The diagnostics of vascular injuries in the context of trauma and fractures are based on a thorough physical examination. In addition, the hard and soft signs preferred by the Western Trauma Association should be included in the decision. Doppler ultrasonography examination is the safest and gentlest noninvasive examination procedure for a suspected vascular injury due to repeatable and comparative measurements. The stabilization of a fracture, ideally using an external fixator, should be performed before vascular reconstruction whenever possible, unless massive bleeding, hypovolemic shock or a rapidly spreading hematoma represent an immediate indication for surgery. In pediatric supracondylar fractures, avascular injury without relevant ischemia has frequently been described (pink pulseless hand). In this case, the fracture should first be reduced as the pulse often recovers. Due to the increasing availability, good technical handling and high technical success rate as well as the relatively limited interventional trauma, endovascular treatment of traumatic vascular injuries has become widely accepted. Traumatic aortic ruptures are associated with a high mortality even at the accident site. Rapid endovascular treatment using a stent prosthesis significantly increases the injured person's chances of survival. Vascular injuries in connection with fractures or multiple injuries require interdisciplinary cooperation between the specialties involved.

Pulmonary Alveolar Microlithiasis in a Young Man Undergoing Lung Transplantation: A Case Report.

Pulmonary alveolar microlithiasis is a rare disease characterized by the deposition of microliths in the alveoli, attributed to mutations in the solute carrier family 34 member 2 (SLC34A2) gene. Diagnosis is often incidental to chest imaging, most frequently occurring between the second and fourth decades of life. The disease follows a progressive course and manifests with a clinical-radiological dissociation. No effective treatment is known except for lung transplantation.We report on a 28-year-old Hispanic male patient with no relevant personal or family history, presenting with progressive exertional dyspnea and intermittent dry cough. He was referred for evaluation by pulmonology due to abnormal findings on chest x-ray. High-resolution computed tomography revealed diffuse lung opacities caused by multiple microcalcifications, suggesting pulmonary alveolar microlithiasis with additional signs of pulmonary hypertension. Throughout his clinical course, he experienced a decline in functional class with severe impairment in pulmonary function tests. He underwent transplant evaluation, and the procedure was performed, with reported complications including airway stenosis, which were managed. Despite these challenges, the patient eventually showed positive progress and maintained an adequate functional class.Pulmonary alveolar microlithiasis is a rare disease with a chronic clinical course and variable manifestations. Its progressive deterioration leads to chronic respiratory failure. A high index of suspicion is required when evaluating characteristic radiological findings and conducting relevant differential diagnoses. No specific treatment guidelines are available, and lung transplantation emerges as the only effective therapy, as illustrated in the described patient.

Novel Cases of Non-Syndromic Hearing Impairment Caused by Pathogenic Variants in Genes Encoding Mitochondrial Aminoacyl-tRNA Synthetases.

Dysfunction of some mitochondrial aminoacyl-tRNA synthetases (encoded by the KARS1, HARS2, LARS2 and NARS2 genes) results in a great variety of phenotypes ranging from non-syndromic hearing impairment (NSHI) to very complex syndromes, with a predominance of neurological signs. The diversity of roles that are played by these moonlighting enzymes and the fact that most pathogenic variants are missense and affect different domains of these proteins in diverse compound heterozygous combinations make it difficult to establish genotype-phenotype correlations. We used a targeted gene-sequencing panel to investigate the presence of pathogenic variants in those four genes in cohorts of 175 Spanish and 18 Colombian familial cases with non-DFNB1 autosomal recessive NSHI. Disease-associated variants were found in five cases. Five mutations were novel as follows: c.766C>T in KARS1, c.475C>T, c.728A>C and c.1012G>A in HARS2, and c.795A>G in LARS2. We provide audiograms from patients at different ages to document the evolution of the hearing loss, which is mostly prelingual and progresses from moderate/severe to profound, the middle frequencies being more severely affected. No additional clinical sign was observed in any affected subject. Our results confirm the involvement of KARS1 in DFNB89 NSHI, for which until now there was limited evidence.

A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior.

The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3',5'-cylicadenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.

Magnetic Resonance Imaging Signs of Idiopathic Intracranial Hypertension

The magnetic resonance imaging (MRI) criteria currently used to diagnose idiopathic intracranial hypertension (IIH) are based on expert opinion and have limited accuracy. Additional neuroimaging signs have been proposed and used with contradictory results; thus, prospective evidence is needed to improve diagnostic accuracy. To provide evidence-based, accurate MRI signs for IIH diagnosis. This prospective cohort study was conducted from January 2018 to May 2021 with 3 validation cohorts at 2 Danish headache centers and with 3 independent international cohorts. Consecutive patients with suspected IIH were enrolled. Eligibility required the clinical suspicion of IIH, age 18 years or older, and written informed consent. The validation cohorts comprised patients with confirmed IIH from Austria and the US, and patients without IIH from the US. Data analysis was performed from December 2021 to August 2023. Standardized diagnostic workup was performed to classify cases according to current criteria, and blinded evaluation of cerebral radiological diagnostics and papilledema was performed. The primary outcomes were MRI signs associated with IIH as assessed by univariate analyses. An MRI score estimating papilledema was calculated using machine learning. Internal validation of associations with lumbar puncture opening pressure and outcome and external validation of accuracy were performed in 3 cohorts. Of 192 eligible patients (185 women [96.4%]; median [IQR] age, 28.0 [23.0-35.0] years), 110 were classified as having IIH, 4 as having probable IIH, and 1 as having suspected IIH without papilledema; 77 did not have IIH and served as controls, with corresponding age, sex, and weight. Papilledema at diagnosis was associated with perioptic subarachnoid space distension (56 patients [68.3%] vs 21 patients [41.2%]), posterior globe flattening (53 patients [66.3%] vs 10 patients [21.3%]), optic nerve disc protrusion (35 patients [30.4%] vs 2 patients [2.3%]), and transverse sinus venous stenosis (75 patients [79.8%] vs 29 patients [46.8%]). The papilledema-estimating MRI score showed optimal balance between sensitivity (49%) and specificity (87%) when 2 of the 3 latter signs were present and was associated with the lumbar puncture opening pressure and ophthalmological outcome. The score showed strong diagnostic accuracy in the external validation cohorts (587 patients; area under the receiver operating characteristic curve, 0.86) and outperformed the current (2013) diagnostic MRI criteria. The findings of this cohort study of patients with IIH and controls suggest that an evidence-based MRI score including posterior globe flattening, optic nerve disc protrusion, and transverse sinus stenosis can estimate the presence of papilledema more accurately than the current diagnostic criteria.

Poststroke Spasticity: Pathophysiology and Management An Accurate Evaluation of Spasticity

Stroke is a major contributor to long-term impairment and disability, affecting up to one-third of survivors and almost half of patients showing neurological deficit at six months. Spasticity affects approximately 25% of individuals within two weeks of a stroke and increases to 44% in patients who have had a second stroke. Severe or incapacitating spasticity affects 15% of post-stroke individuals. Poststroke spasticity is also linked to additional signs and symptoms of the upper motor neuron syndrome, such as simultaneous contraction of agonist and antagonist muscles, weakness of the muscles, and a lack of coordination. Spasticity arises due to aberrant neuroplasticity that develops after a stroke and there is currently no specific intervention method designed to address and correct this abnormal plasticity that takes place during the acute phase. Just before implementing any measures to deal with spasticity, it is crucial to evaluate the influence on the quality of life and level of severity. Several grading scales are used to measure spasticity such as the MAS and modified Tardieu scale.There are various therapeutic approaches that may be categorized into three main classes: physical, pharmaceutical, and surgical. Each class has a distinct purpose and is used at the appropriate moment to reduce the level of spasticity and improve the patient's health. Physiotherapy serves as a base of improving the patient's condition and facilitating the development of brain networks. The objective of post stroke spasticity management must include not only the reduction of muscle hypertonia, but also the evaluation of how post stroke influences functionality and overall mental health. Improper treatment or non-compliance may result in increased pain, joint contraction, and further disability. The goal is to assist the patient in achieving the best possible quality of life. Keywords: Pathophysiology of Post-Stroke Spasticity; Management of Post-Stroke Spasticity; Evaluation of Post-Stroke Spasticity