Blood miRNA levels associated with ADHD traits in children across six European birth cohorts.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable neurodevelopmental disorder of major societal concern. Diagnosis can be challenging and there are large knowledge gaps regarding its etiology, though studies suggest an interplay of genetic and environmental factors involving epigenetic mechanisms. MicroRNAs (miRNAs) show promise as biomarkers of human pathology and novel therapies, and here we aimed to identify blood miRNAs associated with traits of ADHD as possible biomarker candidates and further explore their biological relevance. METHODS: Our study population consisted of 1126 children (aged 5-12 years, 46% female) from the Human Early Life Exposome study, a study spanning six ongoing population-based European birth cohorts. Expression profiles of miRNAs in whole blood samples were quantified by microarray and tested for association with ADHD-related measures of behavior and neuropsychological functions from questionnaires (Conner's Rating Scale and Child Behavior Checklist) and computer-based tests (the N-back task and Attention Network Test). RESULTS: We identified 29 miRNAs significantly associated (false discovery rate < .05) with the Conner's questionnaire-rated trait hyperactivity, 15 of which have been linked to ADHD in previous studies. Investigation into their biological relevance revealed involvement in several pathways related to neurodevelopment and function, as well as being linked with other neurodevelopmental or psychiatric disorders known to overlap with ADHD both in symptomology, genetic risk, and co-occurrence, such as autism spectrum disorder or schizophrenia. An additional three miRNAs were significantly associated with Conner's-rated inattention. No associations were found with questionnaire-rated total ADHD index or with computer-based tests. CONCLUSIONS: The large overlap of our hyperactivity-associated miRNAs with previous studies on ADHD is intriguing and warrant further investigation. Though this study should be considered explorative and preliminary, these findings contribute towards identifying a set of miRNAs for use as blood-based biomarkers to aid in earlier and easier ADHD diagnosis.

Chlorpromazine's Potential Role in Palliating Distressing Symptoms Associated With Hyperactive Delirium in Patients at End of Life.

Background: The hyperactive subtype of delirium is characterized by agitation, restlessness, delusions, and/or hallucinations, which commonly present near end of life (EoL). Symptom relief often requires the use of medications, such as chlorpromazine (CPZ), to reduce patient distress by inducing proportional sedation. Objective: The purpose of this study was to evaluate CPZ's potential role in managing the distress of hyperactive delirium in patients receiving EoL care. Methods: A retrospective observational study among hospitalized patients with advanced cancer at EoL between January 2020 to December 2021. Results: Sustained improvement in symptoms of delirium was seen in 80% of patients as identified in the palliative psychiatrist's progress notes. Meanwhile, 75% of patient's improvement was reported in nursing-driven Delirium Observation Screening Scale. Conclusion: This study elucidates that at doses of ∼100 mg/day, CPZ is potentially an effective medication for patients with advanced cancer, experiencing hyperactive delirium in their final week of life.

"Unvoluntary" Movement Disorders: Distinguishing between Tics, Akathisia, Restless Legs, and Stereotypies.

Tics, stereotypies, akathisia, and restless legs fall at different places on the spectrum of discrete, unwanted and potentially disabling motor routines. Unlike tremor, chorea, myoclonus, or dystonia, this subgroup of abnormal movements is characterized by the subject's variable ability to inhibit or release undesired motor patterns on demand. Though it may be sometimes clinically challenging, it is crucial to distinguish these "unvoluntary" motor behaviors because secondary causes and management approaches differ substantially. To this end, physicians must consider the degree of repetitiveness of the movements, the existence of volitional control, and the association with sensory symptoms, or cognitive-ideational antecedent. This review aims to summarize the current existing knowledge on phenomenology, diagnosis, and treatment of tics, stereotypies, akathisia, and restless leg syndrome.

Visualizing How to Use Antipsychotics for Agitated Delirium in the Last Days of Life.

CONTEXT: How physicians use antipsychotics for agitated delirium in the last days of life varies markedly, which could hamper the quality of care. OBJECTIVES: To examine adherence to an algorithm-based treatment for terminal agitated delirium, and explore its effectiveness and safety. METHODS: A single-center, prospective, observational study was conducted in a 27-bed palliative care unit in Japan. All adult cancer patients who developed agitated delirium with a modified Richmond Agitation-Sedation Scale (RASS) of +1 or more were included; the palliative care specialists determined that the etiology was irreversible, the estimated survival was three weeks or less, and the Eastern Cooperative Oncology Group (ECOG) performance status was three or four. Patients were treated with an algorithm to visualize how to use antipsychotics, with the treatment goal defined as no agitation (RASS≤0) or acceptable agitation for patients and families. We provided all patients nonpharmacological management to alleviate the symptoms of delirium and administered antipsychotic medications when the nonpharmacological approach was insufficient. We measured the adherence rate, RASS, Nursing Delirium Screening Scale items 2, 3, 4 (Nu-DESC), and Agitation Distress Scale item 2 (ADS) on days 0, 1, 3, 7, 14, 21, and 24 hours before death. RESULTS: A total of 164 patients were enrolled. Adherence rates were 99, 94, and 89%, and treatment goals were achieved in 66, 83, and 93% on days one, three, and seven, respectively. The mean RASS decreased from +1.41 to -0.84 on day three; Nu-DESC decreased from 4.19 to 1.83, and ADS decreased from 1.54 to 0.38. There were seven severe adverse events (Common Terminology Criteria for Adverse Events (CTCAE) of 3), including aspiration (n = 3), apnea (n = 2), tremor (n = 1), and muscle rigidity (n = 1) on day three. CONCLUSION: The algorithm-based treatment could be feasible, effective, and safe. Visualizing how palliative care specialists provide pharmacological management could be beneficial for nonspecialist clinicians, and clinical, educational, and research implications warrant further empirical testing.

Acetaminophen improves tardive akathisia induced by dopamine D2 receptor antagonists.

Tardive akathisia is a movement disorder characterized by internal restlessness with an uncontrollable urge to move, leading to repetitive movements. It is a common side effect of long-term treatment with dopamine D2 receptor antagonists. In the present study, we analyzed the FDA Adverse Event Reporting System and IBM MarketScan Research Database to find a drug that can be used concomitantly with dopamine D2 receptor antagonists and still reduce the risk of akathisia. Acetaminophen was determined to be the most effective akathisia-suppressing drug. In an experimental validation of the hypothesis, chronic treatment of rats with haloperidol caused akathisia symptoms, including increased stereotyped behavior and locomotor activity, and decreased immobility time. Acute treatment with acetaminophen significantly attenuated haloperidol-induced akathisia. In the ventral striata of these rats, acetaminophen prevented haloperidol-induced decrease in the number of c-Fos+ preproenkephalin+ neurons. These results suggest that acetaminophen is effective in suppressing tardive akathisia by activating indirect-pathway medium spiny neurons.

Urinary Tract Infection in Infants <1 Month of Age: Demographic, Clinical, and Microbiological Characteristics.

BACKGROUND: This cross-sectional study was conducted on 232 infants aged <1 month with proven UTI admitted to three major teaching hospitals for the period 2010-2018 to assess clinical, demographic, and laboratory findings of urinary tract infection in this age group. METHODS: All information was extracted from the medical records. Urinary tract infection was defined as ≥ 50,000 colony-forming units per milliliter of a single uropathogen isolated from a catheterized or suprapubic aspiration or greater than 100,000 colony-forming units per milliliter from a midstream, clean-catch sample. RESULTS: The most common pathogen isolated was E. coli (78.4%), followed by Enterobacter and Klebsiella, accounting for 12.1 and 4.7% respectively. The main presenting clinical manifestation was jaundice, which was found in 54.7% of cases; it was followed by restlessness (45.6%) and fever (40%). CONCLUSION: During infancy, the signs and symptoms of UTI are often nonspecific and although urine culture is a gold standard diagnostic tool specimen collection is challenging and urine contamination is common in children, therefore it makes the diagnosis difficult. UTI in infants may indicate underlying genitourinary abnormalities; therefore, appropriate diagnosis and immediate initiation of antibiotic therapy are crucial to decrease long-term complications like renal scarring. According to our study, the most common clinical features were jaundice, restlessness, and fever, therefore it is suggested that urine culture should be performed for all infants presenting with these signs and symptoms.

Paroxysmal sympathetic hyperactivity concurrent with hypothalamic injury in a patient with intracerebral hemorrhage: A case report.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is characterized by exacerbated sympathetic discharge following severe brain injury. Here, we reports a patient diagnosed with PSH after ICH concurrent with hypothalamic injury, as demonstrated by diffusion tensor imaging (DTI). METHODS: A 27-year-old man patient was diagnosed with spontaneous intraventricular hemorrhage and intracerebral hemorrhage in both frontal lobes. Two months after onset, brain magnetic resonance imaging of the brain revealed a leukomalactic lesion in the hypothalamus. Three months after the onset, he presented with intermittent high fever, tachycardia, tachypnea, systolic hypertension, diaphoresis, and aggravated rigidity. Infection was ruled out by a physical examination, laboratory tests, and radiological studies. After administrating morphine and bromocriptine, the clinical manifestations improved dramatically. RESULTS: PSH after intracranial hemorrhage concurrent with the hypothalamic injury. Fractional anisotropy and mean diffusivity values of DTI were obtained in the hypothalamus. No significant difference in fractional anisotropy value was observed between the patient and control group (10 age-matched healthy male subjects) (P > .05). On the other hand, the mean diffusivity value was higher in the patient group than in the control group (P < .05), indicating hypothalamic injury. CONCLUSION: PSH concurrent with hypothalamic injury was observed in a patient with stroke. This study suggests that DTI can be a useful imaging method for evaluating the hypothalamic state of patients presenting with PSH after brain injury.

Akathisia superimposed to Hashimoto's encephalopathy in an old lady.

BACKGROUND AND AIM: Hashimoto's encephalopathy (HE) is a rare clinical entity that is associated with encephalopathy with alteration of consciousness, presence of high levels of antithyroid antibodies, and exclusion of other suspected etiologies. METHODS: We describe a 60-year old lady who had been followed up for about 5 years for possible Alzheimer's disease plus Parkinson's disease and presented with akathisia overlapping a progressive encephalopathy compatible with the diagnosis of HE. RESULTS: Initial steroid therapy had shown no clinical benefit, whereas a mild to moderate improvement in clinical condition was observed after a 5-day course of plasmapheresis. CONCLUSIONS: Given this case, it is clear that this challenging yet treatable clinical syndrome should be considered even in older patients. Furthermore, side effects such as akathisia should also be considered when starting antipsychotic treatment, particularly in patients with an unclear diagnosis. The patient is noteworthy due to the extremely rare occurrence of HE presenting with akathisia, especially in the elderly.

[Restlessness and Syncopes in a Patient from a Home for Elderly]. / Eine Frau mit Unruhe und Synkopen im Altersheim.

Restlessness and Syncopes in a Patient from a Home for Elderly Abstract. A broad differential diagnosis should be considered when faced with syncopes. Most common causes are cardiovascular and neurological causes. If there is evidence of epilepsy with sudden loss of tone, look for ictal-triggered arrhythmias. Ictal bradycardias and asystoles are usually benign and self-limiting. In contrast, bradycardias and asystoles in the context of SUDEP are usually fatal and are the result of ictally induced cerebral hypoxemia.

An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death.

OBJECTIVE: To explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying. DESIGN: Latent class analysis using 7,971 participants with MCI. SETTING: Participants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers. PARTICIPANTS: Persons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater. MEASUREMENTS: Neuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit. RESULTS: In addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an "affect" or "negative mood" subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a "hyperactive" subgroup (14%) with agitation, irritability, and disinhibition; and 3) a "psychotic with additional severe NPS" subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the "mild NPS" class, with the "psychotic with additional severe NPS" subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia. CONCLUSION: Our findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.

Neuropsychiatric Symptoms as Predictor of Poor Clinical Outcome in Patients With Vascular Cognitive Impairment.

OBJECTIVE: Examine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury. DESIGN/SETTING: TRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.5 years). PARTICIPANTS: Five hundred and seventy-five memory clinic patients with vascular brain injury on MRI (i.e. possible Vascular Cognitive Impairment [VCI]). Severity of cognitive impairment ranged from no objective cognitive impairment to mild cognitive impairment (MCI) and dementia. MEASUREMENTS: We used Neuropsychiatric Inventory (total score and score on hyperactive, psychotic, affective, and apathetic behavior domains) to measure NPS. We assessed the association between NPS and institutionalization, mortality and cognitive deterioration (increase ≥0.5 on Clinical Dementia Rating scale) with Cox proportional hazards models and logistic regression analyses. RESULTS: NPS were present in 89% of all patients, most commonly in the hyperactive and apathetic behavior domain. Across the whole cohort, affective behavior was associated with institutionalization (HR: 1.98 [1.01-3.87]), mainly driven by the dementia subgroup (HR: 2.06 [1.00-4.21]). Apathetic behavior was associated with mortality and cognitive deterioration (HR: 2.07 [1.10-3.90],OR: 1.67 [1.12-2.49], respectively), mainly driven by the MCI subgroup (HR: 4.93 [1.07-22.86],OR: 3.25 [1.46-7.24], respectively). Conversely, hyperactive behavior was related to lower mortality (HR: 0.54 [0.29-0.98]), again particularly driven by the MCI subgroup (HR:0.17 [0.04-0.75]). Psychotic behavior was associated with cognitive deterioration in patients with no objective cognitive impairment (OR: 3.10 [1.09-8.80]) and with institutionalization in MCI (HR: 12.45 [1.28-121.14]). CONCLUSION: NPS are common and have prognostic value in memory clinic patients with possible VCI. This prognostic value depends on the severity of cognitive impairment.

A biological approach to adult sex differences in skeletal indicators of childhood stress.

OBJECTIVES: In previous work examining the etiology of cribra orbitalia (CO) and porotic hyperostosis (PH) in a contemporary juvenile mortality sample, we noted that males had higher odds of having CO lesions than females. Here, we examine potential reasons for this pattern in greater detail. Four non-mutually exclusive mechanisms could explain the observed sex differences: (1) sex-biased mortality; (2) sexual dimorphism in immune responses; (3) sexual dimorphism in bone turnover; or (4) sexual dimorphism in marrow conversion. SUBJECTS AND METHODS: The sample consists of postmortem computed tomography scans and autopsy reports, field reports, and limited medical records of 488 individuals from New Mexico (203 females; 285 males) aged between 0.5 and 15 years. We used Kaplan-Meier survival analysis, predicted probabilities, and odds ratios to test each mechanism. RESULTS: Males do not have lower survival probabilities than females, and we find no indications of sex differences in immune response. Overall, males have a higher probability of having CO or PH lesions than females. CONCLUSIONS: All results indicate that lesion formation in juveniles is influenced by some combination of sex differences in the pace of red-yellow conversion of the bone marrow and bone turnover. The preponderance of males with CO and PH likely speaks to the potential for heightened osteoblastic activity in males. We find no support for the hypotheses that sex biases in mortality or immune responses impacted lesion frequency in this sample. Sex differences in biological processes experienced by children may affect lesion formation and lesion expression in later life.

[Neuroleptic malignant syndrome - unexpected complication in a COVID-19 patient].

Neuroleptic malignant syndrome is a life-threatening condition that can be fatal if unrecognized and inadequately treated. This disease is rarely seen in infectious diseases wards. As infectiologists, however, we are confronted with an increasingly broader spectrum of diagnoses and this disease should therefore be considered in any patient taking psychiatric medication who develops the typical symptoms of hyperthermia, rigidity and muscle tremors, autonomic lability and impaired consciousness. A case report is presented of a young man with schizophrenia admitted to the intensive care unit with COVID-19, who was treated with antipsychotics (formerly known as neuroleptics) for restlessness and who developed neuroleptic malignant syndrome. In cooperation with psychiatrists, a targeted therapy was initiated, after which the symptoms subsided and the patient's clinical condition resolved.

Neuropsychiatric symptoms and quality of life in Spanish patients with Alzheimer's disease during the COVID-19 lockdown.

BACKGROUND AND PURPOSE: The COVID-19 epidemic is affecting almost all individuals worldwide, and patients with Alzheimer's disease (AD) and amnesic mild cognitive impairment (MCI) are particularly at risk due to their characteristics and age. We analysed the impact of the pandemic on these patients' neuropsychiatric symptoms and their quality of life after 5 weeks of lockdown in Spain. METHODS: A total of 40 patients with a diagnosis of MCI (n = 20) or mild AD (n = 20) from the Cognitive Stimulation Program of the Cognitive Disorders Unit were evaluated. All patients had undergone a previous evaluation during the month before the lockdown, and were re-evaluated after 5 weeks of lockdown. The Neuropsychiatric Inventory (NPI) and EuroQol-5D questionnaire (EQ-5D) were used to assess neuropsychiatric symptoms in patients and the quality of life in patients as well in caregivers. RESULTS: The mean (SD) total baseline NPI score was 33.75 (22.28), compared with 39.05 (27.96) after confinement (P = 0.028). The most frequently affected neuropsychiatric symptoms were apathy [4.15 (3.78) vs. 5.75 (4.02); P = 0.002] and anxiety [3.95 (3.73) vs. 5.30 (4.01); P = 0.006] in patients with MCI, and apathy [2.35 (2.70) vs. 3.75 (3.78); P = 0.036], agitation [0.45 (1.14) vs. 1.50 (2.66); P = 0.029] and aberrant motor behaviour [1.25 (2.86) vs. 2.00 (2.93); P = 0.044] in patients with AD. We did not observe differences in EQ-5D scores during the re-evaluation. The 30% of patients and 40% of caregivers reported a worsening of the patients' health status during confinement. CONCLUSIONS: The results of this study show the worsening of neuropsychiatric symptoms in patients with AD and MCI during 5 weeks of lockdown, with agitation, apathy and aberrant motor activity being the most affected symptoms.

Percutaneous endoscopic gastrostomy: dealing with the issue of dislodgement.

Introduction: Percutaneous Endoscopic Gastrostomy (PEG) is accepted as an efficient method to provide long-term enteral nutrition. PEG accidental dislodgement (device exteriorization confirmed by expert evaluation) rate is high and can lead to major morbidity.Objective: To identify independent risk factors for PEG accidental dislodgement.Methods: Retrospective, single-center study, including consecutive patients submitted to PEG procedure, for 38 consecutive months. Every patient had 12 months minimum follow-up after PEG placement. Univariate analysis selected variables with at least marginal association (p < .15) with the outcome variable, PEG dislodgement, which were included in a logistic regression multivariate model. Discriminative power was assessed using area under curve (AUC) of the receiver operating curve (ROC).Results: We included 164 patients, 67.7% (111) were female, mean age was 81 years. We report 59 (36%) PEG dislodgements, of which 13 (7.9%) corresponded to early dislodgements. The variables with marginal association were hypoalbuminemia (p = .095); living at home (p = .049); living in a nursing home (p = .074); cerebrovascular disease (CVD) (p = .028); weight change of more than 5 kg, either increase or decrease (p = .001); psychomotor agitation (p < .001); distance inner bumper-abdominal wall (p = .034) and irregular appointment follow-up (p = .149). At logistic multivariate regression, the significant variables after model adjustment were CVD OR 4.8 (CI 95% 2.0-11.8), weight change OR 4.7 (CI 95%1.6-13.9) and psychomotor agitation OR 18.5 (CI 95% 5.2-65.6), with excellent discriminative power (AUC ROC 0.797 [CI95% 0.719-0.875]).Conclusion: PEG is a common procedure and accidental dislodgement is a frequent complication. CVD, psychomotor agitation and weight change >5 kg increase the risk of this complication and should be seriously considered when establishing patients' individual care requirements.

Diagnosis, Clinical Features, and Therapeutic Implications of Agitated Depression

Agitated "unipolar" depression is a clinical entity characterized by excitement together with depressed mood during the same episode. The clinical picture of agitated "unipolar" depression is characterized by a depressed and anxious mood with inner, psychic agitation, whereas motor agitation may or may not be present. Some investigators have conceptualized this disorder as a mixed affective state, laying on the bipolar disorder spectrum, but controversies still persist. The diagnosis of agitated "unipolar" depression has important prognostic and therapeutic implications, with many clinicians reporting difficulties to adequately diagnose and treat it.

Activation syndrome induced by the antidepressant tianeptine and suicidal ideation: Evidence from a large depressed outpatient sample.

OBJECTIVE: To determine the characteristics of the activation syndrome (AS) that predict the emergence or worsening of suicidal ideation (SI) in the first month of antidepressant treatment with tianeptine, as well as the temporal relationship between both conditions. METHOD: A naturalistic sample of 2422 depressed outpatients starting a new antidepressant treatment with tianeptine was assessed at 2, 4 and 6 weeks of follow-up using validated questionnaires. Four main dimensions of AS were examined: impulsivity, sleep problems, anxiety and agitation. RESULTS: The emergence of an AS was more likely in long-lasting depressive episodes, but less likely if the patient responded to the antidepressant or benzodiazepines were added as an add-on treatment. Treatment-emergent SI was strongly associated to the presence of an AS, particularly in case of sleep problems (OR = 8.42) or impulsivity upsurges (OR = 3.89), even after adjustment for all relevant confounding factors. CONCLUSIONS: Our findings suggest a dose-effect mechanism modulating the relationship between treatment-related SI and AS. AS symptoms may need to be monitored closely in the weeks that follow the introduction of an antidepressant treatment.