Randomized, Multicenter Study to Assess the Effects of Different Doses of Sildenafil on Mortality in Adults With Pulmonary Arterial Hypertension.

BACKGROUND: Sildenafil, approved for pulmonary arterial hypertension (PAH), has a recommended adult dose of 20 mg TID, with a previously approved 5-mg TID dose by the US Food and Drug Administration. Safety concerns arose because of common off-label use of higher doses, particularly after pediatric data linked higher doses to increased mortality. To assess this, the Food and Drug Administration mandated a study evaluating the effects of various sildenafil doses on mortality in adults with PAH. METHODS: This randomized, double-blind study compared sildenafil at doses of 5, 20, or 80 mg TID in adults with PAH. The primary objective was noninferiority of 80 mg of sildenafil versus 5 mg for all-cause mortality. Secondary end points included time to clinical worsening and change in 6-minute walk distance at 6 months. Interim analyses were planned at 50% and 75% of the anticipated mortality events. Safety and tolerability were assessed in the intention-to-treat population. RESULTS: The study was halted after the first interim analysis, demonstrating noninferiority for 80 mg of sildenafil versus 5 mg. Of 385 patients enrolled across all dose groups, 78 died. The primary analysis showed a hazard ratio of 0.51 (99.7% CI, 0.22-1.21; P<0.001 for noninferiority) for overall survival comparing 80 mg of sildenafil with 5 mg. Time to clinical worsening favored 80 mg of sildenafil compared with 5 mg (hazard ratio, 0.44 [99.7% CI, 0.22-0.89]; P<0.001). Sildenafil at 80 mg improved 6-minute walk distance from baseline at 6 months compared with 5 mg (least square mean change, 18.9 m [95% CI, 2.99-34.86]; P=0.0201). No significant differences were found between 80 mg of sildenafil and 20 mg in mortality, clinical worsening, and 6-minute walk distance. Adverse event-related drug discontinuations were numerically higher with 80 mg of sildenafil. CONCLUSIONS: Sildenafil at 80 mg was noninferior to sildenafil at 5 mg when examining all-cause mortality in adults with PAH. Secondary efficacy end points favored 80 mg of sildenafil over 5 mg. On the basis of these findings, the Food and Drug Administration recently revoked the approval of 5 mg of sildenafil for adults with PAH, reinforced 20 mg TID as the recommended dose, and now allows dose titration up to 80 mg TID, if needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02060487.

Long-term opioid therapy and mental health comorbidity in patients with chronic pain.

OBJECTIVES: Evidence suggests that patients with chronic pain and mental illness are more likely to receive long-term opioid therapy (LTOT) and at higher doses but are also at increased risk of experiencing opioid-related harm. This study investigates LTOT and its relationship to mental illness in the setting of a university-based outpatient pain clinic with liaison psychiatric care. METHODS: Retrospective analysis of patients with chronic pain admitted between 2011 and 2015. After a 1-year treatment period, patients with non-opioid treatment, guideline-recommended LTOT, and high-dose LTOT were compared, and multiple regression analysis was performed to identify predictors of higher opioid dosage. RESULTS: Of 769 patients, 46% received LTOT (opioids for >90 consecutive days), 13% at high dosage (>120 oral morphine milligram equivalents [MME] / day). Two thirds of all patients had mental illness. The prevalence of psychiatric diagnoses and prescription rate of psychotropic medication did not significantly differ between groups. Pain chronicity stages, use of antidepressants, and sex significantly predicted MME/day but explained only a minor part of the variance. The association with antidepressants can be attributed to the prescription of antidepressants for analgesic purposes rather than for treating depression. No association with any other type of psychiatric disorders was observed. CONCLUSION: This study shows that mental health comorbidity is highly prevalent but that the prescribed opioid dosage is independent of it in the clinical setting of this study. The concept of liaison psychiatric care might have essentially contributed to the "detachment" of opioid prescription and psychiatric conditions but cannot be isolated from other potentially contributing factors within this single-center observational study.

The Dyspnea-ALS-Scale (DALS-15) optimizes individual treatment in patients with amyotrophic lateral sclerosis (ALS) suffering from dyspnea.

BACKGROUND: Dyspnea is frequent in amyotrophic lateral sclerosis (ALS) and one of the most bothersome symptoms. The recently developed Dyspnea-ALS-Scale (DALS-15) is a disease-specific patient-reported outcome to detect and quantify dyspnea. OBJECTIVES: To analyze in a case-based approach the diagnostic and clinical implications and the benefit of the DALS-15 for individual patients in daily clinical routine. METHODS: Dyspnea was assessed by the 15-item comprising DALS-15 in two patients with ALS. Spirometry was performed and blood gases were analyzed. Results were evaluated in the clinical context of the respective patients. RESULTS: In one patient the presence of dyspnea detected by the DALS-15 indicated noninvasive ventilation (NIV) although forced vital capacity (FVC) and blood gas analysis were well preserved. After NIV implementation, the DALS-15 was helpful to determine the patient's need for medication, the timing of NIV titration and the adaptation of NIV sessions. In another patient, who was anarthric and no longer able to perform spirometry due to severe bulbar impairment, the DALS-15 allowed a standardized assessment of dyspnea-related distress independently of bulbar dysfunction. CONCLUSION: The DALS-15 provides a deeper insight into the respiratory status of individual patients. It helps to diagnose respiratory impairment in patients in whom NIV should be considered although FVC and blood gas results do not reveal indication for NIV. It is also valuable for the guidance of patients in later stages of respiratory impairment when NIV is already implemented, and in patients with severe bulbar dysfunction. The DALS-15 can improve specific symptom management and coordination of care and therefore has the potential to optimize individual treatment in ALS patients with dyspnea.

Effect of waist circumference on the association between serum 25-hydroxyvitamin D and serum lipids: results from the National Health and Nutrition Examination Survey 2001-2006.

OBJECTIVE: To examine the interaction between waist circumference (WC) and serum 25-hydroxyvitamin D (25(OH)D) level in their associations with serum lipids. DESIGN: Cross-sectional study. The associations of serum 25(OH)D with total cholesterol, HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), LDL-C:HDL-C and TAG were examined using multiple linear regression. Effect modification by WC was assessed through cross-product interaction terms between 25(OH)D and WC categories (abdominal overweight, 80-<88 cm in females/94-<102 cm in males; abdominal obesity, ≥88 cm in females/≥102 cm in males). SETTING: The US National Health and Nutrition Examination Survey waves 2001-2006. SUBJECTS: Non-pregnant fasting participants (n 4342) aged ≥20 years. RESULTS: Lower 25(OH)D levels were significantly associated with lower HDL-C levels as well as with higher LDL-C:HDL-C and TAG levels in abdominally obese participants, but not in abdominally overweight or normal-waist participants. In contrast, lower 25(OH)D levels were associated with lower levels of total cholesterol and LDL-C in abdominally overweight and normal-waist participants only, but this association was only partly significant. However, a significant difference in the association between 25(OH)D and the lipids according to WC category was found only for LDL-C:HDL-C (P for interaction=0·02). CONCLUSIONS: Our results from this large, cross-sectional sample suggest that the association between lower 25(OH)D levels and an unfavourable lipid profile is stronger in individuals with abdominal obesity than in those with abdominal overweight or a normal WC.

Predicting risk of substantial weight gain in German adults-a multi-center cohort approach.

Background: A risk-targeted prevention strategy may efficiently utilize limited resources available for prevention of overweight and obesity. Likewise, more efficient intervention trials could be designed if selection of subjects was based on risk. The aim of the study was to develop a risk score predicting substantial weight gain among German adults. Methods: We developed the risk score using information on 15 socio-demographic, dietary and lifestyle factors from 32 204 participants of five population-based German cohort studies. Substantial weight gain was defined as gaining ≥10% of weight between baseline and follow-up (>6 years apart). The cases were censored according to the theoretical point in time when the threshold of 10% baseline-based weight gain was crossed assuming linearity of weight gain. Beta coefficients derived from proportional hazards regression were used as weights to compute the risk score as a linear combination of the predictors. Cross-validation was used to evaluate the score's discriminatory accuracy. Results: The cross-validated c index (95% CI) was 0.71 (0.67-0.75). A cutoff value of ≥475 score points yielded a sensitivity of 71% and a specificity of 63%. The corresponding positive and negative predictive values were 10.4% and 97.6%, respectively. Conclusions: The proposed risk score may support healthcare providers in decision making and referral and facilitate an efficient selection of subjects into intervention trials.

Observing iconic gestures enhances word learning in typically developing children and children with specific language impairment.

Research has shown that observing iconic gestures helps typically developing children (TD) and children with specific language impairment (SLI) learn new words. So far, studies mostly compared word learning with and without gestures. The present study investigated word learning under two gesture conditions in children with and without language impairment. Twenty children with SLI (age four), twenty age-matched TD children, and twenty language-matched TD children were taught words that were presented with either iconic or non-iconic gestures. Results showed that children of all groups benefited more successfully from observing iconic gestures for word learning. The iconic gesture advantage was similar across groups. Thus, observing iconic gestures prompts richer encoding and makes word learning more efficient in TD and language impaired children.

Comparison of different measures of obesity in their association with health-related quality of life in older adults - results from the KORA-Age study.

OBJECTIVE: As ageing is associated with changes in body composition, BMI may not be the appropriate obesity measure for older adults. To date, little is known about associations between obesity measures and health-related quality of life (HRQoL). Thus, we aimed to compare different obesity measures in their association with HRQoL and self-rated physical constitution (SRPC) in older adults. DESIGN: Seven obesity measures (BMI, waist circumference (WC), waist-to-hip ratio, waist-to-height ratio, fat mass percentage based on bioelectrical impedance analysis, hypertriglyceridaemic waist (HTGW) and sarcopenic obesity) were assessed at baseline in 2009. HRQoL, using the EQ-5D questionnaire, and SRPC, using one single question, were collected at baseline and at the 3-year follow-up in 2012. Linear and logistic regression analyses were used to examine the associations between the obesity measures and both outcomes. Model comparisons were conducted by area under the receiver-operating characteristic curve, R 2, Akaike and Schwarz Bayesian information criteria. SETTING: KORA-Age study in Southern Germany (2009-2012). SUBJECTS: Older adults (n 883; aged ≥65 years). RESULTS: Nearly all obesity measures were significantly inversely associated with both outcomes in cross-sectional analyses. Concerning HRQoL, the WC model explained most of the variance and had the best model adaption, followed by the BMI model. Regarding SRPC, the HTGW and BMI models were best as rated by model quality criteria, followed closely by the WC model. Longitudinal analyses showed no significant associations. CONCLUSIONS: These results suggest that, with regard to HRQoL/SRPC, simple anthropometric measures are sufficient to determine obesity in older adults in medical practice.

Multi-omic signature of body weight change: results from a population-based cohort study.

BACKGROUND: Excess body weight is a major risk factor for cardiometabolic diseases. The complex molecular mechanisms of body weight change-induced metabolic perturbations are not fully understood. Specifically, in-depth molecular characterization of long-term body weight change in the general population is lacking. Here, we pursued a multi-omic approach to comprehensively study metabolic consequences of body weight change during a seven-year follow-up in a large prospective study. METHODS: We used data from the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort. At follow-up (F4), two-platform serum metabolomics and whole blood gene expression measurements were obtained for 1,631 and 689 participants, respectively. Using weighted correlation network analysis, omics data were clustered into modules of closely connected molecules, followed by the formation of a partial correlation network from the modules. Association of the omics modules with previous annual percentage weight change was then determined using linear models. In addition, we performed pathway enrichment analyses, stability analyses, and assessed the relation of the omics modules with clinical traits. RESULTS: Four metabolite and two gene expression modules were significantly and stably associated with body weight change (P-values ranging from 1.9 × 10(-4) to 1.2 × 10(-24)). The four metabolite modules covered major branches of metabolism, with VLDL, LDL and large HDL subclasses, triglycerides, branched-chain amino acids and markers of energy metabolism among the main representative molecules. One gene expression module suggests a role of weight change in red blood cell development. The other gene expression module largely overlaps with the lipid-leukocyte (LL) module previously reported to interact with serum metabolites, for which we identify additional co-expressed genes. The omics modules were interrelated and showed cross-sectional associations with clinical traits. Moreover, weight gain and weight loss showed largely opposing associations with the omics modules. CONCLUSIONS: Long-term weight change in the general population globally associates with serum metabolite concentrations. An integrated metabolomics and transcriptomics approach improved the understanding of molecular mechanisms underlying the association of weight gain with changes in lipid and amino acid metabolism, insulin sensitivity, mitochondrial function as well as blood cell development and function.

Prospective association of vitamin D with frailty status and all-cause mortality in older adults: Results from the KORA-Age Study.

OBJECTIVE: To assess the prospective association of serum 25-hydroxyvitamin D [25(OH)D] levels with frailty status and all-cause mortality in a cohort of community-dwelling participants of the population-based KORA [Cooperative Health Research in the Region of Augsburg]-Age Study. METHODS: 727 non-frail participants, aged ≥65years, with 25(OH)D measurement at baseline in 2009, were followed for 2.9±0.1years. Participants were classified as pre-frail or frail if they met 1-2 or ≥3, respectively, of the following five criteria: weight loss, exhaustion, physical inactivity, low walking speed, weakness. The association between 25(OH)D and mortality was assessed in 954 participants. Multivariable adjusted logistic regression models were calculated for each outcome. RESULTS: The incidence of pre-frailty and frailty was 21.2% and 3.9% respectively. After multivariable adjustment, participants with very low 25(OH)D levels (<15ng/ml vs. ≥30ng/ml) had a significantly higher odds for pre-frailty (OR=2.43 [95% CI: 1.17-5.03]) and pre-frailty/frailty combined (OR=2.53 [95% CI: 1.23-5.22]), but not for frailty alone (OR=2.63 [95% CI: 0.39-17.67]). The association between 25(OH)D and mortality (OR=3.39 [95% CI: 1.08-10.65]) was partly mediated by frailty status. CONCLUSION: Very low 25(OH)D levels were independently associated with incident pre-frailty, pre-frailty/frailty combined and all-cause mortality.

[Fire disaster due to deflagration of a propane gas-air mixture]. / Folgenschwerer Brand durch Entzündung eines Propangas-Luft-Gemisches.

On 26 Nov 2012, a serious fire occurred at Neustadt/Black Forest in which 14 persons in a sheltered workshop died and 10 other individuals were injured. The fire was caused by the unbridled escape of propane gas due to accidental disconnection of the screw fixing between a gas bottle and a catalytic heater. Deflagration of the propane gas-air mixture set the workshop facilities on fire. In spite of partly extensive burns the fatally injured victims could be rapidly identified. The results of the fire investigations at the scene and the autopsy findings are presented. Carboxyhemoglobin concentrations ranged between 8 and 56 % and signs of fire fume inhalation were present in all cases. Three victims had eardrum ruptures due to the sudden increase in air pressure during the deflagration.

A fatal case of aspiration due to consumption of the hallucinogenic tryptamine derivative dipropyltryptamine (DPT).

BACKGROUND AND AIM: This case involves a 20-year-old man with prior hallucinogen-use experience, who sniffed an unknown amount of dipropyltryptamine in an apartment. Dipropyltryptamine, a hallucinogenic compound belonging to the tryptamine class is recognized for inducing effects similar to dimethyltryptamine (DMT) but with a longer duration. Ten to fifteen minutes later he experienced visual hallucinations, followed by increasing apathy. Two hours post consumption he developed abdominal pain, leading to collapse, seizure, and vomiting. Despite emergency medical resuscitation on site, transport to hospital 2.5 hours post consumption and extracorporeal life support he died 21 hours later. Relevant toxicological and morphological findings are presented. METHODS: A serum sample was collected four hours post consumption. Autopsy was performed six days after death. Antemortem serum, as well as postmortem cardiac blood and urine were analyzed for alcohol and psychoactive drugs by systematic toxicological analyses employing gas chromatography-mass spectrometry (Maurer/Pfleger/Weber library among others), liquid chromatography-ion trap mass spectrometry (LC-MSn, Toxtyper™), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Dipropyltryptamine was quantified by LC-MS/MS after solid-phase extraction. RESULTS: Autopsy revealed a state after deep aspiration of gastric contents with consecutive brain edema due to oxygen deprivation. Dipropyltryptamine concentrations were approximately 210 ng/ml, 110 ng/ml and 180 ng/ml in antemortem serum, postmortem cardiac blood and urine, respectively. To the best of our knowledge, these are the first reported concentrations of dipropyltryptamine in a fatal case. CONCLUSION: Unlike typical tryptamine overdose reports, this case did not present with agitation, hyperthermia, or tachycardia. Despite the individual's prior experience with tryptamines and the generally low toxicity associated with this class of hallucinogens, death in this case was an indirect consequence of the nasal consumption of a high dose of dipropyltryptamine.

[Postmortem detection of accidental methadone intoxication in a 10-year-old girl]. / Postmortale Aufdeckung einer akzidentellen Methadon-Intoxikation bei einem 10-jährigen Mädchen.

Intoxications in children still account for a large part of the cases reported to poison control centres. Among drug intoxications, substitution drugs have gained in importance lately. Careless storage of take-home medications puts children living in the same household at risk. The authors report on a fatal case of a 10-year-old girl who died from intoxication with methadone belonging to a carer. The accidental intoxication had not been diagnosed at the hospital where the girl was treated for suspected meningitis. The question of medical malpractice is discussed.

Definition and terminology of developmental language disorders-Interdisciplinary consensus across German-speaking countries.

In recent years, there have been intense international discussions about the definition and terminology of language disorders in childhood, such as those sparked by the publications of the CATALISE consortium. To address this ongoing debate, a Delphi study was conducted in German-speaking countries. This study consisted of three survey waves and involved over 400 experts from relevant disciplines. As a result, a far-reaching consensus was achieved on essential definition criteria and terminology, presented in 23 statements. The German term 'Sprachentwicklungsstörung' was endorsed to refer to children with significant deviations from typical language development that can negatively impact social interactions, educational progress, and/or social participation and do not occur together with a potentially contributing impairment. A significant deviation from typical language development was defined as a child's scores in standardized test procedures being ≥ 1.5 SD below the mean for children of the same age. The results of this Delphi study provide a proposal for a uniform use of terminology for language disorders in childhood in German-speaking countries.

Pain-Related Coping Behavior in ALS: The Interplay between Maladaptive Coping, the Patient's Affective State and Pain.

BACKGROUND: Pain is a common symptom in patients with amyotrophic lateral sclerosis (ALS). Coping plays a central role in adjustment to pain. OBJECTIVE: This study evaluates the use of different pain coping strategies in patients with ALS and investigates the interplay of maladaptive coping, and the patient's affective state and pain. METHODS: One hundred and fifty ALS patients from three German outpatient clinics completed the Brief Pain Inventory (BPI), the ALS-Functional Rating Scale-Extension (ALSFRS-EX), the ALS Depression Inventory (ADI-12), the subscale "emotional functioning" of the ALS Assessment Questionnaire (ALSAQ-40) and the Coping Strategies Questionnaire (CSQ). Based upon the results of correlational analyses, multiple regression analyses were performed to identify predictors of pain severity and to explore factors contributing to maladaptive coping. RESULTS: Pain was prevalent in 56% (n = 84) of the patients. Patients applied different adaptive coping strategies as well as the maladaptive strategy "catastrophizing". Regression analysis indicated that the CSQ-subscale "catastrophizing" significantly predicted pain intensity, explaining 34.0% of the variance (p < 0.001). Pain-related catastrophizing was associated with higher pain-related functional impairments and worse emotional functioning. The ADI-12 sum score as an indicator for depressive symptoms contributed significantly to the maladaptive coping strategy "catastrophizing" (p < 0.001) and explained 40.8% of the variance. CONCLUSION: Patients with ALS apply different strategies to cope with pain. Catastrophizing is an important determinant of higher pain intensity ratings and is associated with higher pain interferences and decreased emotional well-being. Pain-related catastrophizing is promoted by depressive symptoms. Catastrophizing and depressive symptoms thus represent important targets of individualized pain-management strategies.

Characteristics of pain and the burden it causes in patients with amyotrophic lateral sclerosis - a longitudinal study.

OBJECTIVE: Pain currently plays a subordinate role in the clinical care of patients with ALS. We aim to examine epidemiological and clinical characteristics of pain as well as its impact throughout the disease course. METHODS: During a longitudinal follow-up at three time points, 151 ALS patients from three German outpatient clinics completed the Brief Pain Inventory, ALS-Functional Rating Scale-Extension and ALS Depression Inventory. Analysis of variance and covariance with repeated measures were performed. RESULTS: Pain was prevalent in 56% of the 151 patients at baseline and in 70% of the remaining 40 patients at the third survey. Of the 28 patients with pain who participated in all three surveys, about two thirds suffered from an average pain intensity corresponding to at least moderate pain on the numerical rating scale (NRS ≥ 4). Patients reported different pain qualities and localized the pain most frequently in the extremities, back and neck. Pain moderately impaired the functions of daily living. Pain intensity, pain quality and pain-related impairment did not significantly change over time. One third of the patients suffered from clinically relevant depressive symptoms. However, there was no conclusive evidence of a link between pain intensity and depressive symptoms. CONCLUSION: Pain is frequent and constitutes an additional strain on ALS patients who have to endure a rapidly progressive and severely debilitating disease. This study contributes to better understanding of the characteristics of pain and its impact on ALS patients throughout the disease course and may thus help to more effectively address this symptom.

Impairment of mitochondrial oxidative phosphorylation in skin fibroblasts of SALS and FALS patients is rescued by in vitro treatment with ROS scavengers.

Amyotrophic lateral sclerosis (ALS) is a devastating, rapidly progressive, neurodegenerative disorder affecting upper and lower motor neurons. Approximately 10% of patients suffer from familial ALS (FALS) with mutations in different ubiquitously expressed genes including SOD1, C9ORF72, TARDBP, and FUS. There is compelling evidence for mitochondrial involvement in the pathogenic mechanisms of FALS and sporadic ALS (SALS), which is believed to be relevant for disease. Owing to the ubiquitous expression of relevant disease-associated genes, mitochondrial dysfunction is also detectable in peripheral patient tissue. We here report results of a detailed investigation of the functional impairment of mitochondrial oxidative phosphorylation (OXPHOS) in cultured skin fibroblasts from 23 SALS and 17 FALS patients, harboring pathogenic mutations in SOD1, C9ORF72, TARDBP and FUS. A considerable functional and structural mitochondrial impairment was detectable in fibroblasts from patients with SALS. Similarly, fibroblasts from patients with FALS, harboring pathogenic mutations in TARDBP, FUS and SOD1, showed mitochondrial defects, while fibroblasts from C9ORF72 associated FALS showed a very mild impairment detectable in mitochondrial ATP production rates only. While we could not detect alterations in the mtDNA copy number in the SALS or FALS fibroblast cultures, the impairment of OXPHOS in SALS fibroblasts and SOD1 or TARDBP FALS could be rescued by in vitro treatments with CoQ10 (5 µM for 3 weeks) or Trolox (300 µM for 5 days). This underlines the role of elevated oxidative stress as a potential cause for the observed functional effects on mitochondria, which might be relevant disease modifying factors.

A Multi-Center Cohort Study on Characteristics of Pain, Its Impact and Pharmacotherapeutic Management in Patients with ALS.

BACKGROUND: Although pain is common in amyotrophic lateral sclerosis (ALS) and an effectively treatable symptom, it is widely under-recognized and undertreated. This study investigates epidemiological and clinical characteristics of pain, its impact and pharmacological treatment in ALS patients. In addition, opportunities for further optimization of pain therapy need to be identified. METHODS: Patients from three German ALS outpatient clinics were asked to complete the Brief Pain Inventory and the ALS Functional Rating Scale-Extension and to participate in semi-structured telephone interviews. RESULTS: Of the 150 study participants, 84 patients reported pain. Pain occurred across all disease stages, predominantly in the neck, back and lower extremities. It was described with a broad spectrum of pain descriptors and mostly interfered with activity-related functions. Of the 84 pain patients, 53.8% reported an average pain intensity ≥4 on the numerical rating scale (NRS), indicating pain of at least moderate intensity, and 64.3% used pain medication. Irrespective of the medication type, 20.4% of them had no sufficient pain relief. Thirteen out of 30 patients without pain medication reported an average NRS value ≥4. Eleven of them-mainly in the context of high pain interference with daily functions-were supposed to benefit from adequate pain therapy. However, many patients had relevant concerns and misconceptions about pain therapy. CONCLUSION: Given the frequency, extent and multi-faceted impact of pain, it is necessary to systematically assess pain throughout the disease course. Potentials to optimize pain therapy were seen in the subset of patients with insufficient pain relief despite medication and in those patients without pain medication but high pain interference. However, there is a need to respond to patients' barriers to pain therapy.

Lessons of the month 3: Intravenous poppers abuse: case report, management and possible complications.

BACKGROUND: Poppers are nitrite-containing liquids, which are inhaled for their aphrodisiac and hallucinogenic effects. Despite some cases of severe poisonings, poppers are often perceived as harmless by consumers. Inhalation and ingestion of poppers are well known, but, according to our literature review, intravenous abuse has not been reported before. CASE PRESENTATION: A 34-year-old man injected poppers intravenously for recreational purposes. He then suffered from dyspnoea and general discomfort. Upon arrival of emergency medical services, the patient was dyspnoeic with blue-grey skin colour and oxygen saturation was 82% on ambient air. Non-invasive ventilation was necessary, and he was transferred to the intensive care unit. Toluidine blue was administered because of a methaemoglobinaemia of 40% and methaemoglobin levels dropped to 0.4%. He was discharged home after a 24-hour observation. We additionally analysed the contents of the poppers bottle: isopropyl nitrite, isopropanol and acetone were detected. Possible complications and the treatment regarding intravenous administration of poppers are discussed. CONCLUSION: We present the first published case of intravenous poppers abuse. Our patient suffered from methaemoglobinaemia and was rapidly discharged after treatment with toluidine blue. No specific treatment regarding the contents of the poppers bottle, apart from isopropyl nitrite, was necessary.

Dyspnea as a Fatigue-Promoting Factor in ALS and the Role of Objective Indicators of Respiratory Impairment.

CONTEXT: There is no evidence-based treatment for fatigue in amyotrophic lateral sclerosis (ALS), and identification of treatable causes determines management strategies. Although dyspnea is a key symptom of ALS and effectively treatable, it has not been sufficiently investigated whether dyspnea may be a fatigue-promoting factor. OBJECTIVES: To determine the level of fatigue in dyspneic ALS patients and whether fatigue is promoted by dyspnea. We further evaluated the correlation of fatigue with respiratory function tests. METHODS: About 101 dyspneic patients and 20 matched controls completed the ALS Functional Rating Scale-Extension and the Fatigue Severity Scale. Dyspneic patients additionally completed the Dyspnea-ALS Scale and the ALS Assessment Questionnaire and underwent respiratory function tests (forced vital capacity, sniff nasal inspiratory pressure, mean inspiratory and expiratory pressure with respective relaxation rates, and blood gases). Multiple regression and correlation analyses were conducted. RESULTS: Dyspneic patients had significantly higher fatigue scores than nondyspneic patients, and their fatigue significantly affected quality of life. Dyspnea alone explained up to 24% of the variance in fatigue. No associations were observed between fatigue and respiratory function tests. Patients with noninvasive ventilation reported significantly more dyspnea and fatigue. CONCLUSION: Fatigue is a frequent and bothersome symptom in dyspneic ALS patients. Dyspnea-related distress is, in contrast to objective indicators of respiratory impairment, a determining factor of experienced fatigue. There is an urgent need for further symptom relief beyond noninvasive ventilation. Adequate treatment of dyspnea has the potential for synergies in symptom management arising from the association between fatigue and dyspnea.

Sonographic and 3T-MRI-based evaluation of the tongue in ALS.

A few systematic imaging studies employing ultrasound (HRUS) and magnetic resonance imaging (MRI) have suggested tongue measures to aid in diagnosis of amyotrophic lateral sclerosis (ALS). The relationship between structural tongue alterations and the ALS patients' bulbar and overall motor function has not yet been elucidated. We here thus aimed to understand how in-vivo tongue alterations relate to motor function and motor function evolution over time in ALS. Our study included 206 ALS patients and 104 age- and sex-matched controls that underwent HRUS and 3T MRI of the tongue at baseline. Sonographic measures comprised coronal tongue echointensity, area, height, width and height/width ratio, while MRI measures comprised sagittal T1 intensity, tongue area, position and shape. Imaging-derived markers were related to baseline and longitudinal bulbar and overall motor function. Baseline T1 intensity was lower in ALS patients with more severe bulbar involvement at baseline. Smaller baseline coronal (HRUS) and sagittal (MRI) tongue area, smaller coronal height (HRUS) and width (HRUS) as well as more rounded sagittal tongue shape predicated more rapid functional impairment - not only of bulbar, but also of overall motor function - in ALS. Our results suggest that in-vivo sonography und MRI tongue measures could aid as biomarkers to reflect bulbar and motor function impairment.