Feasibility and safety of treatment switch from Pirfenidone to Nintedanib in patients with idiopathic pulmonary fibrosis: a real-world observational study.

OBJECTIVE: Idiopathic Pulmonary Fibrosis is a disease characterized by a devastating fibrosing process. Two anti-fibrotic agents, pirfenidone and nintedanib, have been found to alter the disease progression. In this study, we sought to determine whether switching treatment to nintedanib is feasible and safe in patients that had to discontinue treatment with pirfenidone due to side effects. PATIENTS AND METHODS: We analyzed patients that had to discontinue pirfenidone due to side effects. Patients were prospectively enrolled for treatment with nintedanib between March 2015 and June 2019. Side effects and Pulmonary Function Tests were recorded. RESULTS: 12 patients received nintedanib after discontinuing treatment with pirfenidone. Side-effects that led to discontinuation were diarrhea (33.3%), nausea (16.6%), photosensitivity (33.3%) and difficulty adhering to pirfenidone's dosage scheme (16.6%). After the initiation of nintedanib, diarrhea was the most common side effect (66.6%). Four patients of these patients could not tolerate the full dose of 300 mg daily and had to reduce it to 200 mg daily. No patient has had experienced liver damage. During the last twelve months of treatment with pirfenidone, mean ΔFCV was +2.47 ± 3.69%, mean ΔDLco was -0.36 ± 2.64% and mean difference of the distance walked during the 6MWT was 5 ± 56.48 meters. During the first year of treatment with nintedanib, mean ΔFCV was -1.32 ± 1.12% (p=0.68), mean ΔDLco was -1.59 ± 3.45% (p=0.54) and mean difference of the distance walked during the 6MWT was 14.17 ± 59 meters (p=0.078). 50% of patients had stable disease under pirfenidone (6-month FVC decline < 5% and/or 6-month DLco decline < 10%) vs. 50% under nintedanib, 33.3% had marginal 6-month decline (5% ≤ 6-month FVC ≤ 10% and/or (≤ 10% 6- month DLco decline ≤15%) under pirfenidone vs. 33.3% under nintedanib and 16.6% had disease progression (6-month FVC decline > 10% and/or 6-month DLco decline > 15%) under pirfenidone vs. 16.6% under nintedanib. CONCLUSIONS: These results suggest that nintedanib is a safe option for the treatment of patients that had to discontinue pirfenidone due to adverse reactions. Further studies with greater patient numbers are needed for accurate results concerning efficacy.

Cardiovascular Disease in Patients with Chronic Obstructive Pulmonary Disease, Obstructive Sleep Apnoea Syndrome and Overlap Syndrome.

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnoea syndrome (OSAS) are among the most prevalent chronic respiratory disorders. Accumulating data suggest that there is a significant burden of cardiovascular disease (CVD) in patients with COPD and OSAS, affecting negatively patients' quality of life and survival. Overlap syndrome (OS), i.e. the co-existence of both COPD and OSAS in the same patient, has an additional impact on the cardiovascular system multiplying the risk of morbidity and mortality. The underlying mechanisms for the development of CVD in patients with either OSAS or COPD and OS are not entirely elucidated. Several mechanisms, in addition to smoking and obesity, may be implicated, including systemic inflammation, increased sympathetic activity, oxidative stress and endothelial dysfunction. Early diagnosis and proper management of these patients might reduce cardiovascular risk and improve patients' survival. In this review, we summarize the current knowledge regarding epidemiological aspects, pathophysiological mechanisms and present point-to-point specific associations between COPD, OSAS, OS and components of CVD, namely, pulmonary hypertension, coronary artery disease, peripheral arterial disease and stroke.

Influence of drugs on prison suicide - A retrospective case study.

The prevalence of mental disorders and comorbidity with substance abuse and personality disorders is high in prisoners. Furthermore, drug abuse in prison is a widespread problem throughout prisons around the world. In this retrospective study, we analyzed the prison deaths over six years (2012-2017). For each death, we collected data of the Berlin prison system, the prison hospital and the State Institute for Forensic and Social Medicine Berlin and the Institute of Legal Medicine and Forensic Sciences, Charité Medical University Berlin. In total, 33 prisoners died during our study period, of which 24 committed suicide. In 25% of the suicide cases, forensic toxicology reports were positive for drugs without cases of lethal intoxication. A direct influence of drug intoxication on prisoner deaths and suicide was not common in our data. Small sample size, a missing control group, and the retrospective study design limit generalizability of the results.

Violent Behavior During Psychiatric Inpatient Treatment in a German Prison Hospital.

Violent behavior in correctional facilities is common and differs substantially in type, target, implication, and trigger. Research on frequency and characteristics of violent behavior in correctional facilities and psychiatric hospitals is limited. Results from recent research suggest that comorbidity of severe mental disorder, personality disorder, and diagnosis of substance abuse is related to a higher risk of violent behavior. In the Berlin prison hospital, a database was created to collect data from all violent incidences (n=210) between 1997 and 2006 and between 2010 and 2016. In a retrospective, case-control study, we analyzed specific socioeconomic data and psychiatric diagnosis and compared the group of prisoners with violent behavior with randomly selected prisoners of the same department without violent behavior (n = 210). Diagnosis of schizophrenia, non-German nationality, no use of an interpreter, no children, and no previous sentence remained significantly associated with the dependent variable violent behavior. There were no significant differences regarding age and legal statuses. Practical implications for clinical work are discussed.

Corrigendum: Violent Behavior During Psychiatric Inpatient Treatment in a German Prison Hospital.

[This corrects the article DOI: 10.3389/fpsyt.2019.00762.].

Vitamin D Levels in Middle-Aged Patients with Obstructive Sleep Apnoea Syndrome.

BACKGROUND: Vitamin D (Vit D) insufficiency has been implicated in the pathophysiology of numerous diseases. Obstructive sleep apnoea syndrome (OSAS), a disorder associated with increased cardiovascular and cerebrovascular morbidity, has been associated with decreased Vit D levels, but reports are inconclusive. AIM: To evaluate the association between serum 25-hydroxyvitamin D [25(OH)D], a marker of Vit D status, with anthropometric and sleep characteristics of OSAS patients and to compare those levels between OSAS patients and non-apnoeic controls. METHOD: Consecutive subjects who had undergone polysomnography and pulmonary function testing were divided into controls (apnoea-hypopnea index, AHI <5/h) and OSAS group (AHI ≥5/h). RESULTS: A total of 169 subjects (135 men) were included. OSAS patients (n=139) significantly differed from non-apnoeic controls in terms of age (53.9±12.8 vs. 44.9±12.8 years, p=0.002) and body mass index (BMI) (35.9±6.9 vs. 29.9±6.8 kg/m2, p<0.001). Serum 25(OH)D levels were lower in OSAS patients (17.8±7.8 vs. 23.9±12.4 ng/ml, p=0.019). In OSAS patients, levels of serum 25(OH)D were negatively correlated with sleep stage transitions (r=-0.205, p=0.028), AHI (r=-0.187, p=0.045), oxygen desaturation index (r=-0.234, p=0.011) and percentage of time with oxyhaemoglobin saturation <90% (r=-0.172, p=0.041). In contrast, they were positively correlated with average oxyhaemoglobin saturation during sleep (r=0.179, p=0.033), forced expiratory volume in 1 sec (r=0.207, p=0.037) and oxygen partial pressure (r=0.197, p=0.029). CONCLUSION: Vit D levels were lower in OSAS patients compared with non-apnoeic controls. Several indices of OSAS severity also correlated with Vit D levels.

Insulin Sensitivity and Insulin Resistance in Non-Diabetic Middle-Aged Patients with Obstructive Sleep Apnoea Syndrome.

BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) has been linked with abnormal glucose metabolism, insulin resistance (IR) and development of diabetes mellitus. METHODS: Non-diabetic patients (n=69) with OSAS, diagnosed by polysomnography, were prospectively recruited. To evaluate IR among OSAS patients, the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Insulin sensitivity by Quantitative Insulin sensitivity Check Index (QUICKI) were used. RESULTS: HOMA-IR was positively associated with body-mass index (BMI) (ρ=0.364, p=0.002), time with oxyhaemoglobin saturation <90% (ρ=0.291, p=0.015), arousal index (ρ=0.268, p=0.027), Epworth sleepiness scale (ESS) score (ρ=0.293, p=0.019) and negatively with average oxyhaemoglobin saturation (ρ=-0.398, p=0.001) and minimum oxyhaemoglobin saturation (ρ=-0.327, p=0.006). QUICKI was positively associated with forced vital capacity (r=0.301, p=0.014), average oxyhaemoglobin saturation (r=0.443, p<0.001), minimum oxyhaemoglobin saturation (ρ=0.318, p=0.008), and negatively associated with sleep stage transitions (r=-0.266, p=0.032), oxygen desaturation index (r=-0.404, p=0.005), time with oxyhaemoglobin saturation <90% (r=-0.311, p=0.019), arousal index (r=-0.344, p=0.004) and ESS score (r=-0.299, p=0.016). After adjustment for age and BMI, HOMA-IR was associated with sleep stage transitions, time with oxyhaemoglobin saturation <90%, average oxyhaemoglobin saturation, minimum oxyhaemoglobin saturation and arousal index. QUICKI was associated with oxygen desaturation index, sleep stage transitions, ESS score, minimum oxyhaemoglobin saturation and arousal index. CONCLUSIONS: An independent association between OSAS and IR in patients without pre-existing diabetes mellitus was observed. Recurrent hypoxia and sleep fragmentation in OSAS are associated with IR in these patients.

ICBP90, a novel human CCAAT binding protein, involved in the regulation of topoisomerase IIalpha expression.

The one-hybrid system with an inverted CCAAT box as the DNA target sequence was used to identify proteins acting on key DNA sequences of the promoter of the topoisomerase IIalpha gene. Screening of cDNA libraries from the leukemia Jurkat cell line and from the adult human thymus resulted in the isolation of a novel protein of 793 amino acids (89,758 Da). This protein has in vitro CCAAT binding properties and has been called ICBP90. Adult thymus, fetal thymus, fetal liver, and bone marrow, known as active tissues in terms of cell proliferation, are the tissues richest in ICBP90 mRNA. In contrast, highly differentiated tissues and cells such as the central nervous system and peripheral leukocytes are free of ICBP90 mRNA. Western blotting experiments showed a simultaneous expression of topoisomerase IIalpha and ICBP90 in proliferating human lung fibroblasts. Simultaneous expression of both proteins has also been observed in HeLa cells, but in both proliferating and confluent cells. Overexpression of ICBP90 in COS-1-transfected cells induced an enhanced expression of endogenous topoisomerase IIalpha. Immunohistochemistry experiments showed that topoisomerase IIalpha and ICBP90 were coexpressed in proliferating areas of paraffin-embedded human appendix tissues and in high-grade breast carcinoma tissues. We have identified ICBP90, which is a novel CCAAT binding protein, and our results suggest that it may be involved in topoisomerase IIalpha expression. ICBP90 may also be useful as a new proliferation marker for cancer tissues.

Effect of low-dose methylprednisolone on calcium balance and bone composition in rats.

Glucocorticoid induced osteoporosis has been associated with high doses and it has been partially attributed to decreased absorption and to increased calcium excretion. The present study examined the effect of low but effective doses of methylprednisolone (MP) on calcium balance and on skeleton in rats. Total duration of the experiment 29 days. Thirty-one male Wistar rats (MP group) were injected with 4mg/kg body weight MP s.c. at the 1st, 11th and 20th day of the experiment and 28 rats (C group) were used as matched controls. The 1st, 11th and 20th day of the experiment rats were placed in individual metabolic cages for three days. Food and water consumption were measured at the 2nd and 3rd days after each injection; urine and faeces were collected at the same days for calcium estimation. Calcium intake and excretion after each injection was significantly lower in the MP group as compared to controls. A statistically significant positive correlation between calcium consumption and calcium excretion was found in both groups resulting in a negative final balance. Rats were killed the 29th day. Adrenal weight was statistically significant lower in MP group (p<0.001). Morphometric properties were evaluated for the right femur. No significant difference was found between the two groups. Mineral and calcium content was slightly increased in the MP group. According to these results, it seems that methylprednisolone while effective on HPA axis did not have any effect on calcium absorption and on bone calcium deposition in rats.

F-persistence studies in L5-S1 lumbosacral radiculopathies.

F-wave persistence of the deep peroneal nerve was studied in 41 patients with L5-S1 compressive root lesion (22 with radicular pain (RP) and 19 with motor and/or sensory (MS) signs), and in 26 normal control subjects. We used specific conditions, i.e., surface electrodes, stronger stimulus and facilitating maneuver in order to enhance the frequency of F-response appearance. EMG and nerve conduction studies were done F-latency was also measured on both sides of the patients. In the affected sides, both RP and MS, F-persistence's mean value was 56.1 and 31.0 respectively, which was significantly (p < 0.01) lower than controls (mean 83.2), and showed a significant correlation with the extensor digitorum brevis maximal interference pattern. These findings possibly reflect demyelination and/or axonal damage of lower motoneuron. Reduced F-persistence was found in 22 selected patient sides with unequivocal dorsal root damage only (mean 56.7, p < 0.01). This finding could be the result of a reduced lower motoneuron excitability because of the disruption of the circuit retaining the muscle tone. The diagnostic utility of F-persistence, F-latency and EMG was also tested. EMG and F-persistence were found statistically equal while F-persistence was found with a significant preponderance in comparison with F-latency. Finally, EMG was found more sensitive than F-latency in the patient sides with neurologic deficits.