Real-world treatment patterns in patients with nontuberculous mycobacterial lung disease in the Netherlands based on medication dispensing data.

PURPOSE: Real-world data on antibiotic management of nontuberculous mycobacterial lung disease (NTM-LD) is limited for many countries. This study aimed to evaluate real-world treatment practices of NTM-LD in the Netherlands using medication dispensing data. METHODS: A retrospective longitudinal real-world study was conducted using IQVIA's Dutch pharmaceutical dispensing database. The data are collected monthly and include approximately 70% of all outpatient prescriptions in the Netherlands. Patients initiated on specific NTM-LD treatment regimens between October 2015 and September 2020 were included. The main areas of investigation were initial treatment regimens, persistence on treatment, treatment switching, treatment compliance in terms of medication possession rate (MPR) and restarts of treatment. RESULTS: The database included 465 unique patients initiated on triple- or dual-drug regimens for the treatment of NTM-LD. Treatment switches were common and occurred approximately 1.6 per quarter throughout the treatment period. The average MPR of patients initiated on triple-drug therapy was 90%. The median time on therapy for these patients was 119 days; after six months and one year, 47% and 20% of the patients, respectively, were still on antibiotic therapy. Of 187 patients initiated on triple-drug therapy, 33 (18%) patients restarted antibiotic therapy after the initial treatment had been stopped. CONCLUSION: When on therapy, patients were compliant with the NTM-LD treatment; however, many patients stopped their therapy prematurely, treatment switches often occurred, and part of patients had to restart their therapy after a longer treatment gap. NTM-LD management should be improved through greater guideline adherence and appropriate involvement of expert centers.

Ultrasound-guided caudal blockade and sedation for paediatric surgery: a retrospective cohort study.

Data on safety and success rates of ultrasound-guided caudal blockade, performed on sedated children with an uninstrumented airway, are scarce. We performed a retrospective observational study of validated data from April 2014 to December 2020 in a paediatric cohort where the initial plan for anaesthetic management was sedation and caudal epidural without general anaesthesia or airway instrumentation. We examined success rates of this approach and rates of block failure and block-related complications. In total, 2547 patients ≤ 15 years of chronological age met inclusion criteria. Among the 2547 cases, including 453 (17.8%) former preterm patients, caudal-plus-sedation success rate was 95.1%. The primary anaesthesia plan was abandoned for general anaesthesia in 124 cases. Pain-related block failure in 83 (3.2%) was the most common cause for conversion. Complications included 39 respiratory events and 9 accidental spinal anaesthetics. Higher odds of pain-related block failure were associated with higher body weight (adjusted OR 1.063, 95%CI 1.035-1.092, p < 0.001) as well as with mid-abdominal surgery (e.g. umbilical hernia repair) (adjusted OR 15.11, 95%CI 7.69-29.7, p < 0.001), whereas extreme (< 28 weeks) former prematurity, regardless of chronological age, was associated with higher odds (adjusted OR 3.62, 95%CI 1.38-9.5, p = 0.009) for respiratory problems. Ultrasound-guided caudal epidural, performed under sedation with an uninstrumented airway, is an effective technique in the daily clinical routine. Higher body weight and mid-abdominal surgical procedures are risk factors for pain-related block failure. Patients who, regardless of chronological age, had been born as extreme preterm babies are at the highest risk for respiratory events.

A non-invasive method for estimating the severity of liver steatosis and the risk of fibrosis in non-obese type 2 diabetes patients with NAFLD.

Context: Prognostic considerations include assessing the risk of liver fibrosis in people with non-alcoholic fatty liver disease (NAFLD). Objectives: This study evaluates the use of hematologic and metabolic parameters regarding liver steatosis and fibrosis scores (FLI and Fib-4) in non-obese type 2 diabetes mellitus (t2DM) patients with NAFLD. Methods: Subjects underwent abdominal ultrasound examinations, and FLI and Fib-4 scores were calculated to evaluate liver steatosis and the risk of liver fibrosis non-invasively: 61 non-obese NAFLD subjects with t2DM were included in the cohort study and were divided into 2 groups depending on the t2DM treatment regimen. Results: Fib-4 and WBC count demonstrated a significant inverse correlation (OR = 0.509, p = 0.007). WBC count had an R2 of 0.237, indicating that this marker could account for up to 23.7% of a variation in Fib-4. Fib-4 and FFA had positive correlation which did not achieve statistically significant prediction (OR=7.122, p=0.062). Additionally, a significant prediction of HbA1c (OR=1.536, p=0.016) and haemoglobin (OR=1.071, p=0.020) for FLI was revealed. Conclusion: HbA1c and other haematological and metabolic parameters, such as haemoglobin and WBC, may be another non-invasive tool for determining whether non-obese NAFLD patients with t2DM are at risk of developing liver steatosis and fibrosis.

17ß-estradiol inhibits hepatic iNOS via the activation of the estrogen receptor ER-α and inhibition of erk1/2-mir-221 axis.

17ß-Estradiol (E2) is known to negatively regulate inducible nitric oxide (NO) synthase (iNOS) expression via estrogen receptor alpha (ER-α) activation in aortic vascular smooth muscle cells.Therefore, we sought to determine whether E2 can inhibit iNOS in vivo in hepatic tissue via the activation of ER-α and whether extracellular signal-regulated kinases 1/2 (ERK1/2)-miR-221 axis is involved in this process. Male Wistar rats were treated with a bolus injection of E2 intraperitoneally (40 µg/kg), and 24 hours after treatment the animals were sacrificed and the livers excised. The protein levels of iNOS, p50 and p65 subunits of nuclear factor κB (NFκB), ERα, ERK1/2 and protein kinase B (Akt), as well as the association of ERα/Src in liver lysates were assessed by Western blot. The expression of hepatic miR-221 was analyzed by qRT-PCR. Results show that E2 reduced hepatic iNOS protein expression (p less than 0.01), the protein level of ERα (p less than 0.05), ERK1/2 (p less than 0.05), Akt phosphorylation (p less than 0.001) and miR-221 expression (p less than 0.05). In contrast, hepatic ERα/Src kinase association level (p less than 0.05) increased after E2 treatment. Our results indicate that E2 inhibits hepatic iNOS via molecular mechanisms involving the activation of the ER-α and inhibition of ERK1/2-miR-221 axis.

The cost of Mycobacterium avium complex lung disease in Canada, France, Germany, and the United Kingdom: a nationally representative observational study.

BACKGROUND: Management of nontuberculous mycobacterial lung disease (NTMLD) consists of a long-term multi-drug antibiotic regimen, yet many patients do not achieve culture conversion. We estimated the NTMLD-related direct medical costs in Canada, France, Germany, and the United Kingdom (UK) among refractory patients who were infected with Mycobacterium avium complex (MAC), without concomitant cystic fibrosis, tuberculosis, or HIV. METHODS: We conducted a retrospective observational physician survey of nationally representative samples. The survey captured anonymized information about patients' treatment histories for NTMLD-related health care resource utilization over a 24-month period. We summarized NTMLD-related resource use and estimated the total economic burden, from each country's health care payer perspective. RESULTS: In total, 59 physicians provided data on 157 patients. The average person time observed during the 24-month period was 1.7 years (SD: 0.4); 17% of patients died by the end of the study period. The major components of NTMLD-related direct medical costs among refractory patients were hospitalizations (varying from 29% of total annual costs in the UK to 69% in France), outpatient visits (8% in Canada to 51% in the UK), and outpatient testing such as post-diagnostic sputum testing, bronchial wash/lavage, spirometry, biopsies, imaging, and electrocardiograms (5% in France to 35% in Canada). In this patient cohort, the average direct medical costs per person-year, in local currencies, were approximately $16,200 (Canada), €11,600 (Germany), €17,900 (France) and £9,700 (UK). CONCLUSIONS: Based on this study's findings, we conclude that managing patients with refractory NTMLD caused by MAC is associated with a substantial economic burden.

Photoluminescence as a Probe of the Electrical Charge Dependence of Gold Nanoparticles.

Electro-optical switching can be achieved by changing the optical absorption of metal nanoparticles by adding or removing electrical charge, corresponding to increased, respectively, decreased electron density. In this work a different approach is taken by changing the photoluminescence properties as a function of electrical charge on gold nanoparticles. Whereas larger gold nanoparticles (diameter d = 5 and 10 nm), exhibiting a plasmon resonance peak in the absorption spectrum, were used to measure changes of the optical absorption spectrum upon electrical charging, for smaller gold nanoparticles (d = 2 and 5 nm) electrical charging was observed via changes of the photoluminescence. Increase and decrease in photoluminescence was observed at positive and negative applied potentials, respectively. The relation between changes of optical absorption and photoluminescence for the 5 nm particles by electrical charging provides information on the influence of the charge state on the electronic properties and therefore the optical transition probability. The reported observation that not only the optical absorption, but also the photoluminescence is affected by alteration of the electrical charge onto gold nanoparticles may open a new way towards electro-optical switching and bio-sensing.

Incontinentia pigmenti diagnostic criteria update.

In 1993 diagnostic criteria for incontinentia pigmenti (IP), a genodermatosis in which skin changes are usually combined with anomalies of other organs, were established. Approximately a decade ago, IKBKG gene mutation was discovered as a cause for IP. This finding has not been included in IP diagnosis so far. In addition, literature data pointed out a few other clinical findings as possible IP diagnostic criteria. Literature facts concerning IP diagnosis were analyzed. Different organ anomalies, their frequency and severity, were analyzed in the context of applicability as IP diagnostic criteria. Taking into account analyzed data from the literature, the proposal of updated IP diagnostic criteria was presented. We propose as major criteria one of the stages of IP skin lesions. As updated IP minor criteria in our proposal we included: dental, ocular; central nervous system (CNS), hair, nail, palate, breast and nipple anomalies; multiple male miscarriages, and IP pathohistological findings. In the diagnosis of IP, the presence of IKBKG mutation typical for IP, and existence of family relatives with diagnosed IP are taken into account.

Impact of treatment modalities on quality of life and depression in type 2 diabetes.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is a chronic disease with numerous complications that increase mortality and reduce the quality of life (QoL). The current study compares QoL in T2DM patients treated with insulin to those treated with oral antihyperglycemics (OAHs), as well as the frequency and severity of depression in patients. SUBJECTS AND METHODS: This prospective cross-sectional study included 200 patients with insulin or OAHs. Triglycerides, total cholesterol, low-density lipoprotein, and high-density lipoprotein cholesterol levels were measured. The Beck Depression Inventory and the SF-36 Quality of Life Questionnaire were used to assess depression symptoms and QoL in response to different treatment modalities. RESULTS: Insulin-treated patients have a longer duration of illness, higher preprandial glycemic levels, lower scores in three of four dimensions of the SF-36 physical component, and a lower score in the SF-36 psychological component's emotional role dimension. Patients on insulin have milder depression symptoms than those with OAHs. Depression symptoms, according to the findings, worsen QoL and glycemic control in insulin-treated patients. CONCLUSIONS: According to these findings, any treatment modality's success in T2DM patients primarily depends on psychological support and preventive measures that promote and maintain mental health.

Caries increment in Bosnian women associated with caries risk factors according to the Cariogram during pregnancy. A four-year longitudinal study.

AIM: The aim of this study was to determine dental caries increment in women after four years associated with caries risk factors according to the Cariogram during pregnancy. MATERIALS: Study design: The study population consisted of 96 pregnant women between 20 and 42 years of age at the start of the study. After four years, 80 women (83.33% recall rate) were re-examined by the baseline examiner using the same procedure employed at baseline. Caries prevalence was registered according to the WHO criteria and presented by the Decayed Missing and Filled Teeth (DMFT) index. Saliva tests were carried out according to instructions of the manufacturer. Nine factors/variables were entered into the Cariogram to obtain an individual caries risk profile. The chance of avoiding caries was scored into the five Cariogram risk categories. CONCLUSION: The results suggest that the dental caries increment in women after four years is significantly associated with caries risk factors according to the Cariogram during pregnancy.

Real-world treatment patterns in patients with nontuberculous mycobacterial lung disease in general and pneumologist practices in Germany.

BACKGROUND: Nontuberculous mycobacterial lung disease (NTMLD) is a rare, progressive disease with an increasing incidence worldwide. AIMS: The aim of this retrospective study was to analyze the baseline characteristics and management of NTMLD in general and pneumologist practices in Germany. METHODS: This retrospective study included patients with a culture-confirmed diagnosis of NTMLD documented between October 1, 2014 and September 30, 2019 by 125 general practitioners (GP) and 31 office-based pulmonologists from the IMS Disease Analyzer Database (IQVIA). RESULTS: A total of 159 patients managed by German GPs (mean age 59 ± 19 years, 51% female) and 236 patients managed by pulmonologists (mean age 62 ± 14 years, 58% female) were analyzed. In total, 45% (72/159) and 40% (94/236) of patients managed by GPs and pulmonologists respectively received antibiotic therapy for NTMLD. This therapy lasted for ≥ 6 months in 42%, for ≥ 12 months in 24%, and ≥ 18 months in 8% of patients. The average therapy duration was longer in patients treated by pulmonologists (241 ± 196 days) than in patients treated by GPs (113 ± 152 days). A total of 27% of patients managed by GPs and 45% of those managed by pulmonologists respectively received guideline-based therapy (GBT), defined as combination therapy with macrolide (azi-/ clarithromycin) + ethambutol + rifabutin/rifampicin, at least once; however, almost all patients (100% in the GP group, 96% in the pulmonologist group) also received non-GBT regimens intermediately. CONCLUSIONS: A considerable number of patients with NTMLD were not managed in accordance with the German guidelines and a substantial proportion also discontinue therapy prematurely. NTMLD management should be improved through appropriate referral pathways and collaboration between expert centers and primary or secondary care physicians.

Controlling the photoluminescence of CdSe/ZnS quantum dots with a magnetic field.

We present an investigation of the photoluminescence of CdSe/ZnS quantum dots at high light intensity and in low magnetic fields. Upon increasing the magnetic field up to 90 G, the photoluminescence intensity drops. When decreasing the magnetic field back to zero the photoluminescence drop remains present. A plausible explanation is the Zeeman splitting of defect-associated energy levels under the influence of a magnetic field. The defect-trapped electrons may then be positioned at a metastable level, thereby reducing the number of recombinations. This effect may be used to control the luminescence of quantum dots.

Hypothesis related to the regulation of inducible nitric oxide synthase during carotid endarterectomy.

Sudden occlusion of an artery caused by a thrombus or emboli is the most frequent cause of acute brain ischemia (ABI). Carotid endarterectomy (CEA) represents the gold standard for preventing strokes of carotid origin. However, neuronal damage caused by ischemia and/or reperfusion may contribute to a poor clinical outcome after CEA. In response to shear stress caused by hypoxic-ischemic conditions in patients undergoing CEA, stimulation of the hypothalamic-pituitaryadrenal axis leads to biological responses known as hypermetabolic stress, characterized by hemodynamic, metabolic, inflammatory and immunological changes. These changes maintain homeostasis and assist recovery, but an unregulated inflammatory response could lead to further tissue damage and death of neurons. Nitric oxide (NO) is an important signaling molecule involved in several physiological and pathological processes, including ABI. However, an excess of NO could have detrimental effects. We hypothesized that the hypoxic-ischemic state induced by carotid clamping leads to overexpression of inducible NO synthase and that uncontrolled production of NO could adversely affect outcome after CEA.

Patterns of Abundance and Host Specificity of Bat Ectoparasites in the Central Balkans.

Bats are hosts to a number of ectoparasites-acarines (ticks, chiggers, other mites), bat flies, and fleas. Bat ectoparasites might have significant ecological and public health importance as they may be potential vectors of zoonotic agents. It is important to identify their distribution, diversity, and host-parasite associations. Bat ectoparasites in the central Balkans have been largely understudied. The present research was conducted in 45 localities at the territory of Bosnia and Herzegovina, former Yugoslav Republic of Macedonia, Montenegro, and Serbia. In total, 1,143 individuals of 18 species of bats have been examined for the presence and abundance of ectoparasite species during 3 yr of research. In total, 21 ectoparasite species have been identified: three species of ticks, seven species of mites (including one species of chigger), eight species of bat flies, and three species of fleas. In total, 80 host-parasite associations have been identified. The largest number of ectoparasites parasitized primarily only one host species. The highest total number of hosts was identified for ectoparasite species Ixodes vespertilionis Koch, Nycteribia schmidlii Schiner, and Spinturnix myoti Kolenati. The spinturnicid mite Spinturnix psi Kolenati was the most abundant ectoparasite species and together with Penicilidia dufouri Westwood the most widely distributed species of bat ectoparasite, being present at 21 localities in the central Balkans. The presented data include the first systematic records of patterns of prevalence, mean intensity, mean abundance, and host specificity for bat ectoparasites in the central Balkans.

Prepulse inhibition of the startle reflex and its attentional modulation in the human S-ketamine and N,N-dimethyltryptamine (DMT) models of psychosis.

Patients with schizophrenia exhibit diminished prepulse inhibition (PPI) of the acoustic startle reflex and deficits in the attentional modulation of PPI. Pharmacological challenges with hallucinogens are used as models for psychosis in both humans and animals. Remarkably, in contrast to the findings in schizophrenic patients and in animal hallucinogen models of psychosis, previous studies with healthy volunteers demonstrated increased levels of PPI after administration of low to moderate doses of either the antiglutamatergic hallucinogen ketamine or the serotonergic hallucinogen psilocybin. The aim of the present study was to investigate the influence of moderate and high doses of the serotonergic hallucinogen N,N-dimethyltryptamine (DMT) and the N-methyl-D-aspartate antagonist S-ketamine on PPI and its attentional modulation in humans. Fifteen healthy volunteers were included in a double-blind cross-over study with two doses of DMT and S-ketamine. Effects on PPI and its attentional modulation were investigated. Nine subjects completed both experimental days with the two doses of both drugs. S-ketamine increased PPI in both dosages, whereas DMT had no significant effects on PPI. S-ketamine decreased and DMT tended to decrease startle magnitude. There were no significant effects of either drug on the attentional modulation of PPI. In human experimental hallucinogen psychoses, and even with high, clearly psychotogenic doses of DMT or S-ketamine, healthy subjects failed to exhibit the predicted attenuation of PPI. In contrast, PPI was augmented and the startle magnitude was decreased after S-ketamine. These data point to important differences between human hallucinogen models and both animal hallucinogen models of psychosis and naturally occurring schizophrenia.

Unexpected high incidence of primary liver cancer in Geneva, Switzerland.

The age-standardized incidence rate of primary liver cancer (PLC) in Geneva was 9.7 per 100,000 in males, a figure four or five times higher than incidence rates reported elsewhere in Europe . These PLC's were often associated with cirrhosis and alcoholism. This indicated that the toll of PLC related to alcoholism and to alcoholic cirrhosis may be greater than anticipated.

Charging gold nanoparticles in ZnO by electric fields.

Controlling the plasmon resonance frequency of metal nanostructures holds promise for both fundamental and applied research in optics. The plasmon resonance frequency depends on the number of free electrons in the metal. By adding or removing electrons to a metal nano-object, the plasmon resonance frequency shifts. In this study we indirectly change the number of free electrons in gold nanoparticles by applying an electrical potential difference over a heterostructure consisting of a ZnO layer with embedded gold nanoparticles. The potential difference induces shifts of defect energy levels in the ZnO by the electric field. This results in an exchange of electrons between particles and matrix which in turn modifies the gold nanoparticle plasmon properties. The positive charge shifts the ZnO optical absorption peak from 377 nm to 386 nm and shifts the nanoparticle plasmon from 549 nm to 542 nm. This electro-optical effect is a promising way to obtain fast optical switching in a solid state composition.

Incidence and role of apoptosis in myelodysplastic syndrome: morphological and ultrastructural assessment.

By application of morphological and ultrastructural methods for identification of apoptosis, we analyzed the incidence of morphologically evident apoptosis in the bone marrow of 30 patients with myelodysplastic syndrome (MDS), and in the bone marrow of 12 healthy individuals. According to FAB classification, out of 30 patients, eight (26.6%) had refractory anemia, three (10%) had refractory anemia with ringed sideroblasts, 14 (46.6%) had refractory anemia with excess of blasts and two (6.8%) had refractory anemia with excess of blasts in transformation. Three patients (10%) had chronic myelomonocytic leukemia. Cells in apoptosis were examined on semithin slides and expressed as the apoptotic index (AI) (percent counted on at least 1000 cells). An overall increase in apoptosis in patients with MDS was found (median AI in patients vs controls, 3.13% vs 1.05%, P < 0.01 by Mann-Whitney U test). Also, negative correlation between AI and white blood cell count was found (linear r= -0.53, or Spearman rank R= -0.52, both P < 0.01). In patients with evident karyotype changes AI was not higher than in patients with normal karyotype. This suggests that discrete alterations in apoptosis are present even in karyotypically 'normal' clones. Our results strongly support the hypothesis that apoptosis has a role in ineffective hematopoiesis and may be a mechanism responsible for the paradox of hypercellular bone marrow and peripheral blood pancytopenia in MDS.

Survival of patients with primary liver cancer, pancreatic cancer and biliary tract cancer in Europe. EUROCARE Working Group.

The EUROCARE Study is a European Union project to assemble survival data from population-based cancer registries and analyse them according to standard procedures. We investigated and compared liver, pancreatic and biliary tract cancer survival in 17 countries from 1985 to 1989. Time trends in survival over the 1978-1989 period were also investigated in 12 countries. The overall European mean 1 year relative survival was 16% for primary liver cancer, 26% for biliary tract cancer and 15% for pancreatic cancer. The corresponding 5-year relative survival was 5, 12 and 4%, respectively. Taking the European average as the reference, the relative risk (RR) of death was at least 20% higher for the three cancers in Denmark and Estonia. Survival tended to be higher in Spain for primary liver cancer and biliary tract cancer. Gender had little influence on survival whilst age at diagnosis was inversely related to prognosis. There was an improvement in 1-year relative survival rate for primary liver cancer: relative risk (RR) of 0.68 (95% confidence interval (CI) of 0.60-0.77) for 1987-1989 versus 1978-1980 and biliary tract cancer (RR 0.77, 95% CI 0.68-0.87). There was less variation in 5-year relative survival rate over time. Some intercountry survival differences for primary liver, biliary tract and pancreatic cancers exist over Europe. Differences in quality of care, in particular treatment aggressiveness, may explain some of these differences in survival. New approaches to the management of these cancers need to be found.