Targeted Combined Endpoint Improvement in Patient and Disease Domains in Atopic Dermatitis: A Treat-to-Target Analysis of Adults with Moderate-to-Severe Atopic Dermatitis Treated with Upadacitinib.

A treat-to-target approach was recently developed to guide systemic treatment for adults with atopic dermatitis (AD). Recommendations outlined criteria for a 3-month initial acceptable treatment target and a 6-month optimal target, evaluated using global assessment of patient-reported disease severity, as well as Eczema Area and Severity Index, itch assessed on an 11-point numerical rating scale, Dermatology Life Quality Index, or Patient-Oriented Eczema Measure. Achievement of these targets with once-daily upadacitinib (15 mg and 30 mg) monotherapy was evaluated using integrated adult data from the Measure Up 1 and 2 phase 3 studies. Among the 852 patients treated with upadacitinib 15 mg or 30 mg, the 3-month initial acceptable target was achieved by >80%, >78%, and ≥87% of patients, and the 6-month optimal target was achieved by ≥53%, >61%, and >73% of patients at weeks 2, 16, and 52, respectively. Achievement of all 6 individual criteria for each of the target goals also increased over time. These findings suggest that upadacitinib 15 mg and 30 mg may help improve standards of care in patients with moderate-to-severe AD by achieving 6-month target goals at 16 weeks and as early as 2 weeks for most patients.

The HP0256 gene product is involved in motility and cell envelope architecture of Helicobacter pylori.

BACKGROUND: Helicobacter pylori is the causative agent for gastritis, and peptic and duodenal ulcers. The bacterium displays 5-6 polar sheathed flagella that are essential for colonisation and persistence in the gastric mucosa. The biochemistry and genetics of flagellar biogenesis in H. pylori has not been fully elucidated. Bioinformatics analysis suggested that the gene HP0256, annotated as hypothetical, was a FliJ homologue. In Salmonella, FliJ is a chaperone escort protein for FlgN and FliT, two proteins that themselves display chaperone activity for components of the hook, the rod and the filament. RESULTS: Ablation of the HP0256 gene in H. pylori significantly reduced motility. However, flagellin and hook protein synthesis was not affected in the HP0256 mutant. Transmission electron transmission microscopy revealed that the HP0256 mutant cells displayed a normal flagellum configuration, suggesting that HP0256 was not essential for assembly and polar localisation of the flagella in the cell. Interestingly, whole genome microarrays of an HP0256 mutant revealed transcriptional changes in a number of genes associated with the flagellar regulon and the cell envelope, such as outer membrane proteins and adhesins. Consistent with the array data, lack of the HP0256 gene significantly reduced adhesion and the inflammatory response in host cells. CONCLUSIONS: We conclude that HP0256 is not a functional counterpart of FliJ in H. pylori. However, it is required for full motility and it is involved, possibly indirectly, in expression of outer membrane proteins and adhesins involved in pathogenesis and adhesion.

Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys.

BACKGROUND: Mental disorders are major causes of disability worldwide, including in the low-income and middle-income countries least able to bear such burdens. We describe mental health care in 17 countries participating in the WHO world mental health (WMH) survey initiative and examine unmet needs for treatment. METHODS: Face-to-face household surveys were undertaken with 84,850 community adult respondents in low-income or middle-income (Colombia, Lebanon, Mexico, Nigeria, China, South Africa, Ukraine) and high-income countries (Belgium, France, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Spain, USA). Prevalence and severity of mental disorders over 12 months, and mental health service use, were assessed with the WMH composite international diagnostic interview. Logistic regression analysis was used to study sociodemographic predictors of receiving any 12-month services. FINDINGS: The number of respondents using any 12-month mental health services (57 [2%; Nigeria] to 1477 [18%; USA]) was generally lower in developing than in developed countries, and the proportion receiving services tended to correspond to countries' percentages of gross domestic product spent on health care. Although seriousness of disorder was related to service use, only five (11%; China) to 46 (61%; Belgium) of patients with severe disorders received any care in the previous year. General medical sectors were the largest sources of mental health services. For respondents initiating treatments, 152 (70%; Germany) to 129 (95%; Italy) received any follow-up care, and one (10%; Nigeria) to 113 (42%; France) received treatments meeting minimum standards for adequacy. Patients who were male, married, less-educated, and at the extremes of age or income were treated less. INTERPRETATION: Unmet needs for mental health treatment are pervasive and especially concerning in less-developed countries. Alleviation of these unmet needs will require expansion and optimum allocation of treatment resources.

DSM-IV personality disorders in the National Comorbidity Survey Replication.

BACKGROUND: The population prevalence of DSM-IV personality disorders (PDs) remains largely unknown. Data are reported here on the prevalence and correlates of clinician-diagnosed Clusters A, B, and C DSM-IV PDs in the general population of the United States. METHODS: Personality disorder screening questions from the International Personality Disorder Examination (IPDE) were administered in Part II (n = 5692) of the National Comorbidity Survey Replication (NCS-R). A probability sub-sample was then interviewed with the IPDE and used to link screening question responses with IPDE clinical diagnoses. The method of Multiple Imputation (MI) was then implemented to estimate prevalence and correlates of PDs in the full sample. RESULTS: The MI prevalence estimates were 5.7% Cluster A, 1.5% Cluster B, 6.0% Cluster C, and 9.1% any PD. All three PD clusters were significantly comorbid with a wide range of DSM-IV Axis I disorders. Significant associations of PDs with functional impairment were largely accounted for by Axis I comorbidity. CONCLUSIONS: Strong Axis I comorbidity raises questions about the somewhat arbitrary separation of PDs from Axis I disorders in the DSM nomenclature. The impairment findings suggest that the main public health significance of PDs lies in their effects on Axis I disorders rather than in their effects on functioning.

Mental and physical comorbid conditions and days in role among persons with arthritis.

OBJECTIVE: To estimate the prevalence of comorbidity among people with arthritis in the US adult population and to determine the role of comorbidity in accounting for the association of arthritis with days out of role (a measure of inability to work or carry out normal activities). METHODS: Data come from the National Comorbidity Survey Replication (NCS-R), a nationally representative household survey of 9,282 respondents ages 18 and older carried out in 2001 to 2003. Arthritis was assessed by self-report in a chronic-conditions checklist, along with a wide range of other physical conditions. Mental and substance use disorders were ascertained with the World Health Organization Composite International Diagnostic Interview (CIDI). Number of days out of role was assessed for the 30 days before the interview. RESULTS: Arthritis was reported by 27.3% of respondents, 80.9% of whom also reported at least one other physical or mental disorder, including 45.6% with another chronic pain condition, 62.3% with another chronic physical condition, and 24.3% with a 12-month mental disorder. Arthritis was significantly associated with days out of role, but comorbidity explained more than half of this association. No significant interactions were found between arthritis and the other conditions in predicting days out of role. CONCLUSION: Comorbidity is the rule rather than the exception among people with arthritis. Comorbidity accounts for most of the days out of role associated with arthritis. The societal burden of arthritis needs to be understood and managed within the context of these comorbid conditions.

Molecular basis of the interaction between the flagellar export proteins FliI and FliH from Helicobacter pylori.

Bacterial flagellar protein export requires an ATPase, FliI, and presumptive inhibitor, FliH. We have explored the molecular basis for FliI/FliH interaction in the human gastric pathogen Helicobacter pylori. By using bioinformatic and biochemical analyses, we showed that residues 1-18 of FliI very likely form an amphipathic alpha-helix upon interaction with FliH, and that residues 21-91 of FliI resemble the N-terminal oligomerization domain of the F1-ATPase catalytic subunits. A truncated FliI-(2-91) protein was shown to be folded, although the N-terminal 18 residues were likely unstructured. Deletion and scanning mutagenesis showed that residues 1-18 of FliI were essential for the FliI/FliH interaction. Scanning mutation of amino acids in the N-terminal 10 residues of FliI indicated that a cluster of hydrophobic residues in this segment was critical for the interaction with FliH. The interaction between FliI and FliH has similarities to the interaction between the N-terminal alpha-helix of the F1-ATPase alpha-subunit and the globular domain of the F1-ATPase delta-subunit, respectively. This similarity suggests that FliH may function as a molecular stator.

Deactivation of the biological activity of paraquat in the soil environment: a review of long-term environmental fate.

During the many years of paraquat usage, wide ranges of investigations of its environmental impact have been conducted. Much of this information has been published, but key, long-term field studies have not previously been presented and assessed. The purpose of this review is to bring together and appraise this information. Due to the nature of paraquat residues in soils, the major part (some 99.99%) of a paraquat application that reaches the soil within the typical Good Agricultural Practice (GAP) is strongly adsorbed to soils of a wide variety of textures. This is in equilibrium with an extremely low concentration in soil solution. However, the paraquat in soil solution is intrinsically biodegradable, being rapidly and completely mineralized by soil microorganisms. The deactivation of the biological activity of paraquat in soils, due to sorption, has been investigated thoroughly and systematically. It is recognized that the determination of total soil residues by severe extraction procedures provides no insight into the amount of paraquat biologically available in soil. Consequently, the key assay developed for this purpose, namely, the strong adsorption capacity-wheat bioassay (SAC-WB) method, has proved to be valuable for determination of the adsorption capacity relevant to paraquat for any particular soil. This method has been validated in the field with a series of long-term (>10 years) trials in different regions of the world. These trials have also shown that, following repeated applications of very high levels of paraquat in the field, residues not only reach a plateau but also subsequently decline. This demonstrates that the known biodegradation of paraquat in soil pore water plays an important role in field dissipation. The biological effects of paraquat in the field have been assessed under unrealistically high treatment regimes. These trials have demonstrated that the continued use of paraquat under GAP conditions will have no detrimental effects on either crops or soil-dwelling flora and fauna. Any such effects can occur only under extreme use conditions (above the SAC-WB), which do not arise in normal agricultural practice.