Venlafaxine's therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis.

INTRODUCTION: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression. METHODS: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal. RESULTS: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml. CONCLUSION: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Instances of avian osteoarthritis from the Unalaska Sea Ice Project, Unalaska Island, Alaska.

OBJECTIVE: This project is designed to examine the prevalence of skeletal pathology in two archaeological avian bone assemblages. MATERIALS: Archaeological avian bone assemblages with Number of Identified Specimens of 14,909 (UNL-055) and 36,866 (UNL-048). METHODS: Visual examination of humeri, coracoids, tarsometatarsi, and cranial elements for pathology during taxonomic identification. RESULTS: 83 instances of skeletal pathology were observed in these assemblages and were most prevalent in the UNL-048 assemblage. Marginal osteophytes around the articular surfaces of the coracoid were the primary bone pathology in the UNL-048 avian assemblage. CONCLUSIONS: The prevalence of osteoarthritis in surface diving birds at the UNL-048 site could be due to changing climate. SIGNIFICANCE: Considering the environmental factors that contribute to instances of animal pathology allows for a more contextual interpretation of the cultural processes that occurred at archaeological sites. LIMITATIONS: Time and budgetary constraints did not allow for examination of the entire avian assemblage. SUGGESTIONS FOR FUTURE RESEARCH: Further intensive review of archaeological avian assemblages alongside consideration of environmental and cultural processes occurring during the site occupation is advised.

The impact of tinnitus distress on cognition.

Tinnitus is the chronic perception of a phantom sound with different levels of related distress. Past research has elucidated interactions of tinnitus distress with audiological, affective and further clinical variables. The influence of tinnitus distress on cognition is underinvestigated. Our study aims at investigating specific influences of tinnitus distress and further associated predictors on cognition in a cohort of n = 146 out-ward clinical tinnitus patients. Age, educational level, hearing loss, Tinnitus Questionnaire (TQ) score, tinnitus duration, speech in noise (SIN), stress, anxiety and depression, and psychological well-being were included as predictors of a machine learning regression approach (elastic net) in three models with scores of a multiple choice vocabulary test (MWT-B), or two trail-making tests (TMT-A and TMT-B), as dependent variables. TQ scores predicted lower MWT-B scores and higher TMT-B test completion time. Stress, emotional, and psychological variables were not found to be relevant predictors in all models with the exception of small positive influences of SIN and depression on TMT-B. Effect sizes were small to medium for all models and predictors. Results are indicative of specific influence of tinnitus distress on cognitive performance, especially on general or crystallized intelligence and executive functions. More research is needed at the delicate intersection of tinnitus distress and cognitive skills needed in daily functioning.

Why predict climate hazards if we need to understand impacts? Putting humans back into the drought equation.

Virtually all climate monitoring and forecasting efforts concentrate on hazards rather than on impacts, while the latter are a priority for planning emergency activities and for the evaluation of mitigation strategies. Effective disaster risk management strategies need to consider the prevailing "human terrain" to predict who is at risk and how communities will be affected. There has been little effort to align the spatiotemporal granularity of socioeconomic assessments with the granularity of weather or climate monitoring. The lack of a high-resolution socioeconomic baseline leaves methodical approaches like machine learning virtually untapped for pattern recognition of extreme climate impacts on livelihood conditions. While the request for "better" socioeconomic data is not new, we highlight the need to collect and analyze environmental and socioeconomic data together and discuss novel strategies for coordinated data collection via mobile technologies from a drought risk management perspective. A better temporal, spatial, and contextual understanding of socioeconomic impacts of extreme climate conditions will help to establish complex causal pathways and quantitative proof about climate-attributable livelihood impacts. Such considerations are particularly important in the context of the latest big data-driven initiatives, such as the World Bank's Famine Action Mechanism (FAM).

Role of wireless motility capsule in the assessment and management of gastrointestinal dysmotility in patients with diabetes mellitus.

BACKGROUND: Gastrointestinal (GI) dysmotility is common in diabetic patients. Wireless Motility Capsule (WMC) provides the transit profile of the entire GI tract in a single study. Factors affecting GI dysmotility and utility of WMC study are not clearly established in diabetic patients. Our aims were to study the pattern of GI dysmotility using WMC and evaluate the effect of glycemic control and presence of diabetic microvascular complications on motility impairment in diabetic patients. We also assessed the impact of WMC findings on clinical management. METHODS: Retrospective chart review of all diabetic patients who underwent WMC testing at our institution from 2010 to 2015 was performed. Demographics, hemoglobinA1c levels, microvascular complications, and WMC findings were obtained. Impact of WMC on clinical management was assessed. KEY RESULTS: A total of 100 patients were included. Mean age was 45±19 years and 76% were female. Seventy-two percentage had abnormal WMC testing, of which 29 (40%) had multiregional dysmotility. There were no significant differences in demographics, diabetic microvascular complications or hemoglobinA1c levels among patients with normal and abnormal WMC testing or among patients with isolated vs multiregional dysmotility. Information about subsequent clinical management was available for 47 patients. WMC testing was abnormal in 33 (70%) patients and treatment changes based on WMC results were made in 24 patients (73%). CONCLUSIONS & INFERENCES: There was no association between hemoglobinA1c levels, microvascular complications and pattern of GI dysmotility in diabetic patients undergoing WMC. WMC testing lead to management changes in approximately 75% of diabetic patients with GI dysmotility.

The Complete Genome Sequence of Plodia Interpunctella Granulovirus: Evidence for Horizontal Gene Transfer and Discovery of an Unusual Inhibitor-of-Apoptosis Gene.

The Indianmeal moth, Plodia interpunctella (Lepidoptera: Pyralidae), is a common pest of stored goods with a worldwide distribution. The complete genome sequence for a larval pathogen of this moth, the baculovirus Plodia interpunctella granulovirus (PiGV), was determined by next-generation sequencing. The PiGV genome was found to be 112, 536 bp in length with a 44.2% G+C nucleotide distribution. A total of 123 open reading frames (ORFs) and seven homologous regions (hrs) were identified and annotated. Phylogenetic inference using concatenated alignments of 36 baculovirus core genes placed PiGV in the "b" clade of viruses from genus Betabaculovirus with a branch length suggesting that PiGV represents a distinct betabaculovirus species. In addition to the baculovirus core genes and orthologues of other genes found in other betabaculovirus genomes, the PiGV genome sequence contained orthologues of the bidensovirus NS3 gene, as well as ORFs that occur in alphabaculoviruses but not betabaculoviruses. While PiGV contained an orthologue of inhibitor of apoptosis-5 (iap-5), an orthologue of inhibitor of apoptosis-3 (iap-3) was not present. Instead, the PiGV sequence contained an ORF (PiGV ORF81) encoding an IAP homologue with sequence similarity to insect cellular IAPs, but not to viral IAPs. Phylogenetic analysis of baculovirus and insect IAP amino acid sequences suggested that the baculovirus IAP-3 genes and the PiGV ORF81 IAP homologue represent different lineages arising from more than one acquisition event. The presence of genes from other sources in the PiGV genome highlights the extent to which baculovirus gene content is shaped by horizontal gene transfer.

Morphometrics of the human thumb metacarpal bone: interest for developing an osseointegrated prosthesis.

INTRODUCTION: Amputation of the thumb presents a serious insult to the hand and diminished quality of life for a patient physically, vocationally, and possibly psychologically. The aim of this study was to define the geometry of the thumb metacarpal in order to help create a standardized set of transcutaneous osseointegrated prostheses to treat patients who have suffered amputation of the thumb at the level of the metacarpophalangeal joint. MATERIALS AND METHODS: A total of 80 metacarpals from 46 cadavers were studied. All soft tissues were removed and the thumb metacarpals were imaged using computed tomography. Three-dimensional models were constructed using images from the coronal, sagittal, and axial planes. Using HyperMesh™ CAD software, the bones were analyzed for overall length, radius of curvature, medullary canal diameter, cortical thickness, and distance to the isthmus, defined as the narrowest portion of the intramedullary canal. RESULTS: The average length of the first metacarpal was 47.6 mm (±3.3 mm, 39.2-56.9 mm). The average radius of curvature was 55.5 mm (±10.7 mm, 33-78.9 mm). Inner bone diameter, measured in two axes, was 10.5 mm (±1.3 mm, 5.4-18.7 mm) for the major axis and 7.7 mm (±0.9 mm, 4.3-17.8 mm) for the minor axis. The average cortical thickness was 1.4 mm (±0.3 mm, 0.7-3.1 mm). The distance to the center of the isthmus from the distal end had an average length of 21.3 mm (±1.9 mm, 17-25 mm). CONCLUSIONS: Using these findings a standardized set of intramedullary stems can be developed as a base for a transcutaneous osseointegrated prosthesis, helping to create a reliable method for treating patients with amputated thumbs.

Knee arthritis pain is reduced and range of motion is increased following moderate pressure massage therapy.

BACKGROUND: The literature on massage therapy effects on knee pain suggests that pain was reduced based on self-report, but little is known about range of motion (ROM) effects. METHODS: Medical School staff and faculty who had knee arthritis pain were randomly assigned to a moderate pressure massage therapy or a waitlist control group (24 per group). Self-reports included the WOMAC (pain, stiffness and function) and the Pittsburgh Sleep Quality Index. ROM and ROM-related pain were assessed before and after the last sessions. RESULTS: The massage group showed an immediate post-massage increase in ROM and a decrease in ROM-associated pain. On the last versus the first day of the study, the massage group showed greater increases in ROM and decreases in ROM-related pain as well as less self-reported pain and sleep disturbances than the waitlist control group. DISCUSSION: These data highlight the effectiveness of moderate pressure massage therapy for increasing ROM and lessening ROM-related pain and long-term pain and sleep disturbances.

Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.

Neck arthritis pain is reduced and range of motion is increased by massage therapy.

BACKGROUND: The literature on the effects of massage therapy on neck arthritis pain is mixed depending on the dose level, and it is also based on self-report. In the present study an attempt was made to enhance the effects of weekly massage therapy by having the participants massage themselves daily. And in addition to self-reports on pain, range of motion (ROM) and the associated ROM pain were assessed before and after the first massage session and pre-post the last session one month later. METHODS: Staff and faculty members at a medical school who were eligible for the study if they had neck arthritis pain were randomly assigned to a massage or a waitlist control group (N = 24 per group). The massage group received moderate pressure massages weekly by a massage therapist plus daily self-massages. The waitlist control group received the same schedule massages one month after being control subjects. RESULTS: The massage group showed significant short-term reductions after the first and last day massages in self-reported pain and in ROM-associated pain as well as an increase in ROM. Comparisons between the massage group (N = 23) and the control group (N = 14) on the last versus the first day data suggested significantly different changes including increased ROM and reduced ROM-associated pain for the massage group and reduced ROM and increased ROM-associated pain for the control group. These changes occurred specifically for flexion and right and left lateral flexion motions. DISCUSSION: These data highlight the importance of designing massage therapy protocols that target the most affected neck muscle groups and then assessing range of motion and related pain before and after the massage therapy. Comparisons with other studies also suggest that moderate pressure may contribute to the massage effects, and the use of daily self-massages between sessions may sustain the effects and serve as a cost-effective therapy for individuals with neck arthritis pain.

Correlation between shape, evaporation mode and mobility of small water droplets on nanorough fibres.

The dynamic wetting behaviour and the mobility of droplets on fibres is a very important factor in coating processes, textile fabrication, in self-cleaning processes and in the filtration of fluids. In principal, filter regeneration depends on the mobility of the droplets on the fibre surface. Mobile droplets tend to coalesce which greatly simplifies their removal from the filter. In this contribution mobility analyses of water droplets on monofilaments in air are performed. Studies of droplet evaporation on pure PET fibres and on nanorough fibres coated with SiO2 nanoparticles of diameters between 6 nm and 50 nm in a hydrophilic binder system were done. We show that the mobility of water droplets correlates with the droplet conformation which in turn is determined by the droplet-fibre interface. We demonstrate that fibre coatings can be used to tailor the conformation and mobility of water droplets. The smaller the nanoparticle diameters in the coating are, the smaller are the contact angles between water droplets and fibre and the better is the mobility of the droplets on the fibre. Our results allow a fast optimization of the fibre surface properties which are directly influencing the contact angle, the mobility and the coalescence of water droplets and thus filter regeneration.

Rheumatoid arthritis in upper limbs benefits from moderate pressure massage therapy.

METHODS: Forty-two adults with rheumatoid arthritis in the upper limbs were randomly assigned to a moderate pressure or a light pressure massage therapy group. A therapist massaged the affected arm and shoulder once a week for a 4-week period and also taught the participant self-massage to be done once daily. RESULTS: The moderate pressure vs. the light pressure massage therapy group had less pain and perceived greater grip strength following the first and last massage sessions. By the end of the one month period the moderate pressure massage group had less pain, greater grip strength and greater range of motion in their wrist and large upper joints (elbows and shoulders).

Infection of human alveolar macrophages by human coronavirus strain 229E.

Human coronavirus strain 229E (HCoV-229E) commonly causes upper respiratory tract infections. However, lower respiratory tract infections can occur in some individuals, indicating that cells in the distal lung are susceptible to HCoV-229E. This study determined the virus susceptibility of primary cultures of human alveolar epithelial cells and alveolar macrophages (AMs). Fluorescent antibody staining indicated that HCoV-229E could readily infect AMs, but no evidence was found for infection in differentiated alveolar epithelial type II cells and only a very low level of infection in type II cells transitioning to the type I-like cell phenotype. However, a human bronchial epithelial cell line (16HBE) was readily infected. The innate immune response of AMs to HCoV-229E infection was evaluated for cytokine production and interferon (IFN) gene expression. AMs secreted significant amounts of tumour necrosis factor alpha (TNF-α), regulated on activation normal T-cell expressed and secreted (RANTES/CCL5) and macrophage inflammatory protein 1ß (MIP-1ß/CCL4) in response to HCoV-229E infection, but these cells exhibited no detectable increase in IFN-ß or interleukin-29 in mRNA levels. AMs from smokers had reduced secretion of TNF-α compared with non-smokers in response to HCoV-229E infection. Surfactant protein A (SP-A) and SP-D are part of the innate immune system in the distal lung. Both surfactant proteins bound to HCoV-229E, and pre-treatment of HCoV-229E with SP-A or SP-D inhibited infection of 16HBE cells. In contrast, there was a modest reduction in infection in AMs by SP-A, but not by SP-D. In summary, AMs are an important target for HCoV-229E, and they can mount a pro-inflammatory innate immune response to infection.

Hand pain is reduced by massage therapy.

METHODS: Forty-six adults with hand pain were randomly assigned to a massage therapy or a standard treatment control group. Those assigned to the massage therapy group were massaged by a therapist on the affected hand once a week for a 4-week period and were also taught self-massage on the hand that was to be done by the individual participant once daily. RESULTS: The massage therapy group versus the control group had less pain and greater grip strength after the first and last sessions, and their anxiety and depressed mood scores decreased more than the control group. Over the four-week period the massage group had a greater decrease in pain and a greater increase in grip strength as well as lower scores on anxiety, depressed mood and sleep disturbance scales.

Rat respiratory coronavirus infection: replication in airway and alveolar epithelial cells and the innate immune response.

The rat coronavirus sialodacryoadenitis virus (SDAV) causes respiratory infection and provides a system for investigating respiratory coronaviruses in a natural host. A viral suspension in the form of a microspray aerosol was delivered by intratracheal instillation into the distal lung of 6-8-week-old Fischer 344 rats. SDAV inoculation produced a 7 % body weight loss over a 5 day period that was followed by recovery over the next 7 days. SDAV caused focal lesions in the lung, which were most severe on day 4 post-inoculation (p.i.). Immunofluorescent staining showed that four cell types supported SDAV virus replication in the lower respiratory tract, namely Clara cells, ciliated cells in the bronchial airway and alveolar type I and type II cells in the lung parenchyma. In bronchial alveolar lavage fluid (BALF) a neutrophil influx increased the population of neutrophils to 45 % compared with 6 % of the cells in control samples on day 2 after mock inoculation. Virus infection induced an increase in surfactant protein SP-D levels in BALF of infected rats on days 4 and 8 p.i. that subsided by day 12. The concentrations of chemokines MCP-1, LIX and CINC-1 in BALF increased on day 4 p.i., but returned to control levels by day 8. Intratracheal instillation of rats with SDAV coronavirus caused an acute, self-limited infection that is a useful model for studying the early events of the innate immune response to respiratory coronavirus infections in lungs of the natural virus host.

Differentiated human alveolar type II cells secrete antiviral IL-29 (IFN-lambda 1) in response to influenza A infection.

Alveolar type II epithelial cells (ATIIs) are one of the primary targets for influenza A pneumonia. The lack of a culture system for maintaining differentiated ATIIs hinders our understanding of pulmonary innate immunity during viral infection. We studied influenza A virus (IAV)-induced innate immune responses in differentiated primary human ATIIs and alveolar macrophages (AMs). Our results indicate that ATIIs, but not AMs, support productive IAV infection. Viral infection elicited strong inflammatory chemokine and cytokine responses in ATIIs, including secretion of IL-8, IL-6, MCP-1, RANTES, and MIP-1beta, but not TNF-alpha, whereas AMs secreted TNF-alpha as well as other cytokines in response to infection. Wild-type virus A/PR/8/34 induced a greater cytokine response than reassortant PR/8 virus, A/Phil/82, despite similar levels of replication. IAV infection increased mRNA expression of IFN genes IFN-beta, IL-29 (IFN-lambda1), and IL-28A (IFN-lambda2). The major IFN protein secreted by type II cells was IL-29 and ATIIs appear to be a major resource for production of IL-29. Administration of IL-29 and IFN-beta before infection significantly reduced the release of infectious viral particles and CXC and CC chemokines. IL-29 treatment of type II cells induced mRNA expression of antiviral genes MX1, OAS, and ISG56 but not IFN-beta. IL-29 induced a dose-dependent decrease of viral nucleoprotein and an increase of antiviral genes but not IFN-beta. These results suggest that IL-29 exerts IFN-beta-independent protection in type II cells through direct activation of antiviral genes during IAV infection.

Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages.

The processing of pro-interleukin-1beta depends on activation of caspase-1. Controversy has arisen whether Toll-like receptor (TLR) ligands alone can activate caspase-1 for release of interleukin-1beta (IL-1beta). Here we demonstrate that human blood monocytes release processed IL-1beta after a one-time stimulation with either TLR2 or TLR4 ligands, resulting from constitutively activated caspase-1 and release of endogenous adenosine triphosphate. The constitutive activation of caspase-1 depends on the inflammasome components, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NALP3, but in monocytes caspase-1 activation is uncoupled from pathogen-associated molecular pattern recognition. In contrast, macrophages are unable to process and release IL-1beta solely by TLR ligands and require a second adenosine triphosphate stimulation. We conclude that IL-1beta production is differentially regulated in monocytes and macrophages, and this reflects their separate functions in host defense and inflammation.

Fully informative microsatellite markers for the tetraploid plant Eritrichium nanum (Boraginaceae).

We characterized eight polymorphic, codominant nuclear microsatellite loci in the tetraploid plant Eritrichium nanum. The different allelic configurations occurring under tetrasomic inheritance were fully resolved at all loci. Two natural populations showed high observed heterozygosities, which were in agreement with Hardy-Weinberg expectations. There was no evidence of genetic linkage disequilibrium for any pair of loci. The results suggest that these microsatellite markers are useful for mating system and population genetic analyses in high-alpine E. nanum.