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Ensuring the successful treatment of tuberculosis (TB) is an essential public health responsibility of national TB programs. This case study describes how the Department of Health and Family Welfare, Kerala state, successfully prevented the disruptions in TB treatment when an unprecedented massive flood, declared as “a calamity of severe nature,” completely disrupted normal operations in the state during August 2018. Unanticipated floods led to the displacement and relocation of more than 1.5 million citizens. The state has ensured continuity of TB treatment for all notified drug sensitive and drug-resistant TB patients (9608 and 434, respectively), including those who were displaced and relocated. A real-time web-enabled, case-based patient management information system has helped preserve the entire patient information, available at multiple levels. Routine strength of the program, including good rapport with patients, frontline multipurpose health workers and treatment supporters, high literacy rate of general population, and well-integrated primary health care system delivering TB services, enabled ensuring continuity of care during the disaster situation. The success of the post-flood TB control measures in Kerala affirms the importance of maintaining an integrated and strong TB control component with general health system ownership.
Cognitive impairment associated with lifetime major depressive disorder (MDD) is well-supported by meta-analytic studies, but population-based estimates remain scarce. Previous UK Biobank studies have only shown limited evidence of cognitive differences related to probable MDD. Using updated cognitive and clinical assessments in UK Biobank, this study investigated population-level differences in cognitive functioning associated with lifetime MDD.
Associations between lifetime MDD and cognition (performance on six tasks and general cognitive functioning [g-factor]) were investigated in UK Biobank (N-range 7,457–14,836, age 45–81 years, 52% female), adjusting for demographics, education, and lifestyle. Lifetime MDD classifications were based on the Composite International Diagnostic Interview. Within the lifetime MDD group, we additionally investigated relationships between cognition and (a) recurrence, (b) current symptoms, (c) severity of psychosocial impairment (while symptomatic), and (d) concurrent psychotropic medication use.
Lifetime MDD was robustly associated with a lower g-factor (β = −0.10, PFDR = 4.7 × 10−5), with impairments in attention, processing speed, and executive functioning (β ≥ 0.06). Clinical characteristics revealed differential profiles of cognitive impairment among case individuals; those who reported severe psychosocial impairment and use of psychotropic medication performed worse on cognitive tests. Severe psychosocial impairment and reasoning showed the strongest association (β = −0.18, PFDR = 7.5 × 10−5).
Findings describe small but robust associations between lifetime MDD and lower cognitive performance within a population-based sample. Overall effects were of modest effect size, suggesting limited clinical relevance. However, deficits within specific cognitive domains were more pronounced in relation to clinical characteristics, particularly severe psychosocial impairment.
Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.
Many institutions evaluate applications for local seed funding by recruiting peer reviewers from their own institutional community. Smaller institutions, however, often face difficulty locating qualified local reviewers who are not in conflict with the proposal. As a larger pool of reviewers may be accessed through a cross-institutional collaborative process, nine Clinical and Translational Science Award (CTSA) hubs formed a consortium in 2016 to facilitate reviewer exchanges. Data were collected to evaluate the feasibility and preliminary efficacy of the consortium.
The CTSA External Reviewer Exchange Consortium (CEREC) has been supported by a custom-built web-based application that facilitates the process and tracks the efficiency and productivity of the exchange.
All nine of the original CEREC members remain actively engaged in the exchange. Between January 2017 and May 2019, CEREC supported the review process for 23 individual calls for proposals. Out of the 412 reviews requested, 368 were received, for a fulfillment ratio of 89.3%. The yield on reviewer invitations has remained consistently high, with approximately one-third of invitations being accepted, and of the reviewers who agreed to provide a review, 88.3% submitted a complete review. Surveys of reviewers and pilot program administrators indicate high satisfaction with the process.
These data indicate that a reviewer exchange consortium is feasible, adds value to participating partners, and is sustainable over time.
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Reductions in insulin sensitivity in periparturient dairy cows develop as a means to support lactation; however, excessive mobilization of fatty acids (FA) increases the risk for peripartal metabolic disorders. Our objectives were to investigate the effect of prepartum body condition score (BCS) on systemic glucose and insulin tolerance, and to compare direct and indirect measurements of insulin sensitivity in peripartal lean and overweight dairy cows. Fourteen multiparous Holstein cows were allocated into two groups according to their BCS at day −28 prepartum: lean (n = 7; BCS ≤ 3.0) or overweight; (n = 7; BCS ≥ 4.0). Liver biopsies were performed on day −27, −14 and 4, relative to expected parturition. Intravenous insulin or glucose tolerances tests were performed following each liver biopsy. Relative to lean cows, overweight cows exhibited lower dry matter intake, lost more BCS and displayed increased plasma FA and β-hydroxybutyrate concentrations and elevated liver lipid content during peripartum. Glucose clearance rate was lower for all cows postpartum. Prepartum BCS had minimal effects on insulin and glucose tolerance; however, the ability of the cow to restore blood glucose levels following an insulin challenge was suppressed by increased BCS. Glucose-dependent parameters of insulin and glucose tolerance were not correlated with surrogate indices of insulin sensitivity. We conclude that prepartum BCS had minimal effect on systemic insulin sensitivity following parturition. The observed inconsistency between surrogate indices of insulin sensitivity and direct measurements of insulin and glucose tolerance adds support to growing concerns regarding their usefulness as tools to estimate systemic insulin action in periparturient cows.
Determining infectious cross-transmission events in healthcare settings involves manual surveillance of case clusters by infection control personnel, followed by strain typing of clinical/environmental isolates suspected in said clusters. Recent advances in genomic sequencing and cloud computing now allow for the rapid molecular typing of infecting isolates.
To facilitate rapid recognition of transmission clusters, we aimed to assess infection control surveillance using whole-genome sequencing (WGS) of microbial pathogens to identify cross-transmission events for epidemiologic review.
Clinical isolates of Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, and Klebsiella pneumoniae were obtained prospectively at an academic medical center, from September 1, 2016, to September 30, 2017. Isolate genomes were sequenced, followed by single-nucleotide variant analysis; a cloud-computing platform was used for whole-genome sequence analysis and cluster identification.
Most strains of the 4 studied pathogens were unrelated, and 34 potential transmission clusters were present. The characteristics of the potential clusters were complex and likely not identifiable by traditional surveillance alone. Notably, only 1 cluster had been suspected by routine manual surveillance.
Our work supports the assertion that integration of genomic and clinical epidemiologic data can augment infection control surveillance for both the identification of cross-transmission events and the inclusion of missed and exclusion of misidentified outbreaks (ie, false alarms). The integration of clinical data is essential to prioritize suspect clusters for investigation, and for existing infections, a timely review of both the clinical and WGS results can hold promise to reduce HAIs. A richer understanding of cross-transmission events within healthcare settings will require the expansion of current surveillance approaches.
OBJECTIVES/SPECIFIC AIMS: More men than women develop urinary stones and their prevalence alters in women with menopause suggesting a steroidal influence. In men the incidence of stones is highest during July and August suggesting that environmental factors such as Vitamin D (VitD), a steroid, may affect stone formation. Previous studies have found differences in the development of stones between men and women; however, the reasons for sex differences in stone formation and type remain unclear. METHODS/STUDY POPULATION: We examined VitD levels in men and women (n = 18,753) that had no diseases based on a lack of an ICD-9 or ICD-10 code in their electronic medical record. We found that normal, healthy women had significantly higher levels of sera VitD compared to men (p = 6x10-6). We then examined whether sex differences existed for key endpoints/data from the Mayo Clinic Urinary Stone Disease (USD) Registry, which has around 1,600 urinary stone patients that are well-phenotyped according to sex, age and stone type. RESULTS/ANTICIPATED RESULTS: Control women were found to have higher sera VitD levels than men, but the sex difference no longer exists in kidney stone disease patients. When we further separated by race, we found that differences in VitD levels reappeared; this suggests that race also plays a role in sera VitD variances. DISCUSSION/SIGNIFICANCE OF IMPACT: We are developing a disease severity score, which we will use to correlate to sera VitD levels in patients according to sex, age and race. Future analyses will take into account whether subjects had VitD and calcium supplementation. This project begins to explore the mechanism behind the sex differences known to exist in urinary stone disease, which is critically needed to provide improved diagnosis and therapy for this debilitating disease.
Buprenorphine (BUP)/samidorphan (SAM) combination is an opioid system modulator being investigated as an adjunctive treatment for major depressive disorder (MDD). BUP/SAM is a fixed-dose combination of BUP, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and SAM, a µ-opioid receptor antagonist added to address the abuse and dependence potential of BUP.1,2
We assessed the effects of SAM on the abuse potential of BUP in the BUP/SAM combination in two ways: (1) a human abuse potential (HAP) study in volunteers; and (2) an evaluation of the clinical experience across studies of patients with MDD.
Study 212 (ClinicalTrials.gov ID: NCT02413281) was a HAP study in nondependent, recreational, adult opioid users. Following a qualification period, participants were randomized to 6 treatments in a blinded, crossover design: placebo (PBO), BUP/SAM at the target therapeutic dose (BUP/SAM 2mg/2mg), at 8mg/8mg and 16mg/16mg , and BUP alone (8mg and 16mg). The primary endpoint was maximum effect (Emax) for “At The Moment” Drug Liking Visual Analog Scale (VAS).
The clinical program for BUP/SAM included 4 PBO-controlled studies of patients with MDD (n=961). Pooled safety data were evaluated for adverse events (AEs) that may be associated with abuse, dependence, or withdrawal, as well as for objective signs of withdrawal with the Clinical Opioid Withdrawal Scale (COWS).
In Study 212 (n=38), Emax Drug Liking VAS scores for the BUP/SAM 2mg/2mg dose were similar to those for PBO (median within-subject difference [90% CI]: 2.5 [0.0–9.0]). Emax Drug Liking VAS scores for all BUP/SAM dose groups, including supratherapeutic doses, were significantly lower than those observed for either of the BUP doses. The supratherapeutic doses of BUP/SAM (8mg/8mg and 16mg/16mg) had higher Emax Drug Liking VAS scores than PBO, but the differences were small.
In the MDD controlled studies, the incidence of euphoria-related AEs was low for BUP/SAM 2mg/2mg and PBO (1.6% vs 0.2%, respectively) and there was no evidence of abuse or dependence behavior. Euphoria-related events typically occurred with treatment initiation and resolved with continued treatment. There was minimal evidence of withdrawal by reported AEs or COWS assessment.
These findings indicate that SAM mitigates the abuse potential of BUP in the BUP/SAM combination.
Treatment for hoarding disorder is typically performed by mental health professionals, potentially limiting access to care in underserved areas.
We aimed to conduct a non-inferiority trial of group peer-facilitated therapy (G-PFT) and group psychologist-led cognitive–behavioural therapy (G-CBT).
We randomised 323 adults with hording disorder 15 weeks of G-PFT or 16 weeks of G-CBT and assessed at baseline, post-treatment and longitudinally (≥3 months post-treatment: mean 14.4 months, range 3–25). Predictors of treatment response were examined.
G-PFT (effect size 1.20) was as effective as G-CBT (effect size 1.21; between-group difference 1.82 points, t = −1.71, d.f. = 245, P = 0.04). More homework completion and ongoing help from family and friends resulted in lower severity scores at longitudinal follow-up (t = 2.79, d.f. = 175, P = 0.006; t = 2.89, d.f. = 175, P = 0.004).
Peer-led groups were as effective as psychologist-led groups, providing a novel treatment avenue for individuals without access to mental health professionals.
Declaration of interest
C.A.M. has received grant funding from the National Institutes of Health (NIH) and travel reimbursement and speakers’ honoraria from the Tourette Association of America (TAA), as well as honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. K.D. receives research support from the NIH and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. R.S.M. receives research support from the National Institute of Mental Health, National Institute of Aging, the Hillblom Foundation, Janssen Pharmaceuticals (research grant) and the Alzheimer's Association. R.S.M. has also received travel support from the National Institute of Mental Health for Workshop participation. J.Y.T. receives research support from the NIH, Patient-Centered Outcomes Research Institute and the California Tobacco Related Research Program, and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. All other authors report no conflicts of interest.
The acoustics of a straight annular lined duct containing a swirling mean flow is considered. The classical Ingard–Myers impedance boundary condition is shown not to be correct for swirling flow. By considering behaviour within the thin boundary layers at the duct walls, the correct impedance boundary condition for an infinitely thin boundary layer with swirl is derived, which reduces to the Ingard–Myers condition when the swirl is set to zero. The correct boundary condition contains a spring-like term due to centrifugal acceleration at the walls, and consequently has a different sign at the inner (hub) and outer (tip) walls. Examples are given for mean flows relevant to the interstage region of aeroengines. Surface waves in swirling flows are also considered, and are shown to obey a more complicated dispersion relation than for non-swirling flows. The stability of the surface waves is also investigated, and as in the non-swirling case, one unstable surface wave per wall is found.
To validate a newly introduced cartilage rim augmented temporalis fascia tympanoplasty technique by statistically comparing it with the morphological and audiological outcomes of traditional temporalis fascia tympanoplasty.
A retrospective comparative study was conducted on 115 patients who underwent tympanoplasty during 2013 and 2015. Fifty-eight patients underwent temporalis fascia tympanoplasty and 57 underwent cartilage rim augmented fascia tympanoplasty.
In the cartilage fascia group, graft healing was achieved in 94.7 per cent of cases; in the temporalis fascia group, the graft take-up rate was 70 per cent. In those with a normal ossicular chain, the post-operative air–bone gap was within 20 dB in 92.6 per cent of cartilage fascia group cases and in 69.7 per cent of the temporalis fascia group cases, which was a statistically significant difference. Among the defective ossicular chain cases, the post-operative air–bone gap was within 20 dB in 76.9 per cent in the cartilage fascia group, as against 57.1 per cent in the temporalis fascia group.
Cartilage rim augmented temporalis fascia tympanoplasty has a definite advantage over the temporalis fascia technique in terms of superior graft take up and statistically significant hearing gain in those with normal ossicular mobility.
Inflammation of the mammary gland following bacterial infection, commonly known as mastitis, affects all mammalian species. Although the aetiology and epidemiology of mastitis in the dairy cow are well described, the genetic factors mediating resistance to mammary gland infection are not well known, due in part to the difficulty in obtaining robust phenotypic information from sufficiently large numbers of individuals. To address this problem, an experimental mammary gland infection experiment was undertaken, using a Friesian-Jersey cross breed F2 herd. A total of 604 animals received an intramammary infusion of Streptococcus uberis in one gland, and the clinical response over 13 milkings was used for linkage mapping and genome-wide association analysis. A quantitative trait locus (QTL) was detected on bovine chromosome 11 for clinical mastitis status using micro-satellite and Affymetrix 10 K SNP markers, and then exome and genome sequence data used from the six F1 sires of the experimental animals to examine this region in more detail. A total of 485 sequence variants were typed in the QTL interval, and association mapping using these and an additional 37 986 genome-wide markers from the Illumina SNP50 bovine SNP panel revealed association with markers encompassing the interleukin-1 gene cluster locus. This study highlights a region on bovine chromosome 11, consistent with earlier studies, as conferring resistance to experimentally induced mammary gland infection, and newly prioritises the IL1 gene cluster for further analysis in genetic resistance to mastitis.
Both direct observations and reconstructions from various datasets, suggest that conditions were radically different during the Maunder Minimum (MM) than during the space era. Using an MHD model, we develop a set of feasible solutions to infer the properties of the solar wind during this interval. Additionally, we use these results to drive a global magnetospheric model. Finally, using the 2008/2009 solar minimum as an upper limit for MM conditions, we use results from the International Reference Ionosphere (ILI) model to speculate on the state of the ionosphere. The results describe interplanetary, magnetospheric, and ionospheric conditions that were substantially different than today. For example: (1) the solar wind density and magnetic field strength were an order of magnitude lower; (2) the Earth’s magnetopause and shock standoff distances were a factor of two larger; and (3) the maximum electron density in the ionosphere was substantially lower.
Reconstructions of long-term solar variability underpin our understanding of the solar dynamo, potential tropospheric climate implications and future space weather scenarios. Prior to direct spacecraft measurements of the heliospheric magnetic field (HMF) and solar wind, accurate annual reconstructions are possible using geomagnetic and sunspot records. On longer timescales, information about the HMF can be extracted from cosmogenic radionuclide records, particularly 14C in ancient trees and 10Be in ice sheets. These proxies, and what they reveal about the HMF and solar wind, are briefly reviewed here.
Most major modern families of Hymenoptera were established in the Mesozoic, but the diversifications within ecologically key trophic guilds and lineages that significantly influence the character of modern terrestrial ecosystems – bees (Apiformes), ants (Formicidae), social Vespidae, parasitoids (Ichneumonidae), and phytophagous Tenthredinoidea – were previously known to occur mostly in the middle to late Eocene. We find these changes earlier, seen here in the early Eocene Okanagan Highlands fossil deposits of western North America. Some of these may have occurred even earlier, but have been obscured by taphonomic processes. We provide an overview of the Okanagan Highlands Hymenoptera to family level and in some cases below that, with a minimum of 25 named families and at least 30 when those tentatively assigned or distinct at family level, but not named are included. Some are poorly known as fossils (Trigonalidae, Siricidae, Peradeniidae, Monomachidae), and some represent the oldest confirmed occurrences (Trigonalidae, Pompilidae, Sphecidae sensu stricto, Peradeniidae, Monomachidae, and possibly Halictidae). Some taxa previously thought to be relictual or extinct by the end of the Cretaceous (Angarosphecidae, Archaeoscoliinae, some Diapriidae) are present and sometimes abundant in the early Eocene. Living relatives of some taxa are now present in different climate regimes or on different continents.
Dissecting Bioethics, edited by Tuija Takala and Matti Hayry, welcomes contributions on the conceptual and theoretical dimensions of bioethics. The department is dedicated to the idea that words defined by bioethicists and others should not be allowed to imprison people’s actual concerns, emotions, and thoughts. Papers that expose the many meanings of a concept, describe the different readings of a moral doctrine, or provide an alternative angle to seemingly self-evident issues are particularly appreciated. To submit a paper or to discuss a suitable topic, contact Tuija Takala at email@example.com.
Advanced forecasting of space weather requires prediction of near-Earth solar-wind conditions on the basis of remote solar observations. This is typically achieved using numerical magnetohydrodynamic models initiated by photospheric magnetic field observations. The accuracy of such forecasts is being continually improved through better numerics, better determination of the boundary conditions and better representation of the underlying physical processes. Thus it is not unreasonable to conclude that simple, empirical solar-wind forecasts have been rendered obsolete. However, empirical models arguably have more to contribute now than ever before. In addition to providing quick, cheap, independent forecasts, simple empirical models aid in numerical model validation and verification, and add value to numerical model forecasts through parameterization, uncertainty estimation and ‘downscaling’ of sub-grid processes.
Our study combines new geological and paleoecological information to reconstruct the glacial history and terrestrial paleoenvironments on Haida Gwaii during the advance phase of the Fraser glaciation (Marine Isotope Stage 2). At Cape Ball on eastern Graham Island, five accelerator mass spectrometry radiocarbon ages ranging from 23,200±280 to 26,650±390 14C yr BP (ca. 27,000–31,400 cal yr BP) record the earliest approach of mainland glaciers to Haida Gwaii. Abundant marine dinoflagellate cysts indicate isostatic depression by glacial ice in Hecate Strait to the east. At Mary Point on the north coast of Graham Island, similar outwash of a piedmont lobe advancing westward along Dixon Entrance preserves plant remains dated from 19,270±360 to 23,740±300 14C yr BP (22,500–28,600 cal yr BP). These sediments also contain marine indicators. Plant macrofossils, pollen, and invertebrates support the geological evidence of a proglacial environment under a colder-than-present macroclimate. Although some trees were likely present on Graham Island at this time, tundra-like plant communities dominated low-lying areas. A large area that appears to have been ice-free during this time is a portion of the continental shelf off the east coast of Moresby Island, referred to provisionally as the “Hecate Refugium.”