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White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell-specific transcriptional aberrations that occur in WAT with aging. We leveraged full-length snRNA-Seq and histology to characterize the cellular landscape of human abdominal subcutaneous WAT in a prospective cohort of 10 younger (≤30 years) and 10 older individuals (≥65 years) balanced for sex and body mass index (BMI). The older group had greater cholesterol, very-low-density lipoprotein, triglycerides, thyroid stimulating hormone, and aspartate transaminase compared to the younger group (p < 0.05). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of lipid-associated macrophages and mast cells, an upregulation of immune responses linked to fibrosis in pre-adipocyte, adipocyte, and vascular populations, and highlight CXCL14 as a biomarker of these processes. We show that older WAT has elevated levels of senescence marker p16 in adipocytes and identify the adipocyte subpopulation driving this senescence profile. We confirm that these transcriptional and phenotypical changes occur without overt fibrosis and in older individuals that have comparable WAT insulin sensitivity to the younger individuals.
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Pediatric MASLD (previously referred to as NAFLD) incidence has continued to rise along with the obesity pandemic. Pediatric MASLD increases the risk of liver fibrosis and cirrhosis in adulthood. Early detection and intervention can prevent and reduce complications. Liver biopsy remains the gold standard for diagnosis, although imaging modalities are increasingly being used. We performed a retrospective study of 202 children seen in a pediatric gastroenterology clinic with a complaint of abdominal pain, elevated liver enzymes or MASLD, or a combination of the three to evaluate screening methods for MASLD. A total of 134 of the 202 patients included in the study underwent laboratory testing and abdominal ultrasound. Ultrasound images were reviewed with attention to liver size and echotexture by a fellowship-trained pediatric radiologist for liver size and echotexture. Overall, 76.2% of the initial radiology reports correctly identified hepatomegaly based on age and 75.4% of the initial radiology reports correctly described hepatic echogenicity that was consistent with increased hepatic fat deposition. Use of screening ultrasound in concert with other clinical evaluations can be helpful to identify children at risk of MASLD. Utilizing ranges for liver span according to age can help to diagnose hepatomegaly, and understanding how to identify hepatic echogenicity is important for identifying possible hepatic steatosis.
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AIM: The aim of this study was to determine whether biparametric magnetic resonance imaging (MRI) is effective in the diagnosis of clinically significant prostate cancer in prostate peripheral zone Prostate Imaging Reporting and Data System (PIRADS) 3 lesions without the use of dynamic contrast enhancement. MATERIALS AND METHODS: Patients who underwent biparametric MRI over a 12-month period from January 2022 to December 2022 and were diagnosed with PIRADS 3 lesion in the peripheral zone were included in the study. No patient received dynamic contrast enhancement. Histological analysis was done after performing local anesthetic transperineal biopsy to determine detection rate of clinically significant prostate cancer. Prostate-specific antigen density (PSAD) and biopsy complication rates were also reviewed. RESULTS: Sixty-one out of 688 MRIs (8.8%) performed over the study period had a PIRADS 3 lesion in the peripheral zone where contrast is supposed to add value. Fifty-eight of the 61 went ahead to biopsy, and csPCa (Gleason score: ≥3 + 4, with a max core length of ≥6 mm and above) was diagnosed in 17%. Among those diagnosed with csPCa, 80% had a PSAD of >0.15 ng/ml/cc. No postbiopsy complications were reported. CONCLUSION: Biparametric MRI without contrast offers a reliable alternative to multiparametric MRI with minimum or neglible impact on clinically significant prostate cancer (csPCa) diagnosis in peripheral zone PIRADS 3 lesions, especially when used in conjunction with other factors such as PSAD. There is potential to address health economics and patient burden in prostate cancer investigation.
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More than half of women will experience a urinary tract infection (UTI) with most cases caused by uropathogenic Escherichia coli (UPEC). Bacterial swimming motility enhances UPEC pathogenicity, resulting in more severe disease outcomes including kidney infection. Surprisingly, the connection between motility and iron limitation is mostly unexplored despite the lack of free iron available in the host. We sought to investigate a potential connection between iron restriction and regulation of motility in UPEC. We cultured E. coli CFT073, a prototypical UPEC strain, under iron limitation and observed that CFT073 had elevated fliC (flagella) promoter activity, and this iron-specific response was repressed by the addition of exogenous iron. We confirmed increased flagellar expression in CFT073 by measuring fliC transcript, FliC protein, and surface-expressed flagella under iron-limited conditions. Interestingly, known motility regulator flhDC did not have altered transcription under these conditions. To define the regulatory mechanism of this response, we constructed single knockouts of eight master regulators and found the iron-regulated response was lost in crp, arcA, and fis mutants. Thus, we focused on the five genes regulated by all three regulators. Of the five genes knocked out, the iron-regulated motility response was most strongly dysregulated in the lpdA mutant, which also resulted in significantly lowered fitness in the murine model of ascending UTI, both against the WT and a non-motile fliC mutant. Collectively, we demonstrated that iron-mediated motility in CFT073 is partially regulated by lpdA, which contributes to the understanding of how uropathogens differentially regulate motility mechanisms in the iron-restricted host. IMPORTANCE: Urinary tract infections (UTIs) are ubiquitous and responsible for over five billion dollars in associated health care costs annually. Both iron acquisition and motility are highly studied virulence factors associated with uropathogenic Escherichia coli (UPEC), the main causative agent of uncomplicated UTI. This work is innovative by providing mechanistic insight into the synergistic relationship between these two critical virulence properties. Here, we demonstrate that iron limitation has pleiotropic effects with consequences that extend beyond metabolism and impact other virulence mechanisms. Indeed, targeting iron acquisition as a therapy may lead to an undesirable enhancement of UPEC pathogenesis through increased motility. It is vital to understand the full breadth of UPEC pathogenesis to adequately respond to this common infection, especially with the increase of antibiotic-resistant pathogens.
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Infecciones por Escherichia coli , Proteínas de Escherichia coli , Regulación Bacteriana de la Expresión Génica , Infecciones Urinarias , Escherichia coli Uropatógena , Animales , Femenino , Ratones , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/microbiología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Flagelos/genética , Flagelos/metabolismo , Flagelina , Hierro/metabolismo , Locomoción , Infecciones Urinarias/microbiología , Escherichia coli Uropatógena/efectos de los fármacos , Escherichia coli Uropatógena/genética , Escherichia coli Uropatógena/metabolismo , Escherichia coli Uropatógena/patogenicidad , VirulenciaRESUMEN
BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). METHODS: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). RESULTS: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. CONCLUSION: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.
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The crises of climate change and biodiversity loss are interlinked and must be addressed jointly. A proposed solution for reducing reliance on fossil fuels, and thus mitigating climate change, is the transition from conventional combustion-engine to electric vehicles. This transition currently requires additional mineral resources, such as nickel and cobalt used in car batteries, presently obtained from land-based mines. Most options to meet this demand are associated with some biodiversity loss. One proposal is to mine the deep seabed, a vast, relatively pristine and mostly unexplored region of our planet. Few comparisons of environmental impacts of solely expanding land-based mining versus extending mining to the deep seabed for the additional resources exist and for biodiversity only qualitative. Here, we present a framework that facilitates a holistic comparison of relative ecosystem impacts by mining, using empirical data from relevant environmental metrics. This framework (Environmental Impact Wheel) includes a suite of physicochemical and biological components, rather than a few selected metrics, surrogates, or proxies. It is modified from the "recovery wheel" presented in the International Standards for the Practice of Ecological Restoration to address impacts rather than recovery. The wheel includes six attributes (physical condition, community composition, structural diversity, ecosystem function, external exchanges and absence of threats). Each has 3-5 sub attributes, in turn measured with several indicators. The framework includes five steps: (1) identifying geographic scope; (2) identifying relevant spatiotemporal scales; (3) selecting relevant indicators for each sub-attribute; (4) aggregating changes in indicators to scores; and (5) generating Environmental Impact Wheels for targeted comparisons. To move forward comparisons of land-based with deep seabed mining, thresholds of the indicators that reflect the range in severity of environmental impacts are needed. Indicators should be based on clearly articulated environmental goals, with objectives and targets that are specific, measurable, achievable, relevant, and time bound.
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Minería , Biodiversidad , Ecosistema , Ambiente , Conservación de los Recursos Naturales , Cambio ClimáticoRESUMEN
OBJECTIVES: This aimed to develop a blueprint for an effective community pharmacy Hepatitis C virus (HCV) testing service by producing a consensus statement. STUDY DESIGN: This was a modified Delphi process. METHODS: We recruited a heterogenous panel of experts (who had been involved in the setup or delivery of a community pharmacy HCV testing service) by purposive and chain referral methods. We had three rounds of a modified Delphi process. The first was a series of questions with free text responses and was analysed using thematic analysis, and the second and third were statements for the respondents to rate using a 7-point Likert scale. Consensus was predefined in a published protocol, and the results were reviewed by a public and patient involvement panel before the statement was finalised. RESULTS: We had 24 participants, including community and hospital-based pharmacists, local pharmaceutical committee members, charity representatives (Hepatitis C Trust), local clinical service lead, nurse specialists and doctors. The response rate of the first, second and third rounds were 100%, 96% and 88%, respectively. After the third round, we had 60 statements that reached consensus. We discussed the accepted statements with a patient and public involvement group. We used these statements to produce the I-COPTIC statement and a graphical summary. CONCLUSIONS: We developed a blueprint for the design of a gold standard community pharmacy HCV testing service. We believe this will support the successful implementation of community pharmacy testing for HCV. Community pharmacy testing is an important service to help achieve and maintain HCV elimination.
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Servicios Comunitarios de Farmacia , Consenso , Técnica Delphi , Hepatitis C , Humanos , Hepatitis C/diagnóstico , Servicios Comunitarios de Farmacia/organización & administración , Tamizaje Masivo/métodos , Tamizaje Masivo/normas , Farmacias/organización & administraciónRESUMEN
INTRODUCTION: Late-life treatment-resistant depression (LL-TRD) is common and increases risk for accelerated ageing and cognitive decline. Impaired sleep is common in LL-TRD and is a risk factor for cognitive decline. Slow wave sleep (SWS) has been implicated in key processes including synaptic plasticity and memory. A deficiency in SWS may be a core component of depression pathophysiology. The anaesthetic propofol can induce electroencephalographic (EEG) slow waves that resemble SWS. Propofol may enhance SWS and oral antidepressant therapy, but relationships are unclear. We hypothesise that propofol infusions will enhance SWS and improve depression in older adults with LL-TRD. This hypothesis has been supported by a recent small case series. METHODS AND ANALYSIS: SWIPED (Slow Wave Induction by Propofol to Eliminate Depression) phase I is an ongoing open-label, single-arm trial that assesses the safety and feasibility of using propofol to enhance SWS in older adults with LL-TRD. The study is enrolling 15 English-speaking adults over age 60 with LL-TRD. Participants will receive two propofol infusions 2-6 days apart. Propofol infusions are individually titrated to maximise the expression of EEG slow waves. Preinfusion and postinfusion sleep architecture are evaluated through at-home overnight EEG recordings acquired using a wireless headband equipped with dry electrodes. Sleep EEG recordings are scored manually. Key EEG measures include sleep slow wave activity, SWS duration and delta sleep ratio. Longitudinal changes in depression, suicidality and anhedonia are assessed. Assessments are performed prior to the first infusion and up to 10 weeks after the second infusion. Cognitive ability is assessed at enrolment and approximately 3 weeks after the second infusion. ETHICS AND DISSEMINATION: The study was approved by the Washington University Human Research Protection Office. Recruitment began in November 2022. Dissemination plans include presentations at scientific conferences, peer-reviewed publications and mass media. Positive results will lead to a larger phase II randomised placebo-controlled trial. TRIAL REGISTRATION NUMBER: NCT04680910.
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Disfunción Cognitiva , Propofol , Sueño de Onda Lenta , Humanos , Propofol/administración & dosificación , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Anciano , Sueño de Onda Lenta/efectos de los fármacos , Electroencefalografía , Masculino , Anestésicos Intravenosos/administración & dosificación , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Ensayos Clínicos Fase I como AsuntoRESUMEN
Studies of vertebrate bone biomechanics often focus on skeletal adaptations at upper extremes of body mass, disregarding the importance of skeletal adaptations at lower extremes. Yet mammals are ancestrally small and most modern species have masses under 5 kg, so the evolution of morphology and function at small size should be prioritized for understanding how mammals subsist. We examined allometric scaling of lumbar vertebrae in the small-bodied Philippine endemic rodents known as cloud rats, which vary in mass across two orders of magnitude (15.5 g-2700 g). External vertebral dimensions scale with isometry or positive allometry, likely relating to body size and nuances in quadrupedal posture. In contrast to most mammalian trabecular bone studies, bone volume fraction and trabecular thickness scale with positive allometry and isometry, respectively. It is physiologically impossible for these trends to continue to the upper extremes of mammalian body size, and we demonstrate a fundamental difference in trabecular bone allometry between large- and small-bodied mammals. These findings have important implications for the biomechanical capabilities of mammalian bone at small body size; for the selective pressures that govern skeletal evolution in small mammals; and for the way we define 'small' and 'large' in the context of vertebrate skeletons.
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Vértebras Lumbares , Mamíferos , Ratas , Animales , Mamíferos/fisiología , Huesos , Tamaño Corporal , VertebradosRESUMEN
Helicobacter pylori and intestinal parasites cause gastrointestinal diseases with a high prevalence in children in resource limited developing countries. There is paucity of information in Nigeria on co-infection of H. pylori and intestinal parasites. The study was conducted to determine the prevalence of H. pylori and parasite co-infection in children from selected low-income communities in Lagos, Nigeria. Fecal samples were collected from 151 healthy children aged ≤11 years across six low-income communities in Lagos. H. pylori was detected using stool antigen test and conventional PCR assay, intestinal parasites were detected using formol-ether concentration and nested PCR assay. Structured questionnaires were administered to parents and legal guardians of the children by an interviewer to collect relevant data on demographic and lifestyle factors. The prevalence of H. pylori was 31.79% (48), with a higher prevalence in children aged 2-3 years. The prevalence of intestinal parasites was 21.19% (32) with the lowest frequency found in children aged 8-9 years. The parasites detected include: A. lumbricoides (10.6%), G. intestinalis (7.3%), hookworm (1.99%), E. histolytica (0.66%), S. mansoni (0.66%). There was co-infection prevalence of 10.6% (16) which was associated with the parasites: G. intestinalis (7.3%) and A. lumbricoides (3.97%). Polyparasitism with G. intestinalis and A. lumbricoides was reported in 2 children infected with H. pylori. This study which is the first reported in Lagos established a low prevalence of H. pylori and intestinal parasite co-infection in children and provides better understanding of the epidemiology of H. pylori infection associated with intestinal parasites in Nigeria.
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Coinfección , Heces , Infecciones por Helicobacter , Helicobacter pylori , Parasitosis Intestinales , Nigeria/epidemiología , Humanos , Niño , Infecciones por Helicobacter/epidemiología , Coinfección/epidemiología , Coinfección/parasitología , Preescolar , Femenino , Masculino , Parasitosis Intestinales/epidemiología , Parasitosis Intestinales/parasitología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/genética , Prevalencia , Heces/parasitología , Heces/microbiología , Animales , Pobreza , Lactante , Estudios TransversalesRESUMEN
Background: The alpha-2 adrenergic agonist dexmedetomidine induces EEG patterns resembling those of non-rapid eye movement (NREM) sleep. Fulfilment of slow wave sleep (SWS) homeostatic needs would address the assumption that dexmedetomidine induces functional biomimetic sleep states. Methods: In-home sleep EEG recordings were obtained from 13 healthy participants before and after dexmedetomidine sedation. Dexmedetomidine target-controlled infusions and closed-loop acoustic stimulation were implemented to induce and enhance EEG slow waves, respectively. EEG recordings during sedation and sleep were staged using modified American Academy of Sleep Medicine criteria. Slow wave activity (EEG power from 0.5 to 4 Hz) was computed for NREM stage 2 (N2) and NREM stage 3 (N3/SWS) epochs, with the aggregate partitioned into quintiles by time. The first slow wave activity quintile served as a surrogate for slow wave pressure, and the difference between the first and fifth quintiles as a measure of slow wave pressure dissipation. Results: Compared with pre-sedation sleep, post-sedation sleep showed reduced N3 duration (mean difference of -17.1 min, 95% confidence interval -30.0 to -8.2, P=0.015). Dissipation of slow wave pressure was reduced (P=0.02). Changes in combined durations of N2 and N3 between pre- and post-sedation sleep correlated with total dexmedetomidine dose, (r=-0.61, P=0.03). Conclusions: Daytime dexmedetomidine sedation and closed-loop acoustic stimulation targeting EEG slow waves reduced N3/SWS duration and measures of slow wave pressure dissipation on the post-sedation night in healthy young adults. Thus, the paired intervention induces sleep-like states that fulfil certain homeostatic NREM sleep needs in healthy young adults. Clinical trial registration: ClinicalTrials.gov NCT04206059.
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Existing modelling tools, developed to aid the design of efficient molecular wires and to better understand their charge-transport behaviour and mechanism, have limitations in accuracy and computational cost. Further research is required to develop faster and more precise methods that can yield information on how charge transport properties are impacted by changes in the chemical structure of a molecular wire. In this study, we report a clear semilogarithmic correlation between charge transport efficiency and nuclear magnetic resonance chemical shifts in multiple series of molecular wires, also accounting for the presence of chemical substituents. The NMR data was used to inform a simple tight-binding model that accurately captures the experimental single-molecule conductance values, especially useful in this case as more sophisticated density functional theory calculations fail due to inherent limitations. Our study demonstrates the potential of NMR spectroscopy as a valuable tool for characterising, rationalising, and gaining additional insights on the charge transport properties of single-molecule junctions.
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BACKGROUND: Loss of smell is one of the most bothersome and difficult-to-treat symptoms in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). METHODOLOGY: SYNAPSE was a 52-week Phase III study of 4-weekly mepolizumab (100 mg subcutaneously) plus standard of care in adults with severe bilateral CRSwNP. This post hoc analysis assessed changes from baseline to study end in loss of smell visual analogue scale (VAS) symptom score, in patients stratified by several baseline clinical characteristics. SinoNasal Outcomes Test (SNOT)-22 sense of smell/taste item and University of Pennsylvania Smell Identification Test (UPSIT) scores were also assessed. RESULTS: SYNAPSE enrolled 407 patients (mepolizumab=206; placebo=201) with impaired sense of smell at baseline. Improvements from baseline to study end in loss of smell VAS score were greater with mepolizumab versus placebo (treatment difference: -0.37) and most notable in patients with fewer or more recent prior surgeries (treatment difference: 1 vs 2 vs more than 2 prior surgeries,-1.29 vs -0.23 vs -0.07; =3 years since last surgery, -.89 vs 0.22). Approximately 25% of patients had baseline UPSIT scoresavailable; among those scoring =19 by study end. The SNOT-22 sense of smell/taste item score improved with mepolizumab versus placebo. CONCLUSIONS: Mepolizumab treatment improved patients' perceived sense of smell, as measured by loss of smell VAS score and SNOT-22 sense of smell/taste item score in patients with severe refractory CRSwNP.
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Anticuerpos Monoclonales Humanizados , Pólipos Nasales , Rinitis , Sinusitis , Humanos , Sinusitis/tratamiento farmacológico , Sinusitis/complicaciones , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/complicaciones , Enfermedad Crónica , Rinitis/tratamiento farmacológico , Rinitis/complicaciones , Femenino , Masculino , Adulto , Persona de Mediana Edad , Trastornos del Olfato/tratamiento farmacológico , Trastornos del Olfato/etiología , Olfato/efectos de los fármacos , Olfato/fisiología , Método Doble Ciego , Resultado del Tratamiento , Prueba de Resultado Sino-Nasal , RinosinusitisRESUMEN
Use of nutrients recycled from societal waste streams in agriculture is part of the circular economy, and in line with organic farming principles. Nevertheless, diverse contaminants in waste streams create doubts among organic farmers about potential risks for soil health. Here, we gather the current knowledge on contaminant levels in waste streams and recycled nutrient sources, and discuss associated risks. For potentially toxic elements (PTEs), the input of zinc (Zn) and copper (Cu) from mineral feed supplements remains of concern, while concentrations of PTEs in many waste streams have decreased substantially in Europe. The same applies to organic contaminants, although new chemical groups such as flame retardants are of emerging concern and globally contamination levels differ strongly. Compared to inorganic fertilizers, application of organic fertilizers derived from human or animal feces is associated with an increased risk for environmental dissemination of antibiotic resistance. The risk depends on the quality of the organic fertilizers, which varies between geographical regions, but farmland application of sewage sludge appears to be a safe practice as shown by some studies (e.g. from Sweden). Microplastic concentrations in agricultural soils show a wide spread and our understanding of its toxicity is limited, hampering a sound risk assessment. Methods for assessing public health risks for organic contaminants must include emerging contaminants and potential interactions of multiple compounds. Evidence from long-term field experiments suggests that soils may be more resilient and capable to degrade or stabilize pollutants than often assumed. In view of the need to source nutrients for expanding areas under organic farming, we discuss inputs originating from conventional farms vs. non-agricultural (i.e. societal) inputs. Closing nutrient cycles between agriculture and society is feasible in many cases, without being compromised by contaminants, and should be enhanced, aided by improved source control, waste treatment and sound risk assessments.
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Agricultura Orgánica , Contaminantes del Suelo , Animales , Humanos , Fertilizantes/análisis , Plásticos , Agricultura/métodos , Suelo/química , Medición de Riesgo , Nutrientes , Contaminantes del Suelo/análisis , Aguas del Alcantarillado/químicaRESUMEN
OBJECTIVES: The largest epidemiologic study conducted about painful temporomandibular disorders (pTMDs) to date identified 3 clusters of individuals with similar symptoms-adaptive, pain sensitive, and global symptoms-which hold promise as a means of personalizing pain care. Our goal was to compare the clinical and psychological characteristics that are consistent with a pTMD clinical examination among patients who are seeking care and assigned to the different clusters. METHODS: This cross-sectional study used data from the medical records of patients attending Duke Innovative Pain Therapies between August 2017 and April 2021 who received a pTMD diagnosis (i.e., myalgia) and consented to have their data used for research. Data included orofacial and pain-related measures, dental features, and psychological measures. We used the Rapid OPPERA Algorithm to assign clusters to patients and multinomial regression to determine the likelihood (odds ratios [OR] and 95% confidence intervals [CI]) of being assigned to the pain sensitive or global symptoms cluster attributed to each measure. RESULTS: In total, 131 patients were included in this study and assigned a cluster: adaptive (n = 54, 41.2%), pain sensitive (n = 49, 37.4%), and global symptoms (n = 28, 21.4%). The PS cluster displayed greater numbers of temporomandibular joint sites (OR, 1.29; 95% CI, 1.01 to 1.65) and masticatory (1.48; 1.19 to 1.83) and cervical (1.23; 1.09 to 1.39) muscles with pain evoked by palpation. The GS cluster displayed greater scores of pain catastrophizing (1.04; 1.01 to 1.06) and perceived stress (1.23; 1.03 to 1.46) and was more likely to report persistent pain (16.23; 1.92 to 137.1) of higher impact (1.43; 1.14 to 1.80). CONCLUSION: Our findings support that care-seeking patients with pTMDs who are assigned to the GS cluster display a poorer psychological profile, even though those assigned to the PS cluster display more measures consistent with orofacial pain. Findings also establish the PS cluster as a group that does not display psychological comorbidities despite being hypersensitive. KNOWLEDGE TRANSFER STATEMENT: This study informs clinicians that patients seeking care for painful temporomandibular disorders, in specific cases of myalgia, can be classified into 1 of 3 groups that display unique profiles of symptoms. Most importantly, it emphasizes the importance of examining patients with painful temporomandibular disorders in a holistic manner that includes assessing symptoms of psychological distress. Patients with greater psychological distress will likely benefit from multidisciplinary treatment strategies that may include psychological treatments.
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Mialgia , Trastornos de la Articulación Temporomandibular , Humanos , Estudios Transversales , Dolor Facial/diagnóstico , Dolor Facial/epidemiología , Dolor Facial/etiología , Trastornos de la Articulación Temporomandibular/diagnóstico , Trastornos de la Articulación Temporomandibular/epidemiología , Trastornos de la Articulación Temporomandibular/psicología , Articulación TemporomandibularRESUMEN
In natural populations, hybridization is known to occur between a wide range of species. However, its evolutionary significance is less clear. Genes involved in fighting pathogens are considered excellent candidates for studying adaptive introgression, although both introgression and balancing selection can generate similar patterns of diversity and differentiation. Here, we compared DQA and DQB MHC class II and microsatellite allelic diversity of sympatric and parapatric mountain (Lepus timidus) and brown hare (L. europaeus) populations from Switzerland. We detected higher genetic diversity in brown hares compared to mountain hares at both MHC and microsatellite loci. We consider the observed patterns of microsatellite diversity both for L. europaeus and L. timidus as result of stochastic demographic processes while the pattern of MHC polymorphism of the studied hare populations can be explained by pathogen-driven selection. Rare bidirectional gene flow between both hare species seems to occur specifically for MHC alleles. However, the high number of shared alleles showing similar high frequency in both species suggests that reciprocally exchanged MHC alleles are being maintained via balancing selection. Adaptation to similar pathogen communities can also lead to parallel selection of MHC alleles. Positive selection, recombination and mutations have played different roles in shaping the patterns of MHC allelic diversity in and differentiation between both species. Results for the latter evolutionary forces do not show a better matching between the sympatric populations compared to the parapatric ones, suggesting a minor role of introgression for the observed evolutionary patterns of the studied hare species.
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Liebres , Animales , Liebres/genética , Suiza , Filogenia , Polimorfismo Genético , ExonesRESUMEN
INTRODUCTION: Given the chronic nature of psoriasis (PsO), more studies are needed that directly compare the effectiveness of different biologics over long observation periods. This study compares the effectiveness and durability through 12 months of anti-interleukin (IL)-17A biologics relative to other approved biologics in patients with moderate-to-severe psoriasis in a real-world setting. METHODS: The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of 1981 adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. The study compares the effectiveness of anti-IL-17A biologics with other approved biologics and provides pairwise comparisons of seven individual biologics versus ixekizumab. The primary outcome was defined as the proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA). Secondary objective comparisons included the proportion of patients who achieved PASI90, PASI100, a Dermatology Life Quality Index (DLQI) score of 0 or 1, and three different measures of durability of treatment response. Unadjusted response rates are presented alongside the primary analysis, which uses frequentist model averaging (FMA) to evaluate the adjusted comparative effectiveness. RESULTS: Compared to the other biologics cohort, the anti-IL-17A cohort had a higher response rate (68.0% vs. 65.1%) and significantly higher odds of achieving the primary outcome at month 12. The two cohorts had similar response rates for PASI100 (40.5% and 37.1%) and PASI90 (53.9% and 51.7%) at month 12, with no significant differences between the cohorts in the adjusted analyses. At month 12, the response rates across the individual biologics were 53.5-72.6% for the primary outcome, 27.6-48.3% for PASI100, and 41.7-61.4% for PASI90. CONCLUSIONS: These results show the comparative effectiveness of biologics at 6 and 12 months in the real-world setting.
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OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.
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Disfunción Cognitiva , Demencia , Humanos , Anciano , Disfunción Cognitiva/prevención & control , Cognición , Dieta , Estilo de Vida , Demencia/prevención & controlRESUMEN
INTRODUCTION: The COVID-19 pandemic has prompted governments internationally to consider strengthening their public health systems. To support the work of Ireland's Public Health Reform Expert Advisory Group, the Health Information and Quality Authority, an independent governmental agency, was asked to describe the lessons learnt regarding the public health response to COVID-19 internationally and the applicability of this response for future pandemic preparedness. METHODS: Semi-structured interviews with key public health representatives from nine countries were conducted. Interviews were conducted in March and April 2022 remotely via Zoom and were recorded. Notes were taken by two researchers, and a thematic analysis undertaken. RESULTS: Lessons learnt from the COVID-19 pandemic related to three main themes: 1) setting policy; 2) delivering public health interventions; and 3) providing effective communication. Real-time surveillance, evidence synthesis, and cross-sectoral collaboration were reported as essential for policy setting; it was noted that having these functions established prior to the pandemic would lead to a more efficient implementation in a health emergency. Delivering public health interventions such as testing, contact tracing, and vaccination were key to limiting and or mitigating the spread of the SARS-CoV-2 virus. However, a number of challenges were highlighted such as staff capacity and burnout, delays in vaccination procurement, and reduced delivery of regular healthcare services. Clear, consistent, and regular communication of the scientific evidence was key to engaging citizens with mitigation strategies. However, these communication strategies had to compete with an infodemic of information being circulated, particularly through social media. CONCLUSIONS: Overall, functions relating to policy setting, public health interventions, and communication are key to pandemic response. Ideally, these should be established in the preparedness phase so that they can be rapidly scaled-up during a pandemic.