Visual Information Is Predictively Encoded in Occipital Alpha/Low-Beta Oscillations.

Hierarchical predictive coding networks are a general model of sensory processing in the brain. Under neural delays, these networks have been suggested to naturally generate oscillatory activity in approximately the α frequency range (∼8-12 Hz). This suggests that α oscillations, a prominent feature of EEG recordings, may be a spectral "fingerprint" of predictive sensory processing. Here, we probed this possibility by investigating whether oscillations over the visual cortex predictively encode visual information. Specifically, we examined whether their power carries information about the position of a moving stimulus, in a temporally predictive fashion. In two experiments (N = 32, 18 female; N = 34, 17 female), participants viewed an apparent-motion stimulus moving along a circular path while EEG was recorded. To investigate the encoding of stimulus-position information, we developed a method of deriving probabilistic spatial maps from oscillatory power estimates. With this method, we demonstrate that it is possible to reconstruct the trajectory of a moving stimulus from α/low-ß oscillations, tracking its position even across unexpected motion reversals. We also show that future position representations are activated in the absence of direct visual input, demonstrating that temporally predictive mechanisms manifest in α/ß band oscillations. In a second experiment, we replicate these findings and show that the encoding of information in this range is not driven by visual entrainment. By demonstrating that occipital α/ß oscillations carry stimulus-related information, in a temporally predictive fashion, we provide empirical evidence of these rhythms as a spectral "fingerprint" of hierarchical predictive processing in the human visual system.SIGNIFICANCE STATEMENT "Hierarchical predictive coding" is a general model of sensory information processing in the brain. When in silico predictive coding models are constrained by neural transmission delays, their activity naturally oscillates in roughly the α range (∼8-12 Hz). Using time-resolved EEG decoding, we show that neural rhythms in this approximate range (α/low-ß) over the human visual cortex predictively encode the position of a moving stimulus. From the amplitude of these oscillations, we are able to reconstruct the stimulus' trajectory, revealing signatures of temporally predictive processing. This provides direct neural evidence linking occipital α/ß rhythms to predictive visual processing, supporting the emerging view of such oscillations as a potential spectral "fingerprint" of hierarchical predictive processing in the human visual system.

Excitation and Inhibition Delays within a Feedforward Inhibitory Pathway Modulate Cerebellar Purkinje Cell Output in Mice.

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell (GC) layer, and the output stage, the Purkinje cells (PCs). Although in other brain areas FFI underlies a precise excitation versus inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at GC-molecular layer interneuron (MLI)-PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined ex vivo patch-clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that although light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PC temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.SIGNIFICANCE STATEMENT Sensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability controls how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

Understanding attosecond streaking.

This tutorial provides an overview on the theory of attosecond streaking, a pump-probe scheme to extract timing information of ionization processes that has been widely used in the past decade. Emphasis is put on the origin of the Coulomb-laser-coupling (CLC) term, which is crucial in the interpretation of streaking delays. Having gained a proper understanding of how the CLC terms in various publications relate to each other, we will be able to analyze in which regime the streaking delay can be split into a measurement-induced CLC term and a 'pure' ionization delay and under which conditions this splitting may break down. Thus we address the long-standing question of the validity of the widely applied interpretation of the streaking delay as a sum of the CLC term and a 'pure' ionization delay.

TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.

Transportin-2 (TNPO2) mediates multiple pathways including non-classical nucleocytoplasmic shuttling of >60 cargoes, such as developmental and neuronal proteins. We identified 15 individuals carrying de novo coding variants in TNPO2 who presented with global developmental delay (GDD), dysmorphic features, ophthalmologic abnormalities, and neurological features. To assess the nature of these variants, functional studies were performed in Drosophila. We found that fly dTnpo (orthologous to TNPO2) is expressed in a subset of neurons. dTnpo is critical for neuronal maintenance and function as downregulating dTnpo in mature neurons using RNAi disrupts neuronal activity and survival. Altering the activity and expression of dTnpo using mutant alleles or RNAi causes developmental defects, including eye and wing deformities and lethality. These effects are dosage dependent as more severe phenotypes are associated with stronger dTnpo loss. Interestingly, similar phenotypes are observed with dTnpo upregulation and ectopic expression of TNPO2, showing that loss and gain of Transportin activity causes developmental defects. Further, proband-associated variants can cause more or less severe developmental abnormalities compared to wild-type TNPO2 when ectopically expressed. The impact of the variants tested seems to correlate with their position within the protein. Specifically, those that fall within the RAN binding domain cause more severe toxicity and those in the acidic loop are less toxic. Variants within the cargo binding domain show tissue-dependent effects. In summary, dTnpo is an essential gene in flies during development and in neurons. Further, proband-associated de novo variants within TNPO2 disrupt the function of the encoded protein. Hence, TNPO2 variants are causative for neurodevelopmental abnormalities.

Zika virus infection leads to hormone deficiencies of the hypothalamic-pituitary-gonadal axis and diminished fertility in mice.

IMPORTANCE: Zika virus (ZIKV) infection in pregnant women during the third trimester can cause neurodevelopmental delays and cryptorchidism in children without microcephaly. However, the consequences of congenital ZIKV infection on fertility in these children remain unclear. Here, using an immunocompetent mouse model, we reveal that congenital ZIKV infection can cause hormonal disorders of the hypothalamic-pituitary-gonadal axis, leading to reduced fertility and decreased sexual preference. Our study has for the first time linked the hypothalamus to the reproductive system and social behaviors after ZIKV infection. Although the extent to which these observations in mice translate to humans remains unclear, these findings did suggest that the reproductive health and hormone levels of ZIKV-exposed children should receive more attention to improve their living quality.

Nativity differences in socioeconomic barriers and healthcare delays among cancer survivors in the All of Us cohort.

PURPOSE: We aimed to assess whether nativity differences in socioeconomic (SES) barriers and health literacy were associated with healthcare delays among US cancer survivors. METHODS: "All of Us" survey data were analyzed among adult participants ever diagnosed with cancer. A binary measure of healthcare delay (1+ delays versus no delays) was created. Health literacy was assessed using the Brief Health Literacy Screen. A composite measure of SES barriers (education, employment, housing, income, and insurance statuses) was created as 0, 1, 2, or 3+. Multivariable logistic regression model tested the associations of (1) SES barriers and health literacy with healthcare delays, and (2) whether nativity modified this relationship. RESULTS: Median participant age was 64 years (n = 10,020), with 8% foreign-born and 18% ethnic minorities. Compared to survivors with no SES barriers, those with 3+ had higher likelihood of experiencing healthcare delays (OR 2.18, 95% CI 1.84, 2.58). For every additional barrier, the odds of healthcare delays were greater among foreign-born (1.72, 1.43, 2.08) than US-born (1.27, 1.21, 1.34). For every 1-unit increase in health literacy among US-born, the odds of healthcare delay decreased by 9% (0.91, 0.89, 0.94). CONCLUSION: We found that SES barriers to healthcare delays have a greater impact among foreign-born than US-born cancer survivors. Higher health literacy may mitigate healthcare delays among US cancer survivors. Healthcare providers, systems and policymakers should assess and address social determinants of health and promote health literacy as a way to minimize healthcare delays among both foreign- and US-born cancer survivors.

Association of Race, Ethnicity, Language, and Insurance with Time to Treatment Initiation Among Women with Breast Cancer at an Urban, Academic, Safety-Net Hospital.

INTRODUCTION: Initial treatment for nonmetastatic breast cancer is resection or neoadjuvant systemic therapy, depending on tumor biology and patient factors. Delays in treatment have been shown to impact survival and quality of life. Little has been published on the performance of safety-net hospitals in delivering timely care for all patients. METHODS: We conducted a retrospective study of patients with invasive ductal or lobular breast cancer, diagnosed and treated between 2009 and 2019 at an academic, safety-net hospital. Time to treatment initiation was calculated for all patients. Consistent with a recently published Committee on Cancer timeliness metric, a treatment delay was defined as time from tissue diagnosis to treatment of greater than 60 days. RESULTS: A total of 799 eligible women with stage 1-3 breast cancer met study criteria. Median age was 60 years, 55.7% were non-white, 35.5% were non-English-speaking, 18.9% were Hispanic, and 49.4% were Medicaid/uninsured. Median time to treatment was 41 days (IQR 27-56 days), while 81.1% of patients initiated treatment within 60 days. The frequency of treatment delays did not vary by race, ethnicity, insurance, or language. Diagnosis year was inversely associated with the occurrence of a treatment delay (OR: 0.944, 95% CI 0.893-0.997, p value: 0.039). CONCLUSION: At our institution, race, ethnicity, insurance, and language were not associated with treatment delay. Additional research is needed to determine how our safety-net hospital delivered timely care to all patients with breast cancer, as reducing delays in care may be one mechanism by which health systems can mitigate disparities in the treatment of breast cancer.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Reduced healthcare access contributes to delay of care in endometrial cancer.

OBJECTIVE: We aimed to characterize delays to care in patients with endometrioid endometrial cancer and the role healthcare access plays in these delays. METHODS: A chart review was performed of patients with endometrioid endometrial cancer who presented with postmenopausal bleeding at a diverse, urban medical center between 2006 and 2018. The time from symptom onset to treatment was abstracted from the medical record. This interval was subdivided to assess for delay to presentation, delay to diagnosis, and delay to treatment. RESULTS: We identified 484 patients who met the inclusion criteria. The median time from symptom onset to treatment was 4 months with an interquartile range of 2 to 8 months. Most patients had stage I disease at diagnosis (88.6%). There was no significant difference in race/ethnicity or disease stage at time of diagnosis between different groups. Patients who had not seen a primary care physician or general obstetrician-gynecologist in the year before symptom onset were more likely to have significantly delayed care (27.7% vs 14.3%, p = 0.02) and extrauterine disease (20.2% vs 4.9%, p < 0.01) compared to those with established care. Black and Hispanic patients were more likely to experience significant delays from initial biopsy to diagnosis. CONCLUSIONS: Delays exist in the evaluation of endometrial cancer. This delay is most pronounced in patients without an established outpatient primary care provider or obstetrician-gynecologist.

Reducing maternal mortality in low- and middle-income countries: the Nepalese approach of helicopter retrieval.

Ninety-four percent of global maternal deaths occur in low- and middle-income countries (LMICs). The UN has a goal of reducing maternal deaths to <70 per 100,000 live births by 2030, but progress is minimal. Maternal deaths in LMICs are associated with 3 delays in the care of women with obstetrical emergencies: 1) in the family of the woman realizing that her life is at risk, 2) in the transport of the woman to a hospital, and 3) in providing care after arrival at the hospital. These 3 delays function like links in a chain, and failure of any link leads to maternal death. LMICs have characteristics that make it likely that the chain will break. Women in LMICs frequently have low standing, and cultural beliefs often lead to delay in the recognition of obstetrical emergencies. LMICs are characterized by poor roads and long distances to hospitals leading to transport delays. Cultural and other factors also lead to treatment delays when a woman reaches a suitably-equipped and staffed hospital. Nepal has addressed these delays and reduced maternal mortality. Firstly, we have reported in the Journal the use of culturally acceptable approaches to improving the knowledge about antenatal care in remote villages. In the case of Nepal, singing songs related to maternal care proved to be a highly effective strategy. We now report that the government of Nepal has repurposed military helicopters to overcome the tyranny of poor roads to allow rapid transport of women with obstetrical emergencies to a small number of fully-equipped and staffed hospitals. As of June 2023, this service has successfully retrieved 625 women in four and half years. The Nepalese government has included questions on maternal mortality in the 2021 national census, followed by a verbal autopsy. These data indicate a fall in the maternal mortality ratio from 239 in 2016 to 151 in 2021. The efficiency of the triage service continues to improve, suggesting that maternal mortality will continue to fall. This may provide a model that can be implemented in other LMICs and highlights factors that may be responsible for recent increases in the US maternal mortality ratio.

Sex-Based Analysis of Treatment, Time Metrics, and Outcomes in Acute Ischemic Stroke Patients Treated in the Netherlands.

INTRODUCTION: Sex disparities in stroke treatment have gained increasing interest, especially since women have worse post-stroke functional outcomes compared with men. Existing studies provide conflicting evidence, with some indicating women have longer delays and less often receive acute treatment, whereas others show no differences between men and women. We aimed to explore sex differences in acute treatment modalities and time metrics of patients with acute ischemic stroke (AIS) in a real-world setting. Second, we examined whether functional outcomes differed by sex and whether this was influenced by treatment timing. METHODS: We analyzed data from the Dutch Acute Stroke Audit, a prospective consecutive registry of AIS patients from 72 hospitals in the Netherlands, between 2017 and 2020. We captured data on type of treatment administered (intravenous thrombolysis [IVT] and endovascular thrombectomy [EVT]), time metrics (onset-to-door time [OTDT], door-to-needle and door-to-groin times), and functional outcomes at 3 months (modified Rankin scale [mRS]). The association between sex and poor outcome (mRS 3-6) was assessed with Cox proportional hazard models stratified by type of treatment and adjusted for age, additionally for National Institutes of Health Stroke Scale (NIHSS) and OTDT. RESULTS: Of the 58,632 patients, 26,941 (46%) were women. Compared with men, women were older (mean age 74.6 vs. 71.0, p < 0.001) and presented with slightly higher NIHSS scores (median 3 [IQR 2-7] vs. 3 [IQR 1-6], p < 0.001). Treatment modalities distribution (no treatment, IVT, EVT) was similar between women and men (64; 29; 10 vs. 63; 30; 9%, p = 0.16). Women had a slightly longer OTDT (median 145 vs. 139 min, p < 0.01). Women had increased odds of poor outcomes (OR 1.49 [95% CI: 1.43-1.56]). This was still statistically significant after adjusting for age and NIHSS score (OR 1.22 [95% CI: 1.16-1.28]). Neither treatment modality nor OTDT had an additional influence on this association. CONCLUSION: In this large real-world registry, we observed no differences in distribution of treatment modalities between sexes. We did find a minor pre-hospital delay in women and worse functional outcomes in women. The minor delay in OTDT does not fully explain the observed worse outcomes in women. Our results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Dutch centers.

High all-cause mortality and increasing proportion of older adults with tuberculosis in Texas, 2008-2020.

Pulmonary tuberculosis (PTB) elimination efforts must consider the global growth of the ageing population. Here we used TB surveillance data from Texas, United States (2008-2020; total n = 10656) to identify unique characteristics and outcomes in older adults (OA, ≥65 years) with PTB, compared to young adults (YA, 18-39 years) or middle-aged adults (40-64 years). We found that the proportion of OA with PTB increased from 15% in 2008 to 24% in 2020 (trend p < 0.05). Diabetes was highly prevalent in OA (32%) but not associated with adverse outcomes. Death was 13-fold higher in OA compared to YA and was 7% at the time of diagnosis which suggests diagnostic delays. However, once TB was suspected, we found no differences in culture, smear, or nucleic acid detection of mycobacteria (although less lung cavitations) in OA. During treatment, OA had less drug-resistant TB, few adverse reactions and adhered with TB treatment. We recommend training healthcare workers to 'think TB' in OA, for prompt treatment initiation to diminish deaths. Furthermore, OA should be added as a priority group to the latent TB treatment guidelines by the World Health Organization, to prevent TB disease in this highly vulnerable group.

Neurodevelopmental profile of infants and toddlers awaiting a kidney transplant.

BACKGROUND: Infants and toddlers with kidney failure are susceptible to neurodevelopmental delays due to medical comorbidities and rapid brain development in early childhood. However, research on the neuropsychological development of this patient population has been limited over the past 10 years. METHODS: We performed a retrospective study to evaluate the neurodevelopmental functioning of infants/toddlers with kidney failure who completed the Bayley Scales of Infant and Toddler Development (3rd and 4th Edition) as part of a pretransplant evaluation between 2010 and 2022 (n = 23; Mage = 18 months, SD = 8.53; 16 males) using t-tests, linear model, and Pearson correlations. RESULTS: Mean Bayley scores of participants were below normative means for cognition (M = 86.74, 95% CI = 80.53-92.94, p < 0.001), language (M = 79.20, 95% CI = 73.32-85.08, p < 0.001), and motor (M = 78.00, 95% CI = 70.15-85.85, p < 0.001) domains. After adjusting for prematurity and epilepsy, patients on dialysis had significantly lower cognitive (78.7 vs. 93.8; p = 0.001) and motor scores (67.1 vs. 85.5; p = 0.01) compared to no dialysis. Pretransplant cognitive scores were positively correlated with posttransplant Full-Scale IQ (r(8) = 0.65 p = 0.04), verbal comprehension (r(8) = 0.75 p = 0.02), and fluid reasoning (r(7) = 0.68 p = 0.045). Similarly, pretransplant language scores were positively correlated with posttransplant Full-Scale IQ (r(7) = 0.74 p = 0.03) and verbal comprehension (r(7) = 0.73 p = 0.03). Of the 16 participants who reached age > 5 years during the study period, seven were diagnosed with a neurodevelopmental disorder, including three with autism spectrum disorder. CONCLUSIONS: Infants and toddlers with kidney failure are at risk of developmental delays and later neurodevelopmental disorders. Dialysis is associated with cognitive and motor delays independent of prematurity and epilepsy.

Multiple Reaction Monitoring-Mass Spectrometry Enables Robust Quantitation of Plasma Proteins Regardless of Whole Blood Processing Delays That May Occur in the Clinic.

Plasma is an important biofluid for clinical research and diagnostics. In the clinic, unpredictable delays-from minutes to hours-between blood collection and plasma generation are often unavoidable. These delays can potentially lead to protein degradation and modification and might considerably affect intact protein measurement methods such as sandwich enzyme-linked immunosorbent assays that bind proteins on two epitopes to increase specificity, thus requiring largely intact protein structures. Here, we investigated, using multiple reaction monitoring mass spectrometry (MRM-MS), how delays in plasma processing affect peptide-centric "bottom-up" proteomics. We used validated assays for proteotypic peptide surrogates of 270 human proteins to analyze plasma generated after whole blood had been kept at room temperature from 0 to 40 h to mimic delays that occur in the clinic. Moreover, we evaluated the impact of different plasma-thawing conditions on MRM-based plasma protein quantitation. We demonstrate that >90% of protein concentration measurements were unaffected by the thawing procedure and by up to 40-h delayed plasma generation, reflected by relative standard deviations (RSDs) of <30%. Of the 159 MRM assays that yielded quantitative results in 60% of the measured time points, 139 enabled a stable protein quantitation (RSD <20%), 14 showed a slight variation (RSD 20-30%), and 6 appeared unstable/irreproducible (RSD > 30%). These results demonstrate the high robustness and thus the potential for MRM-based plasma-protein quantitation to be used in a clinical setting. In contrast to enzyme-linked immunosorbent assay, peptide-based MRM assays do not require intact three-dimensional protein structures for an accurate and precise quantitation of protein concentrations in the original sample.

Transmission dynamics of a reaction-advection-diffusion dengue fever model with seasonal developmental durations and intrinsic incubation periods.

In this paper, we propose a reaction-advection-diffusion dengue fever model with seasonal developmental durations and intrinsic incubation periods. Firstly, we establish the well-posedness of the model. Secondly, we define the basic reproduction number ℜ 0 for this model and show that ℜ 0 is a threshold parameter: if ℜ 0 < 1 , then the disease-free periodic solution is globally attractive; if ℜ 0 > 1 , the system is uniformly persistent. Thirdly, we study the global attractivity of the positive steady state when the spatial environment is homogeneous and the advection of mosquitoes is ignored. As an example, we use the model to investigate the dengue fever transmission case in Guangdong Province, China, and explore the impact of model parameters on ℜ 0 . Our findings indicate that ignoring seasonality may underestimate ℜ 0 . Additionally, the spatial heterogeneity of transmission may increase the risk of disease transmission, while the increase of seasonal developmental durations, intrinsic incubation periods and advection rates can all reduce the risk of disease transmission.

Dynamical analysis of a general delayed HBV infection model with capsids and adaptive immune response in presence of exposed infected hepatocytes.

The aim of this paper is to develop and investigate a novel mathematical model of the dynamical behaviors of chronic hepatitis B virus infection. The model includes exposed infected hepatocytes, intracellular HBV DNA-containing capsids, uses a general incidence function for viral infection covering a variety of special cases available in the literature, and describes the interaction of cytotoxic T lymphocytes that kill the infected hepatocytes and the magnitude of B-cells that send antibody immune defense to neutralize free virions. Further, one time delay is incorporated to account for actual capsids production. The other time delays are used to account for maturation of capsids and free viruses. We start with the analysis of the proposed model by establishing the local and global existence, uniqueness, non-negativity and boundedness of solutions. After defined the threshold parameters, we discuss the stability properties of all possible steady state constants by using the crafty Lyapunov functionals, the LaSalle's invariance principle and linearization methods. The impacts of the three time delays on the HBV infection transmission are discussed through local and global sensitivity analysis of the basic reproduction number and of the classes of infected states. Finally, an application is provided and numerical simulations are performed to illustrate and interpret the theoretical results obtained. It is suggested that, a good strategy to eradicate or to control HBV infection within a host should concentrate on any drugs that may prolong the values of the three delays.

Living with axial spondyloarthritis: a cross-sectional survey of patient knowledge and perceptions.

Diagnosis and effective treatment of axial spondyloarthritis (AxSpA) are often delayed due to inadequate awareness and poor patient-physician communication. Some AxSpA patients fail to maintain an active lifestyle by exercising regularly, further worsening their disease management. The evolving concept of patient-centred care necessitates better understanding of patient awareness and their needs. We aimed to survey AxSpA patients to reflect on healthcare planning and management perspectives. Our self-administered questionnaire focused on perceptions of AxSpA diagnosis and management, particularly exploring issues of physical activity and active lifestyle. Satisfaction with AxSpA medical care and its accessibility, diagnostic delays, patient-physician communication, and support for disease management were also explored. This offline survey was arranged at the Department of Rheumatology, Immunology, and Internal Medicine of Jagiellonian University Medical College and Krakow University Hospital. We surveyed patients with AxSpA attending outpatient clinics between December 1st, 2023 and April 22nd, 2024. The questionnaire included questions on types of physical activities, barriers to exercising, satisfaction with medical care, patient-physician interactions, diagnostic delays, and use of teleconsultations. A total of 117 patients with AxSpA were enrolled (mean age 41.62 years). The majority (n = 93, 79.5%) were employed. There was a male predominance (69, 59%). The average diagnostic delay was 5.5 years. Notably, 104 (88.9%) responders perceived physical activity as a factor influencing their disease course. However, only 32 (27.35%) managed to exercise regularly (≥ 30 min, 2-3 times a week). The majority (70, 59.83%) were irregularly engaged in some form of physical activity, with 15 (12.8%) not exercising at all, and nearly half (48%) reported at least one barrier to maintaining a physically active lifestyle. Pain (32, 27.35%), fatigue (27, 23.08%), lack of motivation (17, 14.53%), and lack of time (12, 10.26%) were noted as barriers to exercising. The respondents preferred to exercise at home. The survey identified critical areas where patient dissatisfaction or uncertainty were notably prevalent: 38 (32.5%) were uncertain and 35 (30%) were dissatisfied with rehabilitation access. For spa therapy, 63 (53.85%) reported uncertainty and 23 (19.7%) expressed dissatisfaction. Only 48 (41%) were treated by a rehabilitation specialist last year. Only 23% of AxSpA patients took part in teleconsultations last year, and 65% preferred in-person visits. While AxSpA patients recognize the importance of physical activity, significant barriers exist to engaging them regularly in exercising. Addressing these barriers through personalized, motivational, and educational strategies could improve patient outcomes. Improving patient satisfaction with healthcare services, particularly in areas of rehabilitation and physician-patient communication, is crucial for improving the overall care of AxSpA patients.

Knowledge, attitude, and practices of parents regarding the red flags of developmental milestones in children aged 0-5 years in Karachi, Pakistan: a cross-sectional study.

BACKGROUND: Developmental delays in children are assessed in four basic domains: gross motor, fine motor, social, and language. Early years of life are crucial in a child's development, so it is imperative that parents be aware of developmental milestones to facilitate early diagnosis and treatment in case of a developmental delay. This study assessed parental knowledge, attitude, and practices regarding children's developmental milestones and associated "red flags". METHODS: A cross-sectional study was conducted at the Department of Pediatrics at Liaquat National Hospital, Karachi. 390 parents, who had at least one child under 5 years of age, with no diagnosed developmental delay, were interviewed during outpatient clinic visits. The questionnaire consisted of three components to assess parental knowledge, attitude, and practices. RESULTS: 59% and 54% of parents had poor knowledge of gross and fine motor milestones respectively; In the social domain, 56% of the respondents had inadequate knowledge. 42% had inadequate knowledge of language milestones; 29% of parents strongly agreed that their pediatricians provide satisfactory information regarding red flags of developmental milestones. 60% of parents strongly agreed that their child's developmental delay would be a cause of concern for them. In the case of developmental delay, 55% of parents said they would consult a general pediatrician, 11% preferred a pediatric neurologist, 21% opted for a developmental pediatrician and 13% opted for a family physician. Residence and family systems were found to be associated with language-related milestones with significantly higher odds of knowledge among urban residents than rural ones and a significantly lower likelihood of language milestones knowledge among joint families than nuclear families. Female gender was found to be significantly associated with positive attitude. CONCLUSION: The majority of our respondents showed considerably poor knowledge regarding developmental milestones. This highlights the need to devise ways to educate parents on this subject to enable them to vigilantly monitor their child's developmental status and any associated abnormalities and ultimately facilitate the right course of action.

Prevalence and socio-economic determinants of growth and developmental delays among Iranian children aged under five years: A cross sectional study.

BACKGROUND: The main cause of growth and development delays remains unknown, but it can occur as an interaction between genetic, environmental, and socio-economic factors. OBJECTIVE: The aim of the study was to investigate the prevalence and social determinants of growth and developmental delays among children aged under five years in Qazvin, Iran. METHODS: A cross-sectional study was conducted between January 2019 to December 2020 with participation of 1800 mothers with children aged 4-60 months who were referred to comprehensive health centers in Qazvin city, Iran. Structural and intermediate social determinants of health were assessed including: parents and children socio-demographic characteristics, families' living and economic status, parents' behavioral factors, household food security, mother's general health, and perceived social support. Children's growth was assessed based on their anthropometric assessment and their development was assessed using their age-specific Ages and Stages Questionnaire. Data were analyzed using univariable and multivariable logistic regression models using SPSS software version 24 and Stata version 14. RESULTS: The prevalence of developmental problems in each domain were 4.28% for personal and social delay, 5.72% for gross motor delay, 6.5% for communication delay, 6.72% for fine motor delay, and 8% for problem-solving delay. The prevalence of weight growth delays was 13.56% and height growth delays was 4.66%. Communication, gross motor, and problem-solving delays were higher among children whose fathers' smoked cigarettes. Fine motor delays were lower among mothers with education status of high school diploma and university degree vs. the under diploma group. Personal and social delay was significantly higher among families with fair economic status and lower among children when their fathers were employed (vs. unemployed). Weight and height growth delays were higher among mothers who had experienced pregnancy complications and household food insecure families, respectively. CONCLUSION: There are different predictors of growth and developmental delay problems among Iranian children aged under five years including fathers' smoking, families' economic status, and household food insecurity as well as history of mothers' pregnancy complications. The present study's findings can be used to screen for at-risk of growth and developmental delays among children and could help in designing and implementation of timely interventions.