Driving opposing behaviors with ensembles of piriform neurons.

Anatomic and physiologic studies have suggested a model in which neurons of the piriform cortex receive convergent input from random collections of glomeruli. In this model, odor representations can only be afforded behavioral significance upon experience. We have devised an experimental strategy that permits us to ask whether the activation of an arbitrarily chosen subpopulation of neurons in piriform cortex can elicit different behavioral responses dependent upon learning. Activation of a small subpopulation of piriform neurons expressing channelrhodopsin at multiple loci in the piriform cortex, when paired with reward or shock, elicits either appetitive or aversive behavior. Moreover, we demonstrate that different subpopulations of piriform neurons expressing ChR2 can be discriminated and independently entrained to elicit distinct behaviors. These observations demonstrate that the piriform cortex is sufficient to elicit learned behavioral outputs in the absence of sensory input. These data imply that the piriform does not use spatial order to map odorant identity or behavioral output.

Likelihood-based deconvolution of bulk gene expression data using single-cell references.

Direct comparison of bulk gene expression profiles is complicated by distinct cell type mixtures in each sample that obscure whether observed differences are actually caused by changes in the expression levels themselves or are simply a result of differing cell type compositions. Single-cell technology has made it possible to measure gene expression in individual cells, achieving higher resolution at the expense of increased noise. If carefully incorporated, such single-cell data can be used to deconvolve bulk samples to yield accurate estimates of the true cell type proportions, thus enabling one to disentangle the effects of differential expression and cell type mixtures. Here, we propose a generative model and a likelihood-based inference method that uses asymptotic statistical theory and a novel optimization procedure to perform deconvolution of bulk RNA-seq data to produce accurate cell type proportion estimates. We show the effectiveness of our method, called RNA-Sieve, across a diverse array of scenarios involving real data and discuss extensions made uniquely possible by our probabilistic framework, including a demonstration of well-calibrated confidence intervals.

Breast Cancer Surgery: A Qualitative Exploration of Concerns Over Time.

INTRODUCTION: As outcomes for breast cancer patients improve, addressing the side effects and distress of treatment can optimize survivorship. Although distress in breast cancer is well known in literature, there is a lack of information on how these concerns change through the phases of the cancer care continuum. Therefore, this study investigates the longitudinal trajectory of worry in patients with nonmetastatic breast cancer. METHODS: Female patients with newly diagnosed stage I-III breast cancer comprised a mixed-methods, longitudinal study at a cancer center from June 2019 to June 2023. Patients completed an open-ended survey regarding their top three concerns. Responses were obtained before surgery and two weeks, three, six, nine months, and one year postoperatively. Responses were qualitatively coded and analyzed to determine themes of cancer-related distress. RESULTS: Participants (n = 262) were aged an average 57.53 y (±12.54), 65.8% had stage I disease at diagnosis, and 91.1% were White. Responses revealed that patients' top three sources of concerns varied by treatment phase. Overall, patients were worried about their cancer diagnosis and the risk of recurrence. Preoperatively, patients were worried about treatment timeline, while postoperative concerns transitioned to physical appearance and surgical side effects. CONCLUSIONS: Breast cancer patients consistently reported worries about cancer diagnosis, recurrence, and metastasis as well as the side effects and fear of treatments. However, patient worry appeared to be intrinsically linked with their treatment phase. Therefore, support and interventions should be catered to reflect the changing patterns of patients' sources of distress to optimize breast cancer patients' quality of life.

Inadvertent Orbital Mitomycin C Injection as a Cause of Ptosis and Ophthalmoplegia from Orbital Necrosis.

Mitomycin C is an alkylating agent with the ability to suppress fibroblast proliferation and activity, making it a powerful antifibrotic. It has therefore become popular in glaucoma filtering surgeries, used both intraoperatively during bleb formation and postoperatively as an adjunct to bleb needling. This report presents a rare but serious risk of bleb needling with Mitomycin C at the slit lamp, where inadvertent movement of the patient resulted in an orbital injection. The patient quickly developed focal tissue inflammation and necrosis, presenting one day after the procedure with complete ptosis, ophthalmoplegia, and a palpable orbital mass. After appropriate imaging and an excisional biopsy to exclude infectious, infiltrative, and neoplastic causes, this was managed with close observation and continued improvement, and resolution of most orbital sequelae.

The Economic Burden of Heart Failure with Reduced Ejection Fraction: Living Longer but Poorer?

Treatment of heart failure with reduced ejection fraction (HFrEF) has benefitted from a proliferation of new medications and devices. These treatments carry important clinical benefits, but also come with costs relevant to payers, providers, and patients. Patient out-of-pocket costs have been implicated in the avoidance of medical care, nonadherence to medications, and the exacerbation of health care disparities. In the absence of major health care policy and payment redesign, high-quality HFrEF care delivery requires transparent integration of cost considerations into system design, patient-clinician interactions, and medical decision making.

Ocular injuries associated with motor vehicle accidents: long term effects on quality of life.

PURPOSE: To describe the prevalence and outcome of motor vehicle accidents-associated ocular injuries. METHODS: A survey of patients who presented to the emergency room at a level 1 trauma center with motor vehicle accidents-associated ocular injuries. A patient questionnaire and review of clinical notes were conducted for all patients. RESULTS: Of 274 motor vehicle accident victims with ocular injuries who presented to the emergency room, 40 (15%) responded to the survey. Over half of them were driving a vehicle, and most reported wearing a seat belt or a helmet. Most ocular injuries were mild. The most common injuries were bone fractures, subconjunctival hemorrhage, eyelid involvement and corneal injury. Most respondents had no change in vision and perceived their ocular involvement as a minor part of their injury. Most respondents returned to work and to driving within a year. CONCLUSION: Our study sheds light on the details and extent of ocular involvement and the visual ability to perform daily activities following motor vehicle accidents.

Age- and gender-specific normative data on computerized dynamic posturography in a cohort of Danish adults.

PURPOSE: Balance performance can be measured with a computerized dynamic posturography (CDP). Frequently used CDP protocols include the sensory organization test (SOT), motor control test (MCT) and adaptation test (ADT). The primary aim of this study was to produce normative data using the Bertec® Balance Advantage CDP on a cohort of healthy adults aged 20-79 years for the SOT, MCT and ADT. The secondary aim was to determine age- and gender-related differences. METHODS: The study population of 120 participants were divided into age groups of 20-29, 30-39 years, etc., with an equal number of men and women in each group. Using the Bertec® CDP, the SOT, MCT and ADT protocols were performed. RESULTS: SOT found that the 70-79 age group and men scored lower equilibrium scores (ES) on SOT4, and SOT6. Women had higher ES on SOT1. For the MCT, backward translation. latencies were higher for the 60 s and 70 s age groups. The 60 s age group had higher forward translation latencies. Women had lower latencies on all MCTs. For the ADT toes up test, the 70-79 age group scored higher sway energy. On the toes down test, higher sway energy was registered for the 50-79 age groups. Women had lower sway energy for both ADT's. CONCLUSION: We have produced normative data for healthy adults aged 20-79 years for the SOT, MCT and ADT protocols using the Bertec® Balance Advantage CDP. Balance performance differences might be due to decline in visual acuity, presbyvestibulopathy and differences in body composition.

No One-Size-Fits-All: Sexual Health Education Preferences in Patients with Breast Cancer.

BACKGROUND: Using explanatory mixed methods, we characterize the education that patients with breast cancer received about potential sexual health effects of treatment and explore preferences in format, content, and timing of education. PATIENTS AND METHODS: Adult patients with stage 0-IV breast cancer seen at an academic breast center during December 2020 were emailed questionnaires assessing sexual health symptoms experienced during treatment. Patients interested in further study involvement were invited to participate in semistructured interviews. These interviews explored sexual health education provided by the oncology team and patient preferences in content, format, and timing of education delivery. RESULTS: Eighty-seven (32%) patients completed the questionnaire. Most patients reported decreased sexual desire (69%), vaginal dryness (63%), and less energy for sexual activity (62%) during/after treatment. Sixteen patients participated in interviews. Few women reported receiving information about potential sexual effects of breast cancer treatment; patients who did reported a focus on menopausal symptoms or fertility rather than sexual function. Regarding preferences in format, patients were in favor of multiple options being offered rather than a one-size-fits-all approach, with particular emphasis on in-person options and support groups. Patients desired education early and often throughout breast cancer treatment, not only about sexual side effects but also on mitigation strategies, sexual function, dating and partner intimacy, and body image changes. CONCLUSION: Few patients received information about the sexual health effects of breast cancer treatment, though many experienced symptoms. Potential adverse effects should be discussed early and addressed often throughout treatment, with attention to strategies to prevent and alleviate symptoms and improve overall sexual health.

Conformational regulation of Escherichia coli DNA polymerase V by RecA and ATP.

Mutagenic translesion DNA polymerase V (UmuD'2C) is induced as part of the DNA damage-induced SOS response in Escherichia coli, and is subjected to multiple levels of regulation. The UmuC subunit is sequestered on the cell membrane (spatial regulation) and enters the cytosol after forming a UmuD'2C complex, ~ 45 min post-SOS induction (temporal regulation). However, DNA binding and synthesis cannot occur until pol V interacts with a RecA nucleoprotein filament (RecA*) and ATP to form a mutasome complex, pol V Mut = UmuD'2C-RecA-ATP. The location of RecA relative to UmuC determines whether pol V Mut is catalytically on or off (conformational regulation). Here, we present three interrelated experiments to address the biochemical basis of conformational regulation. We first investigate dynamic deactivation during DNA synthesis and static deactivation in the absence of DNA synthesis. Single-molecule (sm) TIRF-FRET microscopy is then used to explore multiple aspects of pol V Mut dynamics. Binding of ATP/ATPγS triggers a conformational switch that reorients RecA relative to UmuC to activate pol V Mut. This process is required for polymerase-DNA binding and synthesis. Both dynamic and static deactivation processes are governed by temperature and time, in which on → off switching is "rapid" at 37°C (~ 1 to 1.5 h), "slow" at 30°C (~ 3 to 4 h) and does not require ATP hydrolysis. Pol V Mut retains RecA in activated and deactivated states, but binding to primer-template (p/t) DNA occurs only when activated. Studies are performed with two forms of the polymerase, pol V Mut-RecA wt, and the constitutively induced and hypermutagenic pol V Mut-RecA E38K/ΔC17. We discuss conformational regulation of pol V Mut, determined from biochemical analysis in vitro, in relation to the properties of pol V Mut in RecA wild-type and SOS constitutive genetic backgrounds in vivo.

Wideband tympanometry as a diagnostic tool for Meniere's disease: a retrospective case-control study.

PURPOSE: The main purpose of this study was to investigate the usefulness of wide band tympanometry (WBT) as a diagnostic tool for Ménière's disease (MD) by comparing differences in absorbance measures between normal hearing ears and patient diagnosed with MD. METHODS: We conducted a retrospective case-control study. From a cohort of 116 patients diagnosed with Ménière disease, 52 MD patients and 99 normal hearing adults with no history of otological disease served as subjects. Wideband tympanometry was conducted using at Titan Impedance module and audiometry was performed with a MADSEN Astera2. Mean energy absorbance curves with 95% confidence intervals were computed across cases with MD and controls in the frequency range 226-8000 Hz. An overall test for difference between curves of cases and controls was calculated by multivariate analysis of variance. RESULTS: The MD group and the subpopulations of MD patients who fulfilled the International criteria for MD showed a statistically significant lower absorbance at tympanic peak pressure compared to the control group (p < 0.001). No overlap of confidence intervals between mean curves was found within the frequency range of 2000-4000 Hz. CONCLUSION: Absorbance measures obtained by WBT were able to distinguish between MD ears and normal ears within the frequency range of 2000-4000 Hz. The results indicate that WBT potentially could be a useful and simple non-invasive diagnostic tool for MD. However, more research on the association between absorbance measures and inner ear pathologies is needed.

EGGTART: A tool to visualize the dynamics of biophysical transport under the inhomogeneous l-TASEP.

The totally asymmetric simple exclusion process (TASEP), which describes the stochastic dynamics of interacting particles on a lattice, has been actively studied over the past several decades and applied to model important biological transport processes. Here, we present a software package, called EGGTART (Extensive GUI gives TASEP-realization in Real Time), which quantifies and visualizes the dynamics associated with a generalized version of the TASEP with an extended particle size and heterogeneous jump rates. This computational tool is based on analytic formulas obtained from deriving and solving the hydrodynamic limit of the process. It allows an immediate quantification of the particle density, flux, and phase diagram, as a function of a few key parameters associated with the system, which would be difficult to achieve via conventional stochastic simulations. Our software should therefore be of interest to biophysicists studying general transport processes and can in particular be used in the context of gene expression to model and quantify mRNA translation of different coding sequences.

Early Trajectories of Patient Reported Outcomes in Breast Cancer Patients Undergoing Lumpectomy Versus Mastectomy.

PURPOSE: This study was designed to: (1) characterize longitudinal patient-reported outcomes (PROs) between breast cancer patients undergoing lumpectomy and mastectomy and (2) compare return to baseline scores at 3 months and 6 months postoperatively. METHODS: Newly diagnosed breast cancer patients seen at an academic breast center between June 2019 and February 2021 were invited to participate in longitudinal PRO surveys at their initial clinic visit. If willing to participate, patients were emailed the validated BREAST-Q™ questionnaire at the initial clinic visit (baseline), 2 weeks after surgery, and then every 3 months for the first year. We used linear mixed models to estimate the differences in slopes over time between lumpectomy and mastectomy for each PRO measure. Pearson's Chi-square tests with Yates' continuity correction were used to compare proportions of patients who return to baseline PRO scores. P < 0.05 was considered significant. RESULTS: Of 164 patients invited to participate, 100 (61%) completed a baseline survey and were included in analyses. Mastectomy patients had significantly greater decreases in breast satisfaction (P = 0.002), psychosocial well-being (P < 0.0001), and sexual well-being (P < 0.0001) over time compared with lumpectomy patients. Both surgical groups reported a decrease in physical well-being, although the decline was more significant in lumpectomy patients (P = 0.005). At 3 months and 6 months after surgery, significantly larger proportions of lumpectomy patients returned to their baseline breast satisfaction, psychosocial well-being, and physical well-being compared with mastectomy patients. CONCLUSIONS: Understanding how outcomes important to patients change over the care continuum can provide opportunities for early intervention and may prevent debilitating long-term morbidities of treatment.

Diplopia Following the Insertion of a Canalicular Bypass Tube: Etiology, Risk Factors, Management, and Outcomes.

PURPOSE: To report the etiology, management, and possible risk factors for diplopia after canalicular bypass surgery. METHODS: A multicenter retrospective, noncomparative case series of patients who developed diplopia following canalicular bypass surgery were assessed. RESULTS: Twenty-four cases of diplopia were identified across 12 institutions. Tubes were inserted as a primary procedure with external dacryocystorhinostomy (DCR) (1; 4%) or without DCR (10; 42%) or as a secondary procedure after external (8; 33%) or endonasal (5; 21%) DCR. Factors predisposing to local damage were noted in 17 (71%): these factors included preexisting autoimmune/inflammatory condition (7 cases), medial canthal tumor resection (5 cases), preoperative radiotherapy (2 cases), 2 drug treatments (topical and systemic), and 1 local surgery. Horizontal diplopia was due to restriction of abduction and first noted at a median of 3.5 months (mean: 17.8 months, range: 1 day to 112 months) and persisted in 23 (96%) cases with a mean restriction of -2, affecting primary gaze in 4 patients and activities of daily living in 13 (42%). Seventeen patients received various treatments: 10 were operated on resulting in cure in 1 and improvement in 9. A stable degree of diplopia persisted in all but one patient. CONCLUSIONS: Restriction of abduction causing horizontal diplopia is a rare complication with canalicular bypass surgery and a notably high proportion occurred after tube placement without DCR; carunculectomy was not ubiquitous. Although in some the diplopia may be improved with intervention, the chance of cure is low. This complication should probably be included during informed consent for canalicular bypass tubes.

Custom Outlier Detection for Electrical Energy Consumption Data Applied in Case of Demand Response in Block of Buildings.

The aim of this paper is to provide an extended analysis of the outlier detection, using probabilistic and AI techniques, applied in a demo pilot demand response in blocks of buildings project, based on real experiments and energy data collection with detected anomalies. A numerical algorithm was created to differentiate between natural energy peaks and outliers, so as to first apply a data cleaning. Then, a calculation of the impact in the energy baseline for the demand response computation was implemented, with improved precision, as related to other referenced methods and to the original data processing. For the demo pilot project implemented in the Technical University of Cluj-Napoca block of buildings, without the energy baseline data cleaning, in some cases it was impossible to compute the established key performance indicators (peak power reduction, energy savings, cost savings, CO2 emissions reduction) or the resulted values were far much higher (>50%) and not realistic. Therefore, in real case business models, it is crucial to use outlier's removal. In the past years, both companies and academic communities pulled their efforts in generating input that consist in new abstractions, interfaces, approaches for scalability, and crowdsourcing techniques. Quantitative and qualitative methods were created with the scope of error reduction and were covered in multiple surveys and overviews to cope with outlier detection.

Incidence of non-glaucomatous ocular disease in patients with asymmetric optic disc cupping.

PURPOSE: To evaluate the incidence of non-glaucomatous ocular disease in patients with asymmetric optic disc cupping. METHODS: A retrospective case series, including consecutive patients with cup-to-disc ratio (CDR) asymmetry greater than 0.2. All patients underwent a complete neuro-ophthalmological examination, automated perimetry with the Humphrey 24-2 visual fields program. Retinal nerve fibre layer thickness was measured by optical coherence tomography (OCT). The results of neuroimaging, macular OCT and blood tests were recorded as well. Patients were assigned a diagnosis of glaucomatous optic neuropathy (GON) or non-glaucomatous disease (NGD). The main outcome measure was the rate of non-glaucomatous ocular disease. RESULTS: A total of 120 (67 males) patients with a mean age of 71.1 ± 12.5 years met the inclusion criteria and were included in this study. The mean asymmetry in CDR between the eyes was 0.3 ± 0.13 (range, 0.2-0.9). Twenty patients (16.6%) had a visual field defect not typical for glaucoma and positive relative afferent pupillary defect was found in 24 patients (20%). Six patients were found to have newly diagnosed non-glaucomatous ocular disease: maculopathy in three patients, retinopathy in one patient and traumatic optic neuropathy in two patients. Patients with NGD were significantly younger than the patients with GON (59.8 ± 23.3 vs. 71.3 ± 11.5 years, P = 0.001). Optic disc pallor was found in 4/93 patients with glaucoma compared to 3/6 with newly diagnosed non-glaucomatous disease (4.7% vs. 50.0%, P = 0.03). CONCLUSIONS: Asymmetric optic disc cupping can be associated with non-glaucomatous disease and may warrant neuro-ophthalmological evaluation, especially in younger patients or those with optic disc pallor.

Healthcare Professionals Risk Assessments for Alert Overrides in High-Risk IV Infusions Using Simulated Scenarios.

This study aimed to use healthcare professionals' assessments to calculate expected risk of intravenous (IV) infusion harm for simulated high-risk medications that exceed soft limits and to investigate the impact of relevant risk factors. We designed 30 infusion scenarios for four high-risk medications, propofol, morphine, insulin, and heparin, infused in adult intensive care unit (AICU) and adult medical and surgical care unit (AMSU). A total of 20 pharmacists and 5 nurses provided their assessed expected risk of harm in each scenario. Descriptive statistics, analysis of variance with least square mean, and post hoc test were conducted to test the effects of field limit type, soft (SoftMax), and hard maximum drug limit types (HardMax), and care area-medication combination on risk of harm. The results showed that overdosing scenarios with continuous and bolus dose limit types were assessed with significantly higher risks than those of bolus dose rate type. An overdose infusion in AICU over a large SoftMax was assessed to be of higher risk than over a small one, but not in AMSU. For overdose infusions with three levels of drug amount, greater drug amount in AICU and AMSU was assessed to have higher risk, except insignificant risk difference between the infusions with higher and moderate drug amount in AMSU. This study obtained expected risk for simulated high-risk IV infusions and found that different field limit and SoftMax types can affect expected risk based on healthcare professionals' perspectives. The findings will be regarded as benchmarks for validating risk quantification models in future research.

Characterization and proteomic profiling of pancreatic cancer-derived serum exosomes.

Pancreatic cancer (PC) is one of the most lethal cancers known worldwide, and its prognosis is poor in most patients. Exosomes are nanosized extracellular vesicles, which are released from various cell types. They are involved in cellular communication. The diagnosis and treatment of PC were improved substantially with exosomes. In this study, we isolated PC-derived exosomes and investigated their proteomic profile. Then, we conducted bioinformatic analysis on proteomic data. Differential ultracentrifugation was performed to isolate exosomes from human serum samples and four PC cell lines. Transmission electron microscopy and Western blot analysis were used to characterize the isolated exosomes. Liquid chromatography coupled with tandem mass spectrometry was conducted to identify the proteome of serum exosomes. Proteomic analysis demonstrated that all the serum exosomes were derived from three cohorts of human subjects; these serum exosomes contained a total of 655 proteins, out of which 315 proteins overlapped with ExoCarta database. Gene oncology and kyoto encyclopedia of genes and genomes analyses provided the functional annotation of the proteome. Interestingly, 18 or 14 proteins were upregulated and 11 or 14 proteins were downregulated in serum exosomes derived from patients with PC as compared with in serum exosomes derived from healthy volunteers or from pancreatitis patients respectively. Annexin A11, a calcium-dependent phospholipid-binding protein, was expressed in a PC cell line (CFPAC-1)-derived exosomes and in tumor tissues of patients with PC, respectively. Our data provided a basic foundation for further studies on the protein composition of PC-derived exosomes and its involvement in PC biology.

Use of Transition Models to Design High Performance TESs for the LCLS-II Soft X-Ray Spectrometer.

We are designing an array of transition-edge sensor (TES) microcalorimeters for a soft X-ray spectrometer at the Linac Coherent Light Source at SLAC National Accelerator Laboratory to coincide with upgrades to the free electron laser facility. The complete spectrometer will have 1000 TES pixels with energy resolution of 0.5 eV full-width at half-maximum (FWHM) for incident energies below 1 keV while maintaining pulse decay-time constants shorter than 100 µs. Historically, TES pixels have often been designed for a particular scientific application via a combination of simple scaling relations and trial-and-error experimentation with device geometry. We have improved upon this process by using our understanding of transition physics to guide TES design. Using the two-fluid approximation of the phase-slip line model for TES resistance, we determine how the geometry and critical temperature of a TES will affect the shape of the transition. We have used these techniques to design sensors with a critical temperature of 55 mK. The best sensors achieve an energy resolution of 0.75 eV FWHM at 1.25 keV. Building upon this result, we show how the next generation of sensors can be designed to reach our goal of 0.5 eV resolution.

[OPHTHALMOLOGY - FACING THE FUTURE].

INTRODUCTION: This special issue of HaRefuah is dedicated to Ophthalmology facing the future. This dynamic and forever innovative field of medicine is in a constant state of development in all its sub-specialties. In ophthalmology we often witness immediate rewarding results of treatment and surgery, having a huge impact on one of the most important senses, namely improving sight, stopping deterioration and preventing blindness. We are inviting the readers for an overview of some of the research and special cases, as well as some reviews of the hottest topics in ophthalmology.