Data-Driven Approach to Modeling Microfabricated Chemical Sensor Manufacturing.

We have developed a statistical model-based approach to the quality analysis (QA) and quality control (QC) of a gas micro pre-concentrator chip (µPC) performance when manufactured at scale for chemical and biochemical analysis of volatile organic compounds (VOCs). To test the proposed model, a medium-sized university-led production batch of 30 wafers of chips were subjected to rigorous chemical performance testing. We quantitatively report the outcomes of each manufacturing process step leading to the final functional chemical sensor chip. We implemented a principal component analysis (PCA) model to score individual chip chemical performance, and we observed that the first two principal components represent 74.28% of chemical testing variance with 111 of 118 viable chips falling into the 95% confidence interval. Chemical performance scores and chip manufacturing data were analyzed using a multivariate regression model to determine the most influential manufacturing parameters and steps. In our analysis, we find the amount of sorbent mass present in the chip (variable importance score = 2.6) and heater and the RTD resistance values (variable importance score = 1.1) to be the manufacturing parameters with the greatest impact on chemical performance. Other non-obvious latent manufacturing parameters also had quantified influence. Statistical distributions for each manufacturing step will allow future large-scale production runs to be statistically sampled during production to perform QA/QC in a real-time environment. We report this study as the first data-driven, model-based production of a microfabricated chemical sensor.

A Metabolomics Assay to Diagnose Citrus Huanglongbing Disease and to Aid in Assessment of Treatments to Prevent or Cure Infection.

Citrus greening disease, or Huanglongbing (HLB), has devastated citrus crops globally in recent years. The causal bacterium, 'Candidatus Liberibacter asiaticus', presents a sampling issue for qPCR diagnostics and results in a high false negative rate. In this work, we compared six metabolomics assays to identify HLB-infected citrus trees from leaf tissue extracted from 30 control and 30 HLB-infected trees. A liquid chromatography-mass spectrometry-based assay was most accurate. A final partial least squares-discriminant analysis (PLS-DA) model was trained and validated on 690 leaf samples with corresponding qPCR measures from three citrus varieties (Rio Red grapefruit, Hamlin sweet orange, and Valencia sweet orange) from orchards in Florida and Texas. Trees were naturally infected with HLB transmitted by the insect vector Diaphorina citri. In a randomized validation set, the assay was 99.9% accurate to classify diseased from nondiseased samples. This model was applied to samples from trees receiving plant defense-inducer compounds or biological treatments to prevent or cure HLB infection. From two trials, HLB-related metabolite abundances and PLS-DA scores were tracked longitudinally and compared with those of control trees. We demonstrate how our assay can assess tree health and the efficacy of HLB treatments and conclude that no trialed treatment was efficacious.

Identification of skeletal remains in Croatia and Bosnia and Herzegovina, including the homeland war - a 30-year review.

Over the past 30 years, forensic experts from Croatia and Bosnia and Herzegovina have embraced advanced technologies and innovations to enable great efficacy and proficiency in the identification of war victims. The wartime events in the countries of former Yugoslavia greatly influenced the application of the selected DNA analyses as routine tools for the identification of skeletal remains, especially those from mass graves. Initially, the work was challenging because of the magnitude of the events, technical aspects, and political aspects. Collaboration with reputable foreign forensic experts helped tremendously in the efforts to start applying DNA analysis routinely and with increasing success. In this article, we reviewed the most significant achievements related to the application of DNA analysis in identifying skeletal remains in situations where standard identification methods were insufficient.

Cardiovascular outcomes among patients with castration-resistant prostate cancer: A comparative safety study using US administrative claims data.

BACKGROUND: Cardiovascular conditions are the most prevalent comorbidity among patients with prostate cancer, regardless of treatment. Additionally, cardiovascular risk has been shown to increase following exposure to certain treatments for advanced prostate cancer. There is conflicting evidence on risk of overall and specific cardiovascular outcomes among men treated for metastatic castrate resistant prostate cancer (CRPC). We, therefore, sought to compare incidence of serious cardiovascular events among CRPC patients treated with abiraterone acetate plus predniso(lo)ne (AAP) and enzalutamide (ENZ), the two most widely used CRPC therapies. METHODS: Using US administrative claims data, we selected CRPC patients newly exposed to either treatment after August 31, 2012, with prior androgen deprivation therapy (ADT). We assessed incidence of hospitalization for heart failure (HHF), ischemic stroke, and acute myocardial infarction (AMI) during the period 30-days after AAP or ENZ initiation to discontinuation, outcome occurrence, death, or disenrollment. We matched treatment groups on propensity-scores (PSs) to control for observed confounding to estimate the average treatment effect among the treated (AAP) using conditional Cox proportional hazards models. To account for residual bias, we calibrated our estimates against a distribution of effect estimates from 124 negative-control outcomes. RESULTS: The HHF analysis included 2322 (45.1%) AAP initiators and 2827 (54.9%) ENZ initiators. In this analysis, the median follow-up times among AAP and ENZ initiators (after PS matching) were 144 and 122 days, respectively. The empirically calibrated hazard ratio (HR) estimate for HHF was 2.56 (95% confidence interval [CI]: 1.32, 4.94). Corresponding HRs for AMI and ischemic stroke were 1.94 (95% CI: 0.90, 4.18) and 1.25 (95% CI: 0.54, 2.85), respectively. CONCLUSIONS: Our study sought to quantify risk of HHF, AMI and ischemic stroke among CRPC patients initiating AAP relative to ENZ within a national administrative claims database. Increased risk for HHF among AAP compared to ENZ users was observed. The difference in myocardial infarction did not attain statistical significance after controlling for residual bias, and no differences were noted in ischemic stroke between the two treatments. These findings confirm labeled warnings and precautions for AAP for HHF and contribute to the comparative real-world evidence on AAP relative to ENZ.

Time to treatment and mortality for clinical sepsis subtypes.

BACKGROUND: Sepsis is common, deadly, and heterogenous. Prior analyses of patients with sepsis and septic shock in New York State showed a risk-adjusted association between more rapid antibiotic administration and bundled care completion, but not an intravenous fluid bolus, with reduced in-hospital mortality. However, it is unknown if clinically identifiable sepsis subtypes modify these associations. METHODS: Secondary analysis of patients with sepsis and septic shock enrolled in the New York State Department of Health cohort from January 1, 2015 to December 31, 2016. Patients were classified as clinical sepsis subtypes (α, ß, γ, δ-types) using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Exposure variables included time to 3-h sepsis bundle completion, antibiotic administration, and intravenous fluid bolus completion. Then logistic regression models evaluated the interaction between exposures, clinical sepsis subtypes, and in-hospital mortality. RESULTS: 55,169 hospitalizations from 155 hospitals were included (34% α, 30% ß, 19% γ, 17% δ). The α-subtype had the lowest (N = 1,905, 10%) and δ-subtype had the highest (N = 3,776, 41%) in-hospital mortality. Each hour to completion of the 3-h bundle (aOR, 1.04 [95%CI, 1.02-1.05]) and antibiotic initiation (aOR, 1.03 [95%CI, 1.02-1.04]) was associated with increased risk-adjusted in-hospital mortality. The association differed across subtypes (p-interactions < 0.05). For example, the outcome association for the time to completion of the 3-h bundle was greater in the δ-subtype (aOR, 1.07 [95%CI, 1.05-1.10]) compared to α-subtype (aOR, 1.02 [95%CI, 0.99-1.04]). Time to intravenous fluid bolus completion was not associated with risk-adjusted in-hospital mortality (aOR, 0.99 [95%CI, 0.97-1.01]) and did not differ among subtypes (p-interaction = 0.41). CONCLUSION: Timely completion of a 3-h sepsis bundle and antibiotic initiation was associated with reduced risk-adjusted in-hospital mortality, an association modified by clinically identifiable sepsis subtype.

Comparing broad and narrow phenotype algorithms: differences in performance characteristics and immortal time incurred.

Introduction: When developing phenotype algorithms for observational research, there is usually a trade-off between definitions that are sensitive or specific. The objective of this study was to estimate the performance characteristics of phenotype algorithms designed for increasing specificity and to estimate the immortal time associated with each algorithm. Materials and methods: We examined algorithms for 11 chronic health conditions. The analyses were from data from five databases. For each health condition, we created five algorithms to examine performance (sensitivity and positive predictive value (PPV)) differences: one broad algorithm using a single code for the health condition and four narrow algorithms where a second diagnosis code was required 1-30 days, 1-90 days, 1-365 days, or 1- all days in a subject's continuous observation period after the first code. We also examined the proportion of immortal time relative to time-at-risk (TAR) for four outcomes. The TAR's were: 0-30 days after the first condition occurrence (the index date), 0-90 days post-index, 0-365 days post-index, and 0-1,095 days post-index. Performance of algorithms for chronic health conditions was estimated using PheValuator (V2.1.4) from the OHDSI toolstack. Immortal time was calculated as the time from the index date until the first of the following: 1) the outcome; 2) the end of the outcome TAR; 3) the occurrence of the second code for the chronic health condition. Results: In the first analysis, the narrow phenotype algorithms, i.e., those requiring a second condition code, produced higher estimates for PPV and lower estimates for sensitivity compared to the single code algorithm. In all conditions, increasing the time to the required second code increased the sensitivity of the algorithm. In the second analysis, the amount of immortal time increased as the window used to identify the second diagnosis code increased. The proportion of TAR that was immortal was highest in the 30 days TAR analyses compared to the 1,095 days TAR analyses. Conclusion: Attempting to increase the specificity of a health condition algorithm by adding a second code is a potentially valid approach to increase specificity, albeit at the cost of incurring immortal time.

Effect of nonsteroidal anti-inflammatory drugs on the inflammatory response of bovine endometrial epithelial cells in vitro.

Chronic postpartum uterine infection detrimentally affects subsequent fertility. Nonsteroidal anti-inflammatory drugs (NSAID) are used to alleviate pain and treat inflammatory conditions in transition dairy cows with varying success. To screen the efficacy of NSAID in the absence of animal experiments, we have established an in vitro model to study uterine inflammation. Inflammation was induced in cultured bovine endometrial epithelial cells by challenging cells with an inflammation cocktail: lipopolysaccharide and proinflammatory cytokines, interleukin-1ß (IL1ß) and tumor necrosis factor α (TNFα). Release of the inflammation markers, serum amyloid A (SAA) and α-1-acid glycoprotein (αAGP), was measured by ELISA. Concentration of these markers was used to indicate the effectiveness in dampening inflammation of 5 NSAID: meloxicam, flunixin meglumine, aspirin, ketoprofen, and tolfenamic acid. Three NSAID, meloxicam, flunixin meglumine, and tolfenamic acid, were successful at dampening the release of SAA and αAGP into cell-culture supernatant, and the corresponding treated cells were selected for down-stream mRNA expression analysis. Expression of 192 genes involved in regulation of inflammatory pathways were investigated using Nanostring. Of the genes investigated, 81 were above the mRNA expression-analysis threshold criteria and were included in expression analysis. All SAA genes investigated (SAA2, SAA3, M-SAA3.2) were upregulated in response to the inflammation cocktail, relative to mRNA expression in control cells; however, AGP mRNA expression was below the expression analysis threshold and was, therefore, excluded from analysis. Treatment with NSAID downregulated genes involved in regulating chemokine signaling (e.g., CXCL2, CXCR4, CXCL5, and CXCL16) and genes that regulate the eicosanoid pathway (e.g., LTA4H, PTGS2, PLA2G4A, and PTGDS). Of the 5 NSAID investigated, meloxicam, flunixin meglumine, and tolfenamic acid are recommended for further investigation into treatment of postpartum uterine inflammation. The results from this study confirm the immunomodulatory properties of the endometrial epithelium in response to inflammatory stimuli and suggest that NSAID may be beneficial in alleviating uterine inflammation.

Active Surveillance versus Immediate Intervention for Small Renal Masses: A Cost-Effectiveness and Clinical Decision Analysis.

PURPOSE: Active surveillance (AS) with the possibility of delayed intervention (DI) is emerging as a safe alternative to immediate intervention for many patients with small renal masses (SRMs). However, limited comparative data exist to inform the most appropriate management strategy for SRMs. MATERIALS AND METHODS: Decision analytic Markov modeling was performed to estimate the health outcomes and costs of 4 management strategies for 65-year-old patients with an incidental SRM: AS (with possible DI), immediate partial nephrectomy, radical nephrectomy, and thermal ablation. Mortality, direct medical costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were evaluated over 10 years. RESULTS: The 10-year all-cause mortality was 22.6% for AS, 21.9% for immediate partial nephrectomy, 22.4% for immediate radical nephrectomy, and 23.7% for immediate thermal ablation. At a willingness-to-pay threshold of $100,000/quality-adjusted life-year, AS was the most cost-effective management strategy. The results were robust in univariate, multivariate, and probabilistic sensitivity analyses. Clinical decision analysis demonstrated that the tumor's metastatic potential, patient age, individual preferences, and health status were important factors influencing the optimal management strategy. Notably, if the annual probability of metastatic progression from AS was sufficiently low (under 0.35%-0.45% for most ages at baseline), consistent with the typical metastatic potential of SRMs <2 cm, AS would achieve higher health utilities than the other strategies. CONCLUSIONS: Compared to immediate intervention, AS with timely DI offers a safe and cost-effective approach to managing patients with SRMs. For patients harboring tumors of very low metastatic potential, AS may lead to better patient outcomes than immediate intervention.

Association between Previous Pelvic Radiation and All-Cause and Cause-Specific Failure of Replacement Artificial Urinary Sphincters.

PURPOSE: In order to accurately characterize how a history of radiation therapy affects the lifespan of replacement artificial urinary sphincters (AUSs), all possible sources of device failure must be considered. We assessed the competing risks of device failure based on radiation history in men with replacement AUSs. MATERIALS AND METHODS: We identified men who had a replacement AUS in a single institutional, retrospective database. To assess survival from all-cause device failure based on radiation history and other factors, we conducted Kaplan-Meier, Cox proportional-hazards and competing risks analyses. RESULTS: Among 247 men who had a first replacement AUS, men with a history of radiation had shorter time to all-cause device failure (median 1.4 vs 3.5 years for men with radiation vs without radiation history, p=0.02). On multivariable Cox-proportional hazards analysis, previous radiation was associated with increased risk of all-cause device failure (HR: 2.12, 95% CI: 1.30-3.43, p=0.002). On multivariable cause-specific hazards analysis, prior radiation was associated with a higher risk of erosion/infection (HR: 7.57, 95% CI: 2.27-25.2, p <0.001), but was not associated with risk of urethral atrophy (p=0.5) or mechanical failure (p=0.15). CONCLUSIONS: Among men with a replacement AUS, a history of pelvic radiation was associated with shorter time to device failure of any cause. Radiation was also specifically associated with a sevenfold increase in the risk of erosion or infection of replacement AUS, but not with urethral atrophy or mechanical failure. Patients with a replacement AUS should be appropriately counseled on how radiation history may impact outcomes of future revisions.

Perioperative Aspirin Use Is Associated with Bleeding Complications during Robotic Partial Nephrectomy.

PURPOSE: Daily aspirin use following cardiovascular intervention is commonplace and creates concern regarding bleeding risk in patients undergoing surgery. Despite its cardio-protective role, aspirin is often discontinued 5-7 days prior to major surgery due to bleeding concerns. Single institution studies have investigated perioperative outcomes of aspirin use in robotic partial nephrectomy (RPN). We sought to evaluate the outcomes of perioperative aspirin (pASA) use during RPN in a multicenter setting. MATERIALS AND METHODS: We performed a retrospective evaluation of patients undergoing RPN at 5 high volume RPN institutions. We compared perioperative outcomes of patients taking pASA (81 mg) to those not on aspirin. We analyzed the association between pASA use and perioperative transfusion. RESULTS: Of 1,565 patients undergoing RPN, 228 (14.5%) patients continued pASA and were older (62.8 vs 56.8 years, p <0.001) with higher Charlson scores (mean 3 vs 2, p <0.001). pASA was associated with increased perioperative blood transfusions (11% vs 4%, p <0.001) and major complications (10% vs 3%, p <0.001). On multivariable analysis, pASA was associated with increased transfusion risk (OR 1.94, 1.10-3.45, 95% CI). CONCLUSIONS: In experienced hands, perioperative aspirin 81 mg use during RPN is reasonable and safe; however, there is a higher risk of blood transfusions and major complications. Future studies are needed to clarify the role of antiplatelet therapy in RPN patients requiring pASA for primary or secondary prevention of cardiovascular events.

Exploring statistical weight estimates for mitochondrial DNA matches involving heteroplasmy.

Massively parallel sequencing (MPS) of mitochondrial (mt) DNA allows forensic laboratories to report heteroplasmy on a routine basis. Statistical approaches will be needed to determine the relative frequency of observing an mtDNA haplotype when including the presence of a heteroplasmic site. Here, we examined 1301 control region (CR) sequences, collected from individuals in four major population groups (European, African, Asian, and Latino), and covering 24 geographically distributed haplogroups, to assess the rates of point heteroplasmy (PHP) on an individual and nucleotide position (np) basis. With a minor allele frequency (MAF) threshold of 2%, the data was similar across population groups, with an overall PHP rate of 37.7%, and the majority of heteroplasmic individuals (77.3%) having only one site of heteroplasmy. The majority (75.2%) of identified PHPs had an MAF of 2-10%, and were observed at 12.6% of the nps across the CR. Both the broad and phylogenetic testing suggested that in many cases the low number of observations of heteroplasmy at any one np results in a lack of statistical association. The posterior frequency estimates, which skew conservative to a degree depending on the sample size in a given haplogroup, had a mean of 0.152 (SD 0.134) and ranged from 0.031 to 0.83. As expected, posterior frequency estimates decreased in accordance with 1/n as the sample size (n) increased. This provides a proposed conservative statistical framework for assessing haplotype/heteroplasmy matches when applying an MPS technique in forensic cases and will allow for continual refinement as more data is generated, both within the CR and across the mitochondrial genome.

MaSTR™: an effective probabilistic genotyping tool for interpretation of STR mixtures associated with differentially degraded DNA.

The recently developed probabilistic genotyping software package MaSTR™ (SoftGenetics LLC) was used to develop statistical weight estimates for a variety of two-person STR mixture profiles with differentially degraded sources of DNA. A total of 864 analyses, on 144 two-person profiles, were performed. Mixture ratios ranged from 1:1 to 1:10, including pristine sources of DNA and various combinations of artificially degraded DNA (average size fragments of 150 or 250 bps). Quantities of DNA template were varied (0.1 to 0.5 ngs of total input) and MaSTR™ analysis was performed with eight chains of 10,000 or 40,000 iterations, with or without a conditioning profile to generate likelihood ratio (LR) values. Overall, the software performed as expected. The resulting log(LR) values for pristine mixture profiles were typically greater than 1030. Lower-quality mixture data associated with sources of DNA at ~ 0.05 ngs for each contributor resulted in peak imbalance and allelic dropout which reduced the weight in support of a contributor. This was exacerbated by higher levels of degradation, with some instances resulting in log(LR) values in support of an exclusion. These studies provide additional support for the use of probabilistic genotyping software solutions in forensic investigations, addressing concerns raised by the President's Council of Advisors on Science and Technology (PCAST).

Utility and futility of skin testing to address concerns surrounding messenger RNA coronavirus disease 2019 vaccine reactions.

BACKGROUND: The mechanism of coronavirus disease 2019 (COVID-19) vaccine hypersensitivity reactions is unknown. COVID-19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. OBJECTIVE: To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first messenger RNA COVID-19 vaccine dose and patients with a history of polyethylene glycol allergy who have not yet received a COVID-19 vaccine dose. METHODS: In this multicenter, retrospective review, COVID-19 vaccine and vaccine excipient skin testing was performed in patients referred to 1 of 3 large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. RESULTS: A total of 129 patients underwent skin testing, in whom 12 patients (9.3%) had positive results. There were 101 patients who received a COVID-19 vaccine after the skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of 6 patients with positive skin testing results who received a COVID-19 vaccine after the skin testing. The remaining 11 patients experienced minor allergic symptoms after COVID-19 vaccination, none of whom required treatment beyond antihistamines. CONCLUSION: The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggest a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing when necessary. On the basis of these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.

Preoperative binocular vision characteristics in the age-related cataract population.

BACKGROUND: This study is the first part of the "Binocular Vision Anomalies after Cataract Surgery" study that aimed to investigate the impact of cataract surgery on binocular vision status in adults with age-related cataract. This study aimed to investigate the preoperative binocular vision status of participants with age-related cataract. METHODS: Patients who elected to undergo bilateral cataract surgery (≥50 years of age) were recruited. Clinical measures of binocular vision including stereopsis, ocular alignment, fusional vergence, vergence facility, convergence amplitude and a symptom survey related to binocular vision anomalies were administered. A detailed classification protocol was established to identify the presence of binocular vision anomalies. The frequency of specific binocular vision anomalies and normative data of binocular vision measures were reported. RESULTS: A total of 73 subjects were evaluated. No strabismus was detected in the cohort. Non-strabismic binocular vision anomalies were detected in 24 subjects (32.9%), of whom 18 (24.7%) had convergence insufficiency, 3 (4.1%) had basic exophoria, 2 (2.7%) had convergence excess, and 1 (1.4%) had fusional vergence dysfunction. Decreased vergence facility and convergence amplitude were more common compared to the pre-presbyopes (P < 0.01). CONCLUSION: Binocular vision problems, especially convergence insufficiency, are common in the adults with age-related cataract. The study results demonstrate that the lack of normative binocular vision data for the presbyopic population is a significant gap in the literature and suggest the need for a study of normative data for this population. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT03592615, USA).

Eye Tracking Metrics Differences among Uninjured Adolescents and Those with Acute or Persistent Post-Concussion Symptoms.

SIGNIFICANCE: Eye tracking assessments that include pupil metrics can supplement current clinical assessments of vision and autonomic dysfunction in concussed adolescents. PURPOSE: This study aimed to explore the utility of a 220-second eye tracking assessment in distinguishing eye position, saccadic movement, and pupillary dynamics among uninjured adolescents, those with acute post-concussion symptoms (≤28 days since concussion), or those with persistent post-concussion symptoms (>28 days since concussion). METHODS: Two hundred fifty-six eye tracking metrics across a prospective observational cohort of 180 uninjured adolescents recruited from a private suburban high school and 224 concussed adolescents, with acute or persistent symptoms, recruited from a tertiary care subspecialty concussion care program, 13 to 17 years old, from August 2017 to June 2021 were compared. Kruskal-Wallis tests were used, and Bonferroni corrections were applied to account for multiple comparisons and constructed receiver operating characteristic curves. Principal components analysis and regression models were applied to determine whether eye tracking metrics can augment clinical and demographic information in differentiating uninjured controls from concussed adolescents. RESULTS: Two metrics of eye position were worse in those with concussion than uninjured adolescents, and only one metric was significantly different between acute cases and persistent cases. Concussed adolescents had larger left and right mean, median, minimum, and maximum pupil size than uninjured controls. Concussed adolescents had greater differences in mean, median, and variance of left and right pupil size. Twelve metrics distinguished female concussed participants from uninjured; only four were associated with concussion status in males. A logistic regression model including clinical and demographics data and transformed eye tracking metrics performed better in predicting concussion status than clinical and demographics data alone. CONCLUSIONS: Objective eye tracking technology is capable of quickly identifying vision and pupillary disturbances after concussion, augmenting traditional clinical concussion assessments. These metrics may add to existing clinical practice for monitoring recovery in a heterogeneous adolescent concussion population.

Cataract surgery is not associated with post-operative binocular vision anomalies in age-related cataract patients.

PURPOSE: To compare the binocular vision status of patients pre- and post-cataract surgery, and to investigate the risk factors for patients who develop binocular vision anomalies post-surgery. METHODS: A prospective study of patients (≥50 years) who elected to undergo bilateral cataract surgery was implemented. A comprehensive binocular vision test battery including stereopsis, ocular alignment, fusional vergence, vergence facility, near point of convergence and the Convergence Insufficiency Symptom Survey (CISS) was administered before the first surgery and at the third visit after surgery on the second eye. A detailed diagnostic classification protocol was applied to identify the presence of binocular vision anomalies pre- and post-surgery. RESULTS: Seventy-three participants were included at baseline, 24 (33%) of whom were diagnosed with non-strabismic binocular vision anomalies (NSBVA), mainly convergence insufficiency (18/73, 25%). Fifty-one participants completed the post-operative evaluation, 17 (33%) of whom had NSBVA pre-surgery and 13 (26%) post-surgery (p = 0.48). There were a number of conversions from NSBVA to normal binocular vision and vice versa. Logistic regression showed that the adjusted odds ratio of pre-existing NSBVA diagnosis for predicting the risk of post-operative NSBVA was 6.37 (p < 0.01). There were no significant changes in most binocular vision measures post-surgery, except for a significant improvement in the CISS score (p < 0.01, Cohen's d = 0.83). CONCLUSIONS: Binocular vision anomalies, especially convergence insufficiency, are prevalent in the age-related cataract population. Cataract surgery does not appear to be a significant risk factor for the development of new binocular vision anomalies. A pre-existing binocular vision anomaly is the main risk factor for predicting a post-operative binocular vision anomaly in this population.

Does coexisting accommodative dysfunction impact clinical convergence measures, symptoms and treatment success for symptomatic convergence insufficiency in children?

PURPOSE: To determine whether coexisting accommodative dysfunction in children with symptomatic convergence insufficiency (CI) impacts presenting clinical convergence measures, symptoms and treatment success for CI. METHODS: Secondary data analyses of monocular accommodative amplitude (AA; push-up method), monocular accommodative facility (AF; ±2.00 D lens flippers) and symptoms (CI Symptom Survey [CISS]) in children with symptomatic CI from the Convergence Insufficiency Treatment Trial (N = 218) and CITT-Attention and Reading Trial (N = 302) were conducted. Decreased AA was defined as more than 2D below the minimum expected amplitude for age (15 - » age); those with AA < 5 D were excluded. Decreased AF was defined as <6 cycles per minute. Mean near point of convergence (NPC), near positive fusional vergence (PFV) and symptoms (CISS) were compared between those with and without accommodative dysfunction using analysis of variance and independent samples t-testing. Logistic regression was used to compare the effect of baseline accommodative function on treatment success [defined using a composite of improvements in: (1) clinical convergence measures and symptoms (NPC, PFV and CISS scores) or (2) solely convergence measures (NPC and PFV)]. RESULTS: Accommodative dysfunction was common in children with symptomatic CI (55% had decreased AA; 34% had decreased AF). NPC was significantly worse in those with decreased AA (mean difference = 6.1 cm; p < 0.001). Mean baseline CISS scores were slightly worse in children with coexisting accommodative dysfunction (decreased AA or AF) (30.2 points) than those with normal accommodation (26.9 points) (mean difference = 3.3 points; p < 0.001). Neither baseline accommodative function (p ≥ 0.12 for all) nor interaction of baseline accommodative function and treatment (p ≥ 0.50) were related to treatment success based on the two composite outcomes. CONCLUSIONS: A coexisting accommodative dysfunction in children with symptomatic CI is associated with worse NPC, but it does not impact the severity of symptoms in a clinically meaningful way. Concurrent accommodative dysfunction does not impact treatment response for CI.

Delayed systemic urticarial reactions following mRNA COVID-19 vaccination.

Background: As the vaccination campaign in response to the coronavirus disease 2019 (COVID-19) pandemic continues, concerns with regard to adverse reactions to the vaccine remain. Although immediate hypersensitivity reactions have received much attention, delayed systemic urticarial reactions after vaccination can occur. Objective: To describe the clinical presentation, vaccine excipient skin testing results, and outcomes of subsequent COVID-19 vaccination in patients who experienced delayed systemic urticarial reactions after messenger RNA (mRNA) COVID-19 vaccination. Methods: This was a retrospective case series of 12 patients referred to the Mayo Clinics in Rochester, Minnesota, and Jacksonville, Florida, between January 19, 2021, and April 30, 2021, for evaluation of delayed systemic urticarial reactions after mRNA COVID-19 vaccination. Demographics, medical and allergic history, reaction details, vaccine excipient skin testing results (when performed), and the outcome after subsequent vaccination were collected for each patient. Results: The mean age of the patients was 52 years, all were white, and 9 (75%) were women. Half of the patients had a history of drug allergy, and one had a history of chronic spontaneous urticaria. Seven patients reacted to the Pfizer-BioNTech vaccine and five reacted to the Moderna vaccine. Seven patients developed symptoms between 8 and 24 hours after vaccination. Nine patients required antihistamines for treatment. The median time to symptom resolution was 4 days. Nine patients underwent allergist-directed COVID-19 vaccine excipient skin testing, all of which were negative. Ten patients chose to receive their next mRNA COVID-19 vaccine dose, and four patients experienced recurrent delayed urticaria. Conclusion: Delayed systemic urticarial reactions after mRNA COVID-19 vaccination were not life-threatening, could be treated with antihistamines, and were not predicted with vaccine excipient skin testing. They were not a contraindication to subsequent vaccination, although patients should be counseled with regard to the possibility of recurrence.

Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

Correlations of milk and serum element concentrations with production and management traits in dairy cows.

The present study investigated the potential consequences, positive or negative, that selection for favorable production-related traits may have on concentrations of vitamin B12 and key chemical elements in dairy cow milk and serum and the possible impact on milk healthiness, and associated benefits, for the dairy product consumer. Milk and serum samples (950 and 755, respectively) were collected from Holstein-Friesian dairy cows (n = 479) on 19 occasions over a 59-mo period, generating 34,258 individual records, and analyzed for concentrations of key trace and quantity elements, heavy metals, and milk vitamin B12. These data were then matched to economically important production data (milk, fat, and protein yield) and management data (dry matter intake, liveweight, and body condition score). Multivariate animal models, including full pedigree information, were used to analyze data and investigate relationships between traits of interest. Results highlighted negative genetic correlations between many quantity and trace elements in both milk and serum with production and management traits. Milk yield was strongly negatively correlated with the milk quantity elements Mg and Ca (genetic correlation between traits, ra = -0.58 and -0.63, respectively) as well as the trace elements Mn, Fe, Ni, Cu, Zn, and Mo (ra = -0.32, -0.58, -0.52, -0.40, -0.34, and -0.96, respectively); and in serum, Mg, Ca, Co, Fe, and Zn (ra = -0.50, -0.36, -0.68, -0.54, and -0.90, respectively). Strong genetic correlations were noted between dry matter intake with V (ra = 0.97), Fe (ra = -0.69), Ni (ra = -0.81), and Zn (ra = -0.75), and in serum, strong negative genetic correlations were observed between dry matter intake with Ca and Se (ra = -0.95 and -0.88, respectively). Body condition score was negatively correlated with serum P, Cu, Se, and Pb (ra = -0.45, -0.35, -0.51, and -0.64, respectively) and positively correlated with Mn, Fe, and Zn (ra = 0.40, 0.71, and 0.55, respectively). Our results suggest that breeding strategies aimed at improving economically important production-related traits would most likely result in a negative impact on levels of beneficial nutrients within milk for human consumption (such as Mg, Ca, Fe, Zn, and Se).