Foveal photoreceptor atrophy, persistent fetal vasculature, congenital cataracts, and microphthalmia in a pediatric patient with BCOR-associated oculo-facio-cardio-dental (OFCD) syndrome.

Purpose: To report a case of oculo-facio-cardio-dental (OFCD) syndrome secondary to a novel BCOR variant in a pediatric patient with congenital cataracts, microphthalmia, persistent fetal vasculature (PFV), focal chorioretinal hyperpigmentation, peripheral retinal avascularity, and foveal photoreceptor atrophy. Observations: A 3-month-old female patient was referred for bilateral congenital cataracts with microphthalmia. Her past medical history was significant for syndactyly of the toes, left bifid rib, atrial septal defect, patent ductus arteriosus, mitral regurgitation, pulmonary hypertension, anemia of prematurity, vesicoureteral reflux, and duodenal atresia. Examination under anesthesia revealed persistent fetal vasculature (PFV) with peripheral avascularity, foveal photoreceptor atrophy, and focal chorioretinal hyperpigmentation. A bilateral lensectomy with anterior vitrectomy and posterior capsulotomy were performed. Genetic testing identified a novel heterozygous pathogenic variant in the BCOR gene (c.1612C > T (p.Gln538Ter)), confirming a diagnosis of OFCD syndrome. Conclusions and importance: This case describes novel posterior segment findings in a patient with OFCD. A detailed examination of both anterior and posterior segments in combination with multimodal imaging should be performed in patients suspected of having OFCD, as this may be critical in determining visual potential and appropriate surgical management.

Multiparatopic antibodies induce targeted downregulation of programmed death-ligand 1.

Programmed death-ligand 1 (PD-L1) drives inhibition of antigen-specific T cell responses through engagement of its receptor programmed death-1 (PD-1) on activated T cells. Overexpression of these immune checkpoint proteins in the tumor microenvironment has motivated the design of targeted antibodies that disrupt this interaction. Despite clinical success of these antibodies, response rates remain low, necessitating novel approaches to enhance performance. Here, we report the development of antibody fusion proteins that block immune checkpoint pathways through a distinct mechanism targeting molecular trafficking. By engaging multiple receptor epitopes on PD-L1, our engineered multiparatopic antibodies induce rapid clustering, internalization, and degradation in an epitope- and topology-dependent manner. The complementary mechanisms of ligand blockade and receptor downregulation led to more durable immune cell activation and dramatically reduced PD-L1 availability in mouse tumors. Collectively, these multiparatopic antibodies offer mechanistic insight into immune checkpoint protein trafficking and how it may be manipulated to reprogram immune outcomes.

Propensity score stratified MAP prior and posterior inference for incorporating information across multiple potentially heterogeneous data sources.

Incorporation of external information is becoming increasingly common when designing clinical trials. Availability of multiple sources of information has inspired the development of methodologies that account for potential heterogeneity not only between the prospective trial and the pooled external data sources but also between the different external data sources themselves. Our approach proposes an intuitive way of handling such a scenario for the continuous outcomes setting by using propensity score-based stratification and then utilizing robust meta-analytic predictive priors for each stratum to incorporate the prior data to distinguish among different external data sources in each stratum. Through extensive simulations, our approach proves to be more efficient and less biased than the currently available methods. A real case study using clinical trials that study schizophrenia from multiple different sources is also included.

Leveraging baseline covariates to analyze small cluster-randomized trials with a rare binary outcome.

Cluster-randomized trials (CRTs) involve randomizing entire groups of participants-called clusters-to treatment arms but are often comprised of a limited or fixed number of available clusters. While covariate adjustment can account for chance imbalances between treatment arms and increase statistical efficiency in individually randomized trials, analytical methods for individual-level covariate adjustment in small CRTs have received little attention to date. In this paper, we systematically investigate, through extensive simulations, the operating characteristics of propensity score weighting and multivariable regression as two individual-level covariate adjustment strategies for estimating the participant-average causal effect in small CRTs with a rare binary outcome and identify scenarios where each adjustment strategy has a relative efficiency advantage over the other to make practical recommendations. We also examine the finite-sample performance of the bias-corrected sandwich variance estimators associated with propensity score weighting and multivariable regression for quantifying the uncertainty in estimating the participant-average treatment effect. To illustrate the methods for individual-level covariate adjustment, we reanalyze a recent CRT testing a sedation protocol in 31 pediatric intensive care units.

Association of Emergency Department Evaluation With Public Insurance Use and Treatment Delays for ACL Injury.

Background: Utilization of an emergency department (ED) visit for anterior cruciate ligament (ACL) injury is associated with high cost and diagnostic unreliability. Hypothesis: Patients initially evaluated at an ED for an ACL injury would be more likely to be from a lower income quartile, use public insurance, and experience a delay in treatment. Study Design: Cohort study; Level of evidence, 3. Methods: Patients in the Rhode Island All Payers Claims Database who underwent ACL reconstruction (ACLR) between 2012 and 2021 were identified using the Current Procedure Terminology (CPT) code 29888. Patients were stratified into 2 cohorts based on CPT codes for ED or in-office services within 1 year of ACLR. A chi-square analysis was used to test for differences between cohorts in patient and surgical characteristics. Multivariable linear and logistic regression were used to determine how ED evaluation affected timing and outcome variables. Results: While adjusting for patient and operative characteristics, patients in the ED cohort were more likely to have Medicaid (29% vs 12.5%; P < .001) and be in the lowest income quartile (44.6% vs 32.1%; P < .001). ED visit and Medicaid status were associated with increased time to (1) diagnostic magnetic resonance imaging, adding 7.97 days on average (95% CI, 4.14-11.79 days; P < .001) and 8.40 days (95% CI, 3.44-13.37 days; P = .001), respectively; and (2) surgery, adding 20.30 days (95% CI, 14.10-26.49 days; P < .001) and 12.88 days (95% CI, 5.15-20.60 days; P = .001), respectively. Patients >40 years who were evaluated in the ED were 2.5 times more likely to require subsequent ACLR (odds ratio, 2.50 [95% CI, 1.01-6.21]; P = .049). Conclusion: In this study, patients who visited the ED within 1 year before ACLR were more likely to have a lower income, public insurance, increased time to diagnostic imaging, and increased time to surgery, as well as decreased postoperative physical therapy use and increased subsequent ACLR rates in the 40-49 years age-group.

Multiple Primary Lung Cancers: Treatment Outcomes After Stereotactic Body Radiotherapy (SBRT).

PURPOSE/OBJECTIVES: Patients with lung cancer sometimes present with multiple primary lung cancers (MPLCs), either simultaneously (synchronous) or after treatment of an initial lesion (metachronous). Although open surgery remains a treatment mainstay for patients with stage I-II non-small-cell lung cancer (NSCLC), stereotactic body radiation therapy (SBRT) is an acceptable alternative for patients who are medically unfit for or who refuse surgery. In this study, we retrospectively examine the outcome among patients with early-stage MPLCs treated at our institution with SBRT. MATERIALS/METHODS: Patients at our institution receiving SBRT for MPLC between June 2011 and March 2020 were reviewed retrospectively. Prior to undergoing definitive SBRT, the imaging, and pathology for every patient were reviewed in a multi-disciplinary thoracic/pulmonary tumor board. Dose and fractionation varied with the most common prescriptions being 50 Gy/5 fractions, 56 Gy/4 fractions, and 55 Gy/5 fractions. RESULTS: A total of 38 patients with a total of 80 MPLCs were treated, among which 68 were T1 lesions and 12 were T2 lesions. Median follow-up was 25.9 months, with local control (LC) rates calculated per lesion to be 98.6%, 93.3%, and 88.2% at one, two, and three years. Median overall survival (OS) was 43.5 months; 83.6%, 67.8%, and 52.3% at one, two, and three years, respectively. Sixty-two of the 80 (77.5%) treated lesions were not associated with any subsequent acute or late toxicity. The 18 (22.5%) lesions associated with toxicity included nine acute and nine late events. All toxicity was either grade 1 (13 of 18) or grade 2 (five of 18). CONCLUSIONS: SBRT for early-stage MPLC achieves high control rates with limited toxicity. MPLC patients deemed unfit for open surgical management should be considered for definitive SBRT.

Genome Mining and Discovery of Imiditides, a Family of RiPPs with a Class-Defining Aspartimide Modification.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large and diverse class of natural products of ribosomal origin. In the past decade, various sophisticated machine-learning-based software packages have been established to discover novel RiPPs that do not resemble the known families. Here, we show that tailoring enzymes that cluster with various RiPP families can serve as effective bioinformatic seeds, providing a complementary approach for novel RiPP discovery. Leveraging the fact that O-methyltransferases homologous to protein isoaspartyl methyltransferases (PIMTs) are associated with lasso peptide, graspetide, and lanthipeptide biosynthetic gene clusters (BGCs), we utilized a C-terminal motif unique to RiPP-associated O-methyltransferases as the search query to discover a novel family of RiPPs, the imiditides. Our genome-mining algorithm reveals a total of 670 imiditide BGCs, distributed across Gram-positive bacterial genomes. In addition, we demonstrate the heterologous production of the founding member of the imiditide family, mNmaAM, encoded in the genome of Nonomuraea maritima. In contrast to other RiPP-associated PIMTs that recognize constrained peptides as substrates, the PIMT homologue in the mNmaAM BGC, NmaM, methylates a specific Asp residue on the linear precursor peptide, NmaA. The methyl ester is then turned into an aspartimide spontaneously. Substrate specificity is achieved by extensive charge-charge interactions between the precursor NmaA and the modifying enzyme NmaM suggested by both experiments and an AlphaFold model prediction. Our study shows that PIMT-mediated aspartimide formation is an emerging backbone modification strategy in the biosynthesis of multiple RiPP families.

Association of multi-criteria derived air toxics hazard score with lung cancer incidence in a major metropolitan area.

Background: Lung cancer remains a major health problem world-wide. Environmental exposure to lung cancer carcinogens can affect lung cancer incidence. We investigated the association between lung cancer incidence and an air toxics hazard score of environmental carcinogen exposures derived previously under the exposome concept. Methods: Lung cancer cases diagnosed in Philadelphia and the surrounding counties between 2008 and 2017 were identified from the Pennsylvania Cancer Registry. Age-adjusted incidence rates at the ZIP code level were calculated based on the residential address at diagnosis. The air toxics hazard score, an aggregate measure for lung cancer carcinogen exposures, was derived using the criteria of toxicity, persistence, and occurrence. Areas with high incidence or hazard score were identified. Spatial autoregressive models were fitted to evaluate the association, with and without adjusting for confounders. Stratified analysis by smoking prevalence was performed to examine potential interactions. Results: We observed significantly higher age-adjusted incidence rates in ZIP codes that had higher air toxics hazard score values after controlling for demographic variables, smoking prevalence, and proximity to major highways. Analyzes stratified by smoking prevalence suggested that exposure to environmental lung carcinogens had a larger effect on cancer incidence in locations with higher smoking prevalence. Conclusion: The positive association between the multi-criteria derived air toxics hazard score and lung cancer incidence provides the initial evidence to validate the hazard score as an aggregate measure of carcinogenic exposures in the environment. The hazard score can be used to supplement the existing risk factors in identifying high risk individuals. Communities with higher incidence/hazard score may benefit from greater awareness of lung cancer risk factors and targeted screening programs.

Role of the ocular surface microbiome in allergic eye diseases.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on emerging literature on the role of the ocular surface microbiome (OSM) in allergic eye diseases. RECENT FINDINGS: Findings in the literature suggest that the ocular surface microbiome plays a role in the pathophysiology and course of allergic disease of the ocular surface. SUMMARY: Knowledge regarding the role of the ocular surface microbiome in allergic disease is important to guide development of targets for future therapeutic interventions.

Alternatives to transvenous lead placement in a patient undergoing surgical tricuspid valve repair.

Tricuspid regurgitation is a widely recognised phenomenon in patients with transvenous cardiac rhythm management (CRM) devices. If tricuspid valve repair or replacement is to be considered, what to do with the existing CRM system requires scrutiny with multidisciplinary input. We present a case of multifactorial tricuspid regurgitation in a 48-year-old female with giant cell myocarditis and a transvenous implantable cardioverter-defibrillator (ICD). Key considerations in management and alternative CRM options are discussed.

E-commerce development and its contribution to agricultural non-point source pollution control: Evidence from 283 cities in China.

Agricultural non-point source (ANPS) pollution is a pressing environmental issue in developing countries that poses a substantial threat to sustainable development. With the rapid growth of e-commerce and its great penetration and transformation in many socioeconomic sectors, e-commerce plus agriculture is widely regarded as the solution to sustainable agricultural development. However, the environmental impacts of e-commerce on agriculture, as well as the underlying mechanisms have yet to be fully explored and verified. Based on China's practices of e-commerce development and its integration with agriculture, a panel dataset of 283 prefecture-level cities from 2009 to 2019 was collected, and a spatial difference in difference (SDID) model combined with a Durbin model was constructed to examine the local and spatial spillover effects of e-commerce development on ANPS pollution. It is found out that e-commerce development has significant positive environmental impacts achieved by stimulating industrial structure upgrading and promoting green technology innovation, while the mechanism of cultivation scaling up tends to aggravate the ANPS pollution. Spatial analysis demonstrates that e-commerce development also helps alleviate the ANPS pollution of neighboring regions with a decayed effect over a distance. Meanwhile, the impact of e-commerce on mitigating ANPS pollution shows regional heterogeneity. Those developed regions present significant positive effects, while those regions dominated by agriculture economy and without sufficient supporting facilities for e-commerce development, show significant negative effects. Therefore, we argue that the positive environmental contribution of e-commerce is not bound to happen but instead is contingent, while policies should be adapted to local conditions and enhanced to encourage the integration of e-commerce and other socioeconomic sectors, in order to develop beyond the immature pioneering stage.

Subcutaneous defibrillator use with unipolar pacemakers: Cautiously possible.

Implantation of subcutaneous implantable cardioverter-defibrillator in a patient with existing unipolar pacemaker is against manufacturer recommendations. We report the case of a successful subcutaneous implantable cardioverter-defibrillator implantation in a patient with Fontan circulation and concomitant active unipolar pacing and present a summary of recommendations when considering subcutaneous implantable cardioverter-defibrillator implantation with unipolar pacing. Recommendations included: pre-procedure screening, rescreening during implantation and ventricular fibrillation induction, pacemaker programming, and post-procedure investigations.

Objectively-Assessed Ultraviolet Radiation Exposure and Sunburn Occurrence.

Ultraviolet radiation (UVR) exposure is the primary modifiable risk factor for melanoma. Wearable UVR sensors provide a means of quantifying UVR exposure objectively and with a lower burden than self-report measures used in most research. The purpose of this study was to evaluate the relationship between detected UVR exposure and reported sunburn occurrence. In this study, a UVR monitoring device was worn by 97 parent-child dyads during waking hours for 14 days to measure instantaneous and accumulated UVR exposure. The results showed that the participants' total UVR exposure was associated with reported sunburn after adjusting for Fitzpatrick skin type and geographic location. It was observed that one standard erythemal dose (SED) increase in the participants' daily total UVR exposure was associated with reported sunburn (an odds ratio (OR) of 1.26 with a 95% CI of 1.13 and 1.41, and p < 0.001 for parents and an OR of 1.28 with a 95% CI of 1.12 and 1.47, and p < 0.001 for children). A one-SED increase in the participants' UVR exposure from 10 am to 4 pm was also associated with reported sunburn (an OR of 1.31 with a 95% CI of 1.15 and 1.49, and p < 0.001 for parents and an OR of 1.33 with a 95% CI of 1.12 and 1.59, and p = 0.001 for children). We found that elevated UVR exposure recordings measured by the UVR sensor were associated with reported sunburn occurrence. Future directions for wearable UVR sensors may include their use as an intervention tool to support in-the-moment sunburn prevention.

Genome Mining and Discovery of Imiditides, a Novel Family of RiPPs with a Class-defining Aspartimide Modification.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a fascinating class of natural products of ribosomal origins. In the past decade, various sophisticated machine learning-based software packages have been established to discover novel RiPPs that do not resemble the known families. Instead, we argue that tailoring enzymes that cluster with various RiPP families can serve as effective bioinformatic seeds for novel RiPP discovery. Leveraging that O -methyltransferases homologous to protein isoaspartyl methyltransferases (PIMTs) are associated with lasso peptide, graspetide, and lanthipeptide biosynthetic gene clusters (BGCs), we utilized the C-terminal motif unique to RiPP-associated O -methyltransferases as the search query to discover a novel family of RiPPs, imiditides. Our genome-mining algorithm reveals a total of 670 imiditide BGCs, widely distributed in Gram-positive bacterial genomes. In addition, we demonstrate the heterologous production of the founding member of the imiditide family, mNmaA M , encoded in the genome of Nonomuraea maritima . In contrast to other RiPP associated PIMTs that recognize constrained peptides as substrates, the PIMT homolog in mNmaA M BGC, NmaM, methylates a specific Asp residue on the linear precursor peptide, NmaA. The methyl ester is then turned into an aspartimide spontaneously. The aspartimide moiety formed is unusually stable, leading to the accumulation of the aspartimidylated product in vivo . The substrate specificity is achieved by extensive charge-charge interactions between the precursor NmaA and the modifying enzyme NmaM suggested by both experimental validations as well as an AlphaFold model prediction. Our study suggests that PIMT-mediated aspartimide formation is an underappreciated backbone modification strategy in RiPP biosynthesis, compared to the well-studied backbone rigidification chemistries, such as thiazol(in)e and oxazol(in)e formations. Additionally, our findings suggest that aspartimide formation in Gram-positive bacterial proteomes are not limited to spontaneous protein aging and degradation.

Predictors of Citations for Original Research in Ophthalmology.

There is a dearth of literature on factors associated with citation of publications in ophthalmology. We investigated predictors of citations for original ophthalmologic research articles based on author, study, and journal characteristics. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we extracted articles that studied the leading cause of vision impairment in the United States (cataract, diabetic retinopathy, age-related macular degeneration, and glaucoma) and were published in the top fifteen ophthalmology journals with the highest impact factors that accepted original research. Descriptive statistics, one-way analysis of variance (ANOVA) tests, and negative binomial regression were used to compare citation counts based on author, study, and journal characteristics. In this study, author research productivity, journal impact factor, study funding, and location in high-income countries were predictors of increased citation in ophthalmology.

Locus coeruleus activity improves cochlear implant performance.

Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4-7. Despite extensive studies on how CIs activate the auditory system4,8-12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.

Addressing positivity violations in causal effect estimation using Gaussian process priors.

In observational studies, causal inference relies on several key identifying assumptions. One identifiability condition is the positivity assumption, which requires the probability of treatment be bounded away from 0 and 1. That is, for every covariate combination, it should be possible to observe both treated and control subjects the covariate distributions should overlap between treatment arms. If the positivity assumption is violated, population-level causal inference necessarily involves some extrapolation. Ideally, a greater amount of uncertainty about the causal effect estimate should be reflected in such situations. With that goal in mind, we construct a Gaussian process model for estimating treatment effects in the presence of practical violations of positivity. Advantages of our method include minimal distributional assumptions, a cohesive model for estimating treatment effects, and more uncertainty associated with areas in the covariate space where there is less overlap. We assess the performance of our approach with respect to bias and efficiency using simulation studies. The method is then applied to a study of critically ill female patients to examine the effect of undergoing right heart catheterization.

Outcomes of Nontuberculous Mycobacterial Keratitis After Clear Corneal Incision Phacoemulsification Surgery: A Case Series of 6 Eyes in South Florida.

PURPOSE: The purpose of this study was to present the successful management and outcomes in a series of 6 cases of culture-positive nontuberculous mycobacterial keratitis after clear corneal incision phacoemulsification surgery. METHODS: This is a case series of 6 consecutive eyes that presented at the Cornea Division at an academic institution, diagnosed with culture-positive nontuberculous mycobacterial keratitis after phacoemulsification surgery. RESULTS: Six eyes of 5 patients were included. The mean interval from cataract surgery to presentation was 7.7 weeks. All cases presented with intrastromal abscesses adjacent to corneal incisions, and 2 had scleral extension of the infection. Isolated organisms were Mycobacterium abscessus (n = 4), Mycobacterium chelonae (n = 1), and Mycobacterium mucogenicum (n = 1). All cases were treated with topical amikacin 8 mg/mL for 10.5 weeks on average. All cases received either oral clarithromycin at 500 mg twice-daily dosage or oral azithromycin at 500 mg daily. Two patients with scleral abscesses underwent surgical debridement with amniotic membrane grafts. All 6 eyes achieved infection resolution and good visual recovery, with the final visual acuity ranging from 20/20 to 20/60. None of the patients experienced recurrence of infection. CONCLUSIONS: Prompt medical treatment with combined topical and oral therapy can lead to infection resolution and favorable visual recovery. Early surgical intervention can ensure good outcomes in cases of scleral extension.

Approvals and Timing of New Formulations of Novel Drugs Approved by the US Food and Drug Administration Between 1995 and 2010 and Followed Through 2021.

Importance: New formulations of prescription drugs can improve convenience and tolerability for patients, but they also constitute manufacturer strategies to extend brand-name drug market exclusivity periods. Objective: To examine whether new formulations of brand-name novel drugs were associated with novel drugs' sales and/or therapeutic value, as well as characterize first new formulations' approval timing relative to the novel drug's generic approval. Design Setting and Participants: This cross-sectional study used the Drugs@FDA database to identify all novel tablet and capsule drugs approved by the US Food and Drug Administration (FDA) between 1995 and 2010 and followed through December 31, 2021. Exposures: Novel drugs' blockbuster status, defined as annual sales of $1 billion or greater, and therapeutic value, measured by (1) accelerated approval status, (2) World Health Organization Model Lists of Essential Medicines inclusion, (3) innovativeness, and (4) clinical usefulness. Main Outcomes and Measures: Approval of a new formulation and timing relative to a novel drug's first generic's approval. Results: Among the 206 novel drugs in tablet or capsule form approved by the FDA from 1995 to 2010, 81 (39.3%) were followed by an FDA-approved new formulation, and 167 (81.1%) had a generic version as of December 31, 2021. In multivariable analyses, new formulations were statistically significantly more likely among blockbuster drugs vs not (58.2% vs 27.6%; adjusted odds ratio [AOR], 4.72; 95% CI, 2.26-9.87; P < .001) and those granted accelerated approval vs not (50.0% vs 37.6%; AOR, 5.48; 95% CI, 1.52-19.67; P = .009), and less likely among orphan products vs not (11.8% vs 44.8%; AOR, 0.13; 95% CI, 0.03-0.52; P = .004). Essential medicine listing vs no listing (47.8% vs 36.9%; AOR, 1.32; 95% CI, 0.52-3.34; P = .56), first-in-class or advance-in-class status vs addition-to-class status (37.8% vs 40.5%; AOR, 0.71; 95% CI, 0.32-1.58; P = .40), and categorization as clinically useful vs not useful (40.9% vs 44.8%; AOR, 0.81; 95% CI, 0.34-1.92; P = .64) were not associated with increased likelihood of a new formulation. First new formulations were statistically significantly less likely to be approved after the novel drug's first generic approval (84.6% vs 15.4%; P < .001). Conclusions and Relevance: In this cross-sectional study of novel drugs in tablet or capsule form approved by the FDA between 1995 and 2010, manufacturers pursued new formulations of best-selling brand-name drugs and those granted accelerated approval but did so less frequently once generic competitors entered the market. Other measures of therapeutic value were not associated with new formulations.