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PURPOSE: The purpose of this study was to assess the association between antifungal susceptibility as measured by minimum inhibitory concentration (MIC) and clinical outcomes in fungal keratitis. METHODS: This pre-specified secondary analysis of the Mycotic Ulcer Treatment Trial II (MUTT II) involved patients with filamentous fungal keratitis presenting to Aravind Eye Hospitals in South India. Antifungal susceptibility testing for natamycin and voriconazole was performed on all samples with positive fungal culture results according to Clinical and Laboratory Standards Institute Guidelines. The relationship between MIC and clinical outcomes of best-corrected visual acuity, infiltrate or scar size, corneal perforation, need for therapeutic penetrating keratoplasty, and time to re-epithelialization were assessed. RESULTS: We obtained MIC values from 141 patients with fungal keratitis. The most commonly cultured organisms were Aspergillus (46.81%, n = 66) and Fusarium (44.68%, n = 63) species. Overall, there was no association between antifungal MICs and clinical outcomes. Subgroup analysis revealed that among Fusarium-positive cases, higher voriconazole MIC was correlated with worse three-month best-corrected visual acuity (p = 0.03), increased need for therapeutic penetrating keratoplasty (p = 0.04), and time to re-epithelialization (p = 0.03). No significant correlations were found among Aspergillus-positive cases. There were no significant correlations found between natamycin MIC and clinical outcomes among organism subgroups. CONCLUSIONS: Decreased susceptibility to voriconazole was associated with increased odds of requiring a therapeutic penetrating keratoplasty in Fusarium-positive cases. Susceptibility to natamycin was not associated with any of the measured outcomes.

PURPOSE: This study sought to identify the sources of differential performance and misclassification error among local (Indian) and external (non-Indian) corneal specialists in identifying bacterial and fungal keratitis based on corneal photography. METHODS: This study is a secondary analysis of survey data assessing the ability of corneal specialists to identify acute bacterial versus fungal keratitis by using corneal photography. One-hundred images of 100 eyes from 100 patients with acute bacterial or fungal keratitis in South India were previously presented to an international cohort of cornea specialists for interpretation over the span of April to July 2021. Each expert provided a predicted probability that the ulcer was either bacterial or fungal. Using these data, we performed multivariable linear regression to identify factors predictive of expert performance, accounting for primary practice location and surrogate measures to infer local fungal ulcer prevalence, including locality, latitude, and dew point. In addition, Brier score decomposition was used to determine experts reliability (calibration) and resolution (boldness) and were compared between local (Indian) and external (non-Indian) experts. RESULTS: Sixty-six experts from 16 countries participated. Indian practice location was the only independently significant predictor of performance in multivariable linear regression. Resolution among Indian experts was significantly better (0.08) than among non-Indian experts (0.01; P < 0.001), indicating greater confidence in their predictions. There was no significant difference in reliability between the two groups ( P = 0.40). CONCLUSION: Local cornea experts outperformed their international counterparts independent of regional variability in tropical risk factors for fungal keratitis. This may be explained by regional characteristics of infectious ulcers with which local corneal specialists are familiar.

BackgroundAlthough alcohol abstinence may be an effective intervention for alcohol-associated cirrhosis, its association with prognosis has not been systematically assessed or quantified.AimsTo determine the prevalence of alcohol abstinence, factors associated with alcohol abstinence and the impact of abstinence on morbidity and overall survival in people with alcohol-associated cirrhosis.MethodsWe searched Medline and Embase from inception to 15 April 2023 for prospective and retrospective cohort studies describing alcohol abstinence in people with known alcohol-associated cirrhosis. Meta-analysis of proportions for pooled estimates was performed. The method of inverse variance, employing a random-effects model, was used to pool the hazard ratio (HR) comparing outcomes of abstinent against non-abstinent individuals with alcohol-associated cirrhosis.ResultsWe included 19 studies involving 18,833 people with alcohol-associated cirrhosis. The prevalence of alcohol abstinence was 53.8% (CI: 44.6%-62.7%). Over a mean follow-up duration of 48.6 months, individuals who continued to consume alcohol had significantly lower overall survival compared to those who were abstinent (HR: 0.611, 95% CI: 0.506-0.738). These findings remained consistent in sensitivity/subgroup analysis for the presence of decompensation, study design and studies that assessed abstinence throughout follow-up. Alcohol abstinence was associated with a significantly lower risk of hepatic decompensation (HR: 0.612, 95% CI: 0.473-0.792).ConclusionsAlcohol abstinence is associated with substantial improvement in overall survival in alcohol-associated cirrhosis. However, only half of the individuals with known alcohol-associated cirrhosis are abstinent.

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

BackgroundThe cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC.MethodsData were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men.ResultsA total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P

The floral industry grapples with challenges like changing climatic scenarios, differences in market trends, rising costs, and severe losses posed by insect pests. The management of dipteran pests encompassing diverse species, such as leaf miners, midges, flies, and mosquitoes, has emerged as an obligate adversary, inflicting substantial economic losses in the cut and loose flower industry. Through a comprehensive analysis of existing literature, this paper delves into the diverse array of dipteran species of leaf miners and midges, their life cycles, distribution, host range, damaging symptoms, insecticide resistance, and the management strategies practised to date. Furthermore, this critique underscores the urgent need for innovative approaches and integrated pest management techniques to mitigate the escalating menace of dipteran pests. By elucidating the multifaceted challenges and proposing strategic interventions, this critique aims to foster dialogue and inspire concerted action among researchers, stakeholders, and scholars to safeguard the sustainability and profitability of the floral industry.

Abstract Purpose The purpose of this study was to assess the association between antifungal susceptibility as measured by minimum inhibitory concentration (MIC) and clinical outcomes in fungal keratitis. Methods This pre-specified secondary analysis of the Mycotic Ulcer Treatment Trial II (MUTT II) involved patients with filamentous fungal keratitis presenting to Aravind Eye Hospitals in South India. Antifungal susceptibility testing for natamycin and voriconazole was performed on all samples with positive fungal culture results according to Clinical and Laboratory Standards Institute Guidelines. The relationship between MIC and clinical outcomes of best-corrected visual acuity, infiltrate or scar size, corneal perforation, need for therapeutic penetrating keratoplasty, and time to re-epithelialization were assessed. Results We obtained MIC values from 141 patients with fungal keratitis. The most commonly cultured organisms were Aspergillus (46.81%, n = 66) and Fusarium (44.68%, n = 63) species. Overall, there was no association between antifungal MICs and clinical outcomes. Subgroup analysis revealed that among Fusarium-positive cases, higher voriconazole MIC was correlated with worse three-month best-corrected visual acuity (p = 0.03), increased need for therapeutic penetrating keratoplasty (p = 0.04), and time to re-epithelialization (p = 0.03). No significant correlations were found among Aspergillus-positive cases. There were no significant correlations found between natamycin MIC and clinical outcomes among organism subgroups. Conclusions Decreased susceptibility to voriconazole was associated with increased odds of requiring a therapeutic penetrating keratoplasty in Fusarium-positive cases. Susceptibility to natamycin was not associated with any of the measured outcomes.

Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with HF.This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF.The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period.The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors.SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.

PurposeTo evaluate the diagnostic accuracy of smartphone corneal photography in detecting corneal opacities in a community-based setting.MethodsA case-control, diagnostic accuracy study was nested in a cluster-randomized trial of a corneal ulcer prevention intervention in Nepal. Smartphone corneal photography was performed annually on community members self-reporting a potential risk factor for a corneal infection. Corneal photographs were graded for the presence or absence of an opacity. All cases with an opacity on smartphone photography and an equal number of controls were invited for a comprehensive eye examination with a slit lamp biomicroscope at an eye hospital. A mobile team visited participants unable to come to the hospital, conducting a limited examination with a penlight.ResultsOf 1332 study participants (666 cases and 666 controls), 1097 had a penlight examination (535 cases and 562 controls) and 191 had a slit lamp examination (120 cases and 71 controls). When penlight examination was considered the reference standard, smartphone diagnosis of a corneal opacity had a positive predictive value (PPV) of 47% (95% confidence interval 43-52%) and negative predictive value (NPV) of 95% (93-97%). When slit lamp examination was considered the reference standard, the overall PPV and NPV were 71% (62-78%) and 80% (70-88%), respectively. The NPV was greater for detection of opacities > 1mm, estimated at 95% (90-98%).ConclusionsCorneal photography performed in a resource-limited community-based setting using a smartphone coupled to an external attachment had acceptable diagnostic accuracy for detection of corneal opacities large enough to be clinically meaningful.

Objective: Air-Q intubating laryngeal airway (ILA) is associated with a 58-77% success rate in blind intubation. The newer laryngeal mask airway (LMA) blockbuster is specially designed to facilitate easier endotracheal intubation and may have a higher success rate. The current study aimed to compare the success rate of endotracheal intubation using the Air-Q ILA and LMA blockbuster. Methods: After ethics committee approval and informed written consent, 140 adult patients with normal airways who were scheduled for elective surgery under general anaesthesia requiring endotracheal intubation were recruited for this randomized controlled trial. Blind endotracheal intubation was performed using the Air-Q ILA in group A and the LMA blockbuster in group B with special maneuvers and/or tubes in the second attempt. Fibreoptic bronchoscope (FOB) guidance was used in the third attempt if required. The primary outcome was the success rate of intubation without FOB assistance. The number of attempts for supraglottic airway (SGA) insertion, the time taken for SGA insertion, and the overall intubation time was also noted. Results: The success rate of intubation without FOB guidance was significantly higher in group B than in group A [91.4% vs 55.7%; relative risk (RR) 1.68; (95% confidence interval (CI) 1.34, 2.11); p

One indicator of success in learning mathematics is problem solving ability. There are two types of mathematics questions that are generally known, namely routine and non-routine questions. Based on these reasons, the question arises of how junior high school students represent mathematically in solving non-routine mathematics problems. This research uses a qualitative approach with descriptive research type. Data was collected using research instruments in the form of non-routine mathematics test instruments to measure students' mathematical representation abilities in problem solving. Then the subject will be interviewed about how he represents the answer to the question. The data will be analyzed by researchers using the Miles, Huberman, Saldana model to describe and provide mathematical problem solving skills. There are findings that need attention, namely the existence of differences in variations in problem solving. This can happen because students have different mathematical interpretation and representation abilities.

Abstract Evaluating drought parameters at the basin level is one of the fundamental processes for planning sustainable crop production. This study aimed to evaluate both short-term and long-term meteorological drought parameters within the Vaippar Basin, located in southern India, by employing the standardized precipitation index (SPI). Gridded rainfall values developed from 13 rain gauge stations were employed to calculate the SPI values. Drought parameters, encompassing occurrence, intensity, duration, frequency, and trends, were assessed for both short-term and long-term droughts. The study findings indicated that the occurrence of short-term drought was 51.7%, while that of long-term drought was 49.82%. Notably, the basin experienced extreme short-term droughts in 1980, 1998 and 2016 and long-term droughts in 1981, 2013, and 2017. Utilizing an innovative trend identification method for SPI values, a significant monotonic upwards trend was identified in October and December for short-term drought and in December for long-term drought. This study defined the minimum threshold rainfall, which represents the critical amount required to prevent short-term drought (set at 390 mm) and long-term drought (set at 635 mm). The drought severity recurrence curves developed in this study indicate that when the SPI values fall below − 1.0, short-term drought affects 25% of the basin area, while long-term drought impacts 50% of the basin area at a 20-year recurrence interval. Additionally, the drought hazard index (DHI), which combines drought intensity and severity, demonstrated higher values in the northwestern regions for short-term drought and in the southern areas for long-term drought. The study's findings, highlighting areas of drought vulnerability, severity, and recurrence patterns in the basin, direct the attention for timely intervention when drought initiates.

Chemical modifications are necessary to ensure the metabolic stability and efficacy of oligonucleotide-based therapeutics. Here, we describe analyses of the α-(l)-threofuranosyl nucleic acid (TNA) modification, which has a shorter 3'-2' internucleotide linkage than the natural DNA and RNA, in the context of small interfering RNAs (siRNAs). The TNA modification enhanced nuclease resistance more than 2'-O-methyl or 2'-fluoro ribose modifications. TNA-containing siRNAs were prepared as triantennary N-acetylgalactosamine conjugates and were tested in cultured cells and mice. With the exceptions of position 2 of the antisense strand and position 11 of the sense strand, the TNA modification did not inhibit the activity of the RNA interference machinery. In a rat toxicology study, TNA placed at position 7 of the antisense strand of the siRNA mitigated off-target effects, likely due to the decrease in the thermodynamic binding affinity relative to the 2'-O-methyl residue. Analysis of the crystal structure of an RNA octamer with a single TNA on each strand showed that the tetrose sugar adopts a C4'-exo pucker. Computational models of siRNA antisense strands containing TNA bound to Argonaute 2 suggest that TNA is well accommodated in the region kinked by the enzyme. The combined data indicate that the TNA nucleotides are promising modifications expected to increase the potency, duration of action, and safety of siRNAs.

ImportanceEmerging data suggest that the incidence of early-onset cancers, defined as cancers diagnosed in people younger than 50 years, is increasing, but updated data are limited.ObjectiveTo characterize the patterns in the incidence of early-onset cancers in the US from 2010 to 2019 and provide granular data on the cancers with the fastest-growing incidence rates.Design, setting, and participantsThis population-based cohort study analyzed data from 17 National Cancer Institute Surveillance, Epidemiology, and End Results registries from January 1, 2010, to December 31, 2019. Age-standardized incidence rates per 100 000 people were extracted for early-onset cancers, with rates age adjusted to the US standard population. A total of 562 145 patients with early-onset cancer between 2010 and 2019 were identified and included. Data were analyzed from October 16, 2022, to May 23, 2023.Main outcomes and measuresPrimary outcomes were incidence rates and descriptive epidemiological data for people younger than 50 years with cancer. The annual percentage change (APC) of the age-standardized incidence rate was estimated using the Joinpoint regression program.ResultsAmong 562 145 patients (324 138 [57.7%] aged 40-49 years; 351 120 [62.5%] female) with early-onset cancer, 4565 (0.8%) were American Indian or Alaska Native, 54 876 (9.8%) were Asian or Pacific Islander, 61 048 (10.9%) were Black, 118 099 (21.0%) were Hispanic, 314 610 (56.0%) were White, and 8947 (1.6%) were of unknown race and/or ethnicity. From 2010 to 2019, the age-standardized incidence rate of early-onset cancers increased overall (APC, 0.28%; 95% CI, 0.09%-0.47%; P = .01) and in female individuals (APC, 0.67%; 95% CI, 0.39%-0.94%; P = .001) but decreased in male individuals (APC, -0.37%; 95% CI, -0.51% to -0.22%; P