Nevin Manimala

J Chem Inf Model. 2023 Mar 28. doi: 10.1021/acs.jcim.3c00015. Online ahead of print.

ABSTRACT

To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large data sets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here, we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise. Matcher enables unprecedented control over the search and clustering of MMP transformations based on both variable fragment and constant environment structure, which is critical for disentangling relevant and irrelevant data to a given problem. Users can exert such control through a built-in chemical sketcher and with a few mouse clicks can navigate between resulting MMP transformations, statistics, property distribution graphs, and structures with raw experimental data, for confident and accelerated decision making. Matcher can be used with any collection of structure/property data; here, we demonstrate usage with a public ChEMBL data set of about 20,000 small molecules with CYP3A4 and/or hERG inhibition data. Users can reproduce all examples demonstrated herein via unique links within Matcher’s interface-a functionality that anyone can use to preserve and share their own analyses. Matcher and all its dependencies are open-source, can be used for free, and are available with containerized deployment from code at https://github.com/Merck/Matcher. Matcher makes large structure/property data sets more transparent than ever before and accelerates the data-driven solution of common problems in drug discovery.

PMID:36977316 | DOI:10.1021/acs.jcim.3c00015

J Clin Oncol. 2023 Mar 28:JCO2202553. doi: 10.1200/JCO.22.02553. Online ahead of print.

ABSTRACT

PURPOSE: Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC.

PATIENTS AND METHODS: Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%.

RESULTS: Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002).

CONCLUSION: The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

PMID:36977292 | DOI:10.1200/JCO.22.02553

Vet Sci. 2023 Mar 19;10(3):232. doi: 10.3390/vetsci10030232.

ABSTRACT

Cats urgently visit emergency hospitals due to respiratory distress, and the chief cause is cardiogenic pulmonary edema (CPE). Although cats with CPE were frequently encountered in clinics, the prognostic factors were poorly reported. The objective of this retrospective study was to investigate the association of physical examination and venous blood gas parameters with the survival of cats with CPE in an emergency hospital. Thirty-six cats with CPE were ultimately included in the present study, and eight of them died within 12 h after their presentation to our hospital. Statistical analyses of clinical parameters between cats that died within 12 h and those that survived for 12 h were conducted using Mann-Whitney U test with Bonferroni correction. Cats that died within 12 h had significantly lower rectal temperatures and higher PvCO₂ than those that did not die within 12 h. Moreover, hypotension and vasoconstrictor use were related to death within 12 h of presentation and higher PvCO₂. These findings indicated the prognostic utility of body temperature and PvCO₂, and the association between hypercapnia and the severity of CPE or hypotension. A large number of prospective studies should be performed to validate these results.

PMID:36977271 | DOI:10.3390/vetsci10030232

Vet Sci. 2023 Mar 16;10(3):228. doi: 10.3390/vetsci10030228.

ABSTRACT

Pulmonary disease is often associated with feedlot cattle mortality, and the most common syndromes include bronchopneumonia, acute interstitial pneumonia, and bronchopneumonia with an interstitial pneumonia. The study objective was to utilize gross necropsy and histopathology to determine the frequency of pulmonary lesions from three major syndromes and agreement between gross and histopathological diagnosis. A cross sectional, observational study was performed at six U.S. feedyards using a full systematic necropsy to assess mortalities during summer 2022. A subset of mortalities had four lung samples submitted for histopathological diagnosis. Gross necropsy was performed on 417 mortalities, 402 received a gross diagnosis and 189 had a histopathological diagnosis. Descriptive statistics were used to evaluate pulmonary diagnosis frequency based on method (gross/histopathology), and generalized linear mixed models were used to evaluate agreement between histopathological and gross diagnoses. Using gross diagnosis, bronchopneumonia represented 36.6% of cases with acute interstitial pneumonia and bronchopneumonia with an interstitial pneumonia representing 10.0% and 35.8%, respectively. Results identified bronchopneumonia with an interstitial pneumonia as a frequent syndrome which has only been recently reported. Histopathological diagnosis had similar findings; bronchopneumonia represented 32.3% of cases, with acute interstitial pneumonia and bronchopneumonia with an interstitial pneumonia representing 12.2% and 36.0%, respectively. Histopathological diagnosis tended (p-VALUE = 0.06) to be associated with gross diagnosis. Pulmonary disease was common and both diagnostic modalities illustrated three primary syndromes: bronchopneumonia, acute interstitial pneumonia, and bronchopneumonia with an interstitial pneumonia with similar frequencies. Improved understanding of pulmonary pathology can be valuable for evaluating and adjusting therapeutic interventions.

PMID:36977267 | DOI:10.3390/vetsci10030228

Vet Sci. 2023 Mar 14;10(3):222. doi: 10.3390/vetsci10030222.

ABSTRACT

Transcutaneous abdominal ultrasonography using alcohol saturation is used in the diagnostic workup of a variety of conditions in horses. The duration of the examination and the amount of alcohol used in each case may vary depending on several factors. The aim of this study is to describe the breath alcohol test results obtained by veterinarians performing abdominal ultrasound on horses. Six volunteers were enrolled, after written consent, and a Standardbred mare was used for the whole study protocol. Each operator performed a total of 6 ultrasounds by pouring the ethanol solution from a jar or by spray application, for a duration of 10, 30, and 60 min. An infrared breath alcohol analyzer was used immediately after completing the ultrasonography and at 5-min intervals until a negative result was obtained. Positive results were obtained for 0-60 min after the procedure. A statistically significant difference was found between the groups that used more than 1000 mL, 300-1000 mL, and less than 300 mL of ethanol. No significant differences were observed between the type of ethanol administration and the time of exposure. Based on this study, equine vets who perform ultrasound on horses can test positive at the breath alcohol test for up to 60 min following ethanol exposure.

PMID:36977261 | DOI:10.3390/vetsci10030222

Vet Sci. 2023 Mar 10;10(3):209. doi: 10.3390/vetsci10030209.

ABSTRACT

Limited data exist to predict the severity of pancreatitis in cats. In this retrospective case series, we reviewed the medical records of 45 cats with SP from June 2014 to June 2019. Case definition was based on an internist’s review of clinopathologic data, Spec fPL concentration, and AUS findings. Information extracted from the medical records included signalment, history, physical examination findings, selected clinicopathological data (total bilirubin, glucose, ALP, ALT, and total calcium), Spec fPL concentration, AUS images/clips, length of hospitalization, and survival data. Hazard ratios were used to evaluate the association between clinicopathological data, the Spec fPL assay, AUS findings, and the length of hospitalization. Clinicopathological abnormalities, the Spec fPL, and AUS abnormalities were not statistically associated with the length of hospitalization. Despite a lack of statistical significance, the hazard ratios suggest the potential that an elevated total bilirubin (hazard ratio (HR): 1.19), hypocalcemia (HR: 1.49), and an elevated Spec fPL concentration (HR: 1.54) could be associated with prolonged hospitalization, although additional studies would be needed to verify this. Additionally, hazard ratios suggest that AUS evidence of concurrent gallbladder (HR: 1.61) and gastric abnormalities (HR: 1.36) could be associated with prolonged hospitalization.

PMID:36977248 | DOI:10.3390/vetsci10030209

Vet Sci. 2023 Mar 7;10(3):202. doi: 10.3390/vetsci10030202.

ABSTRACT

A longitudinal study was conducted in five randomly selected farms in Kelantan, Malaysia to determine the seasonal occurrence of cattle fascioliasis and its association with climatic factors. A total of 480 faecal samples were collected by a random purposive sampling method from July 2018 to June 2019. The faecal samples were examined for the presence of Fasciola eggs using a formalin ether sedimentation technique. Meteorological data including temperature, humidity, rainfall, and pan evaporation were obtained from a local meteorological station. The overall prevalence of cattle fascioliasis in Kelantan was 45.8%. The prevalence was observed to be slightly higher during the wet season from August to December (50-58%) than during the dry season from January to June (30-45%). Meanwhile, the mean eggs per gram (EPG) were highest in June (191.1 ± 0.48) and lowest in October (77.62 ± 95.5). However, there were no significant differences in the mean of EPG between the monthly prevalence, tested using one-way ANOVA (p = 0.1828). A statistically significant association (p = 0.014) was observed between the disease and cattle breeds, with Charolais and Brahman showing lower odds of having the disease. There were significant moderate-to-strong positive correlations between cattle fascioliasis and rainfall (r = 0.666; p = 0.018) and humidity (r = 0.808; p = 0.001), as well as strong negative correlations with evaporation (r = -0.829; p = 0.001). The results indicated that the higher prevalence of cattle fascioliasis in Kelantan was correlated with the climatic factors, which include higher rainfall and humidity and lower evaporation.

PMID:36977241 | DOI:10.3390/vetsci10030202

Vet Sci. 2023 Mar 6;10(3):199. doi: 10.3390/vetsci10030199.

ABSTRACT

Feet infrared temperature is associated with feet health and may affect the reproductive performance of sows. In total, 137, 98 and 114 replacement gilts were selected at the age of weaning from 3 herds-A, B and C-with different genetic lines. Dorsal claw length was measured, and anisodactylia was measured in all four feet, at weaning age, and at those gilts that completed their first and second farrowing. At the first and second farrowing stage, the infrared temperature distribution, dew/claw length and backfat thickness were measured concurrently with claw lesion and mobility score evaluation. The maximum temperature significantly differed (p < 0.01) among herds, in the rear feet and in all four feet at the first and second farrowing respectively. Claw lengths statistically differed among herds at all stages (p < 0.05). Anisodactylia in rear feet was lower in herd A (p < 0.05) at weaning, and in herd C at the first and second farrowing (p < 0.05). In addition, the claw lesion score, mobility, backfat thickness and reproductive performance statistically differed among herds (p < 0.05). It is shown that even at an early stage of their reproductive life, claw length differences exist in replacement gilts of different genetic lines.

PMID:36977238 | DOI:10.3390/vetsci10030199

Vet Sci. 2023 Mar 2;10(3):190. doi: 10.3390/vetsci10030190.

ABSTRACT

Canine hemangiosarcoma is a common, highly fatal tumor of older dogs, and predictors of survivability may provide clinically useful information. The objectives of this case series were to determine if a previously published tumor histological grading scheme, the level of tumor cellular atypia, clinical staging, or the level of CD 31 expression were useful for predicting the survival time in dogs with splenic hemangiosarcoma. Canine splenic hemangiosarcomas from 16 dogs were histologically graded, clinically staged, and assessed for CD 31 expression. Medical records were reviewed, the date of death was obtained, and survival data were analyzed statistically. Histopathological grading and clinical staging of canine splenic hemangiosarcomas, and the expression of CD 31 by the tumor cells were not significantly associated with the median survival time of the dogs in this study. However, strong expression of CD 31 by canine splenic hemangiosarcoma tumor cells was observed in dogs with short survival times, which warrants further studies to evaluate the potential prognostic value of CD 31 expression for the survival of dogs with splenic hemangiosarcoma.

PMID:36977229 | DOI:10.3390/vetsci10030190

Vet Sci. 2023 Feb 24;10(3):182. doi: 10.3390/vetsci10030182.

ABSTRACT

Osteoarthritis is a chronic disease that often affects the canine stifle joint. Due to their biomechanical function, the menisci in the canine stifle play an important role in osteoarthritis. They compensate for the incongruence in the joint and distribute and minimize compressive loads, protecting the hyaline articular cartilage from damage. Meniscal degeneration favors the development and progression of stifle joint osteoarthritis. Qualitative magnetic resonance imaging (MRI) is the current golden standard for detecting meniscal changes, but it has limitations in detecting early signs of meniscal degeneration. A quantitative MRI offers new options for detecting early structural changes. T2 mapping can especially visualize structural changes such as altered collagen structures and water content, as well as deviations in proteoglycan content. This study evaluated T2 mapping and performed a histological scoring of menisci in elderly dogs that had no or only low radiographic osteoarthritis grades. A total of 16 stifles from 8 older dogs of different sex and breed underwent ex vivo magnet resonance imaging, including a T2 mapping pulse sequence with multiple echoes. A histological analysis of corresponding menisci was performed using a modified scoring system. The mean T2 relaxation time was 18.2 ms and the mean histological score was 4.25. Descriptive statistics did not reveal a correlation between T2 relaxation time and histological score. Ex vivo T2 mapping of canine menisci did not demonstrate histological changes, suggesting that early meniscal degeneration can be present in the absence of radiological signs of osteoarthritis, including no significant changes in T2 relaxation time.

PMID:36977221 | DOI:10.3390/vetsci10030182