Tag: pubmed

Annu Rev Pharmacol Toxicol. 2023 Jul 31. doi: 10.1146/annurev-pharmtox-022823-113946. Online ahead of print.

ABSTRACT

Here we discuss approaches to K-Ras inhibition and drug resistance scenarios. A breakthrough offered a covalent drug against K-Ras^G12C. Subsequent innovations harnessed same-allele drug combinations, as well as cotargeting K-Ras^G12C with a companion drug to upstream regulators or downstream kinases. However, primary, adaptive, and acquired resistance inevitably emerge. The preexisting mutation load can explain how even exceedingly rare mutations with unobservable effects can promote drug resistance, seeding growth of insensitive cell clones, and proliferation. Statistics confirm the expectation that most resistance-related mutations are in cis, pointing to the high probability of cooperative, same-allele effects. In addition to targeted Ras inhibitors and drug combinations, bifunctional molecules and innovative tri-complex inhibitors to target Ras mutants are also under development. Since the identities and potential contributions of preexisting and evolving mutations are unknown, selecting a pharmacologic combination is taxing. Collectively, our broad review outlines considerations and provides new insights to pharmacology and resistance. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:37524384 | DOI:10.1146/annurev-pharmtox-022823-113946

J Periodontal Implant Sci. 2023 Jun 27. doi: 10.5051/jpis.2204320216. Online ahead of print.

ABSTRACT

PURPOSE: The aim of this study was to investigate the relationships between gingival thickness (GT) and keratinized gingiva width (KGW), papilla height (PH), and crown ratio (CR) by employing transgingival probing and an intraoral scanner (IOS).

METHODS: This cross-sectional study examined 360 maxillary anterior teeth from 60 patients. GT was assessed using transgingival probing with an endodontic spreader. KGW, CR, and PH were measured using an IOS. One-way analysis of variance, the Student’s t-test, and Spearman correlation coefficients were employed for statistical analysis.

RESULTS: Higher GT was significantly associated with thinner KGW in the central region (P=0.019). There was no statistically significant difference in GT between teeth (P=0.06). PH was lower in lateral teeth than in canines (P=0.047), with a PH of 2.99 mm in lateral teeth. The KGW was narrower in canines than in central teeth (P=0.007). A moderate correlation was observed between KGW and PH in the central region (P=0.01), while a weak negative correlation was found between KGW and CR (P=0.043).

CONCLUSIONS: A moderate negative correlation was found between GT and KGW, as well as between PH and KGW in central teeth. In contrast, a weak negative correlation existed between CR and KGW. The PH (2.99 mm) was lower in lateral teeth than in canines. The traditional paradigm, which suggests a positive correlation between KGW and GT, was re-evaluated by measuring KGW using an IOS.

PMID:37524382 | DOI:10.5051/jpis.2204320216

J Periodontal Implant Sci. 2023 Jun 12. doi: 10.5051/jpis.2204360218. Online ahead of print.

ABSTRACT

PURPOSE: The inflammatory response due to inflammatory cytokines, bacterial pathogens, and the altered lipoprotein metabolism in patients with periodontitis indicates that infection with periodontal anaerobic bacteria may influence atherogenesis in vitro and in vivo. We aimed to explore the effect of periodontitis concerning clinical and ultrasound markers of early atherosclerosis.

METHODS: In this case-control study, a total of 30 systemically healthy adults (15 with periodontitis and 15 without periodontitis) over 40 years of age were studied. Periodontitis was determined by measuring the clinical attachment level (CAL) and radiographic bone loss (RBL). Conventional cardiovascular risk factors, including body mass index, serum levels of total cholesterol (TCH), triglycerides (TG), and high-density and low-density lipoprotein (HDL and LDL, respectively) cholesterol were evaluated. Carotid artery intima-media thickness (IMT) was measured using ultrasonography.

RESULTS: The mean values of the CAL and carotid IMT were 5.02±0.9 mm and 0.084±0.01 cm vs. 1.6±0.61 mm and 0.072±0.02 cm in the periodontitis and healthy groups, respectively, reflecting statistically significant differences (P=0.001 and P=0.037, respectively). There were statistically significant differences in the serum levels of TCH, TG, and LDL between the 2 groups (P=0.017). The CAL and RBL were positively associated with carotid IMT and serum cholesterol levels, except for HDL, whereas tooth loss was not associated with any markers (P<0.05). Compared to the healthy group, participants with periodontitis exhibited 2.09 times higher odds (95% confidence interval, 1.22-3.59) of having subclinical atherosclerosis.

CONCLUSIONS: The presence of periodontitis increased the risk of atherosclerosis.

PMID:37524377 | DOI:10.5051/jpis.2204360218

J Am Vet Med Assoc. 2023 Jul 31:1-8. doi: 10.2460/javma.23.05.0288. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe radiotherapy outcomes for canine infiltrative lipomas and provide detailed radiotherapy planning data.

ANIMALS: 24 dogs from 2000 to 2020.

METHODS: In this retrospective study, dogs received 1 to 3 surgeries prior to conventionally fractionated radiotherapy for gross (18) or microscopic (8) infiltrative lipomas. Dogs received 45 to 51 Gray (Gy) in 15 to 20 daily fractions, with 71% of dogs receiving 48 Gy in daily 3-Gy fractions.

RESULTS: Masses were regionally located as follows: limbs (7), trunk (13), head/neck (4). At analysis, 16/24 dogs were deceased, 5/24 were alive (median follow-up for alive dogs: 1,216 days [range, 741 to 1,870 days]), and 3/24 were lost to follow-up. One living dog had progressive disease 923 days after completing conventionally fractionated radiotherapy and received another surgery. The estimated median overall survival (OS) after completing radiotherapy was 4.8 years (1,760 days; 95% CI, 1,215 to 2,777 days; range, 23 to 3,499 days) for any cause of death, and no patients were reported to have been euthanized or died from their tumor. No statistically significant difference was found for dogs based on gross versus microscopic disease (gross OS, 4.8 years vs microscopic OS, 3.6 years; P = .45). Furthermore, the number of surgeries before radiotherapy did not impact survival (P = .96). The survival difference between females (median OS, 7.6 years; 95% CI, 963 days to not reached) versus males (median OS, 4.6 years; 95% CI, 335 to 2,245 days; P = .05) was statistically significant, although 4/5 living dogs were female.

CLINICAL RELEVANCE: This study demonstrates lengthy survivals with radiotherapy, even with gross disease, for dogs with infiltrative lipomas.

PMID:37524353 | DOI:10.2460/javma.23.05.0288

Bone Joint J. 2023 Aug 1;105-B(8):920-927. doi: 10.1302/0301-620X.105B8.BJJ-2022-1104.R2.

ABSTRACT

AIMS: Traumatic central cord syndrome (CCS) typically follows a hyperextension injury and results in motor impairment affecting the upper limbs more than the lower, with occasional sensory impairment and urinary retention. Current evidence on mortality and long-term outcomes is limited. The primary aim of this study was to assess the five-year mortality of CCS, and to determine any difference in mortality between management groups or age.

METHODS: Patients aged ≥ 18 years with a traumatic CCS between January 2012 and December 2017 in Wales were identified. Patient demographics and data about injury, management, and outcome were collected. Statistical analysis was performed to assess mortality and between-group differences.

RESULTS: A total of 65 patients were identified (66.2% male (n = 43), mean age 63.9 years (SD 15.9)). At a minimum of five years’ follow-up, 32.3% of CCS patients (n = 21) had died, of whom six (9.2%) had died within 31 days of their injury. Overall, 69.2% of patients (n = 45) had been managed conservatively. There was no significant difference in age between conservatively and surgically managed patients (p = 0.062). Kaplan-Meier analysis revealed no significant difference in mortality between patients managed conservatively and those managed surgically (p = 0.819). However, there was a significant difference in mortality between the different age groups (< 50 years vs 50 to 70 years vs > 70 years; p = 0.001). At five years’ follow-up, 55.6% of the patient group aged > 70 years at time of injury had died (n = 15). Respiratory failure was the most common cause of death (n = 9; 42.9%).

CONCLUSION: Almost one-third of patients with a traumatic CCS in Wales had died within five years of their injury. The type of management did not significantly affect mortality but their age at the time of injury did. Further work to assess the long-term functional outcomes of surviving patients is needed to generate more reliable prognostic information.

PMID:37524347 | DOI:10.1302/0301-620X.105B8.BJJ-2022-1104.R2

Neuro Endocrinol Lett. 2023 Jul 28;44(5):283-289. Online ahead of print.

ABSTRACT

BACKGROUND: Cognitive impairment (CI) may be present in people with multiple sclerosis (PwMS) in different stages of the disease, as well as in PwMS with various degrees of disability. This study aimed to investigate cognitive decline over a period of 12 months and to examine an association between cognition and the disability in PwMS, also over a period of 12 months.

METHODS: The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery was used, containing the Symbol Digit Modalities Test (SDMT), the Categorical Verbal Learning Test (CVLT), and the Brief Visuospatial Memory Test-Revised (BVMT-R). The Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9-HPT) were used to assess the degree of disability. For the analysis of cognitive decline over the period of 12 months, Wilcoxon signed-rank test (paired sample t-test) was used. For the correlation between cognition and disability, Spearman’s correlation test was used.

RESULTS: We observed statistically meaningful difference only in one measure of cognition (CVLT), not the other two (SDMT and BVMT-R). SDMT significantly correlated with methods assessing the degree of disability in both time points. In the second examination, we observed a correlation between BICAMS and 9-HPT. Similarly, SDMT and BVMT-R also correlated with EDSS.

CONCLUSION: To investigate the cognitive decline in PwMS, a longer period of time probably should have been chosen. EDSS is commonly used to monitor disease progression, but it does not include the evaluation of various parameters, such as cognition or upper limb function. Its use with the 9-HPT and cognitive tests may represent a more reliable and comprehensive assessment of a patient’s clinical condition.

PMID:37524317

Gynecol Endocrinol. 2023 Dec;39(1):2239934. doi: 10.1080/09513590.2023.2239934.

ABSTRACT

OBJECTIVE: Though recent studies have pointed out different manifestations between obese and nonobese patients with polycystic ovarian syndrome (PCOS), there is no clear evidence to confirm this viewpoint. Therefore, the metabolic characteristics of obese and nonobese patients with PCOS were systematically compared through meta-analysis in this study.

METHODS: Data were searched from PubMed, Web of Science, Embase, Cochrane Library, CNKI, and Wanfang databases. Articles on obese and nonobese patients with PCOS published from database inception to January 2022 were included. Meta-analysis was performed using Stata 16.0 statistical software.

RESULTS: A total of 739 articles were initially retrieved, and ultimately 14 studies were involved in the meta-analysis. Specifically, there were 801 patients in the observation group (obese patients with PCOS) and 925 patients in the control group (nonobese patients with PCOS). Compared with the control group, the observation group had significantly lower levels of sex hormone-binding globulin (SHBG), high-density lipoprotein (HDL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and higher levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL). Nevertheless, there were no significant differences between the two groups in systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, and testosterone.

CONCLUSION: Compared with nonobese patients with PCOS, obese patients with PCOS have worse blood lipid parameters and lower levels of LH and FSH. Also, there are significant differences in metabolic characteristics between the two groups of patients. Most importantly, our findings provide guidance for the clinical diagnosis and treatment of PCOS.

PMID:37524309 | DOI:10.1080/09513590.2023.2239934

Clin Microbiol Infect. 2023 Jul 29:S1198-743X(23)00342-7. doi: 10.1016/j.cmi.2023.07.016. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to identify predictors of confirmed mpox among people with mpox-like illness and to develop a multivariable model for confirmed mpox.

METHODS: We performed a retrospective study using national epidemiologic surveillance data in Mexico from May to November 2022. People with mpox-like illness were reported to the Mexican Ministry of Health (MMH) and real-time polymerase chain reaction was performed in clinical samples to confirm mpox. Sociodemographic and clinical data were collected with a case-report form. We performed univariable logistic regressions to estimate predictive capability of individual characteristics, reported with odds ratios and 95% confidence intervals (OR, 95%CI). Variables of interest were included in multivariable logistic regression models and Akaike information criterion was used to retain variables for the final model. Discrimination and calibration of the model were estimated in bootstrap resamples.

RESULTS: 5,078 people were reported with mpox-like illness. 3,291/5,078 (64.8%) had confirmed mpox. The strongest clinical predictors of confirmed mpox in univariable models were proctitis (OR 6.54, 5.93-7.21), inguinal adenopathy (OR 5.91, 5.36-6.52), and anogenital lesions (OR 5.45, 4.94-6.02). The final model included being a man who has sex with men(MSM) (8.75, 7.37-10.38), HIV diagnosis (3.04, 2.51-3.69), inguinal adenopathy (2.24, 1.81-2.77), anogenital lesions (2.32, 1.97-2.74), and pustules (1.55, 1.32-1.81). Discrimination capability was excellent (c statistic 0.88, 95%CI 0.87-0.89) and it was well calibrated (calibration slope 1, 95%CI 0.95-1.05).

CONCLUSION: A third of people with mpox-like illness do not have mpox. Being MSM, HIV diagnosis, inguinal adenopathy, pustules, and anogenital lesions are strongly associated with confirmed mpox.

PMID:37524303 | DOI:10.1016/j.cmi.2023.07.016

Ocul Surf. 2023 Jul 29:S1542-0124(23)00096-4. doi: 10.1016/j.jtos.2023.07.010. Online ahead of print.

ABSTRACT

BACKGROUND: Meibomian gland dysfunction (MGD) is one of the most common conditions in ophthalmic practice and the most frequent cause of evaporative dry eye disease (DED). However, the immune mechanisms leading to this pathology are not fully understood and the diagnostic tests available are limited. Here, we used the nCounter technology to analyze immune gene expression in DED-MGD that can be used for developing diagnostic signatures for DED.

METHODS: Conjunctival cell samples were obtained by aspiration from patients with DED-MGD (n = 27) and asymptomatic controls (n = 22). RNA was purified, converted to cDNA, preamplified and analyzed using the Gene Expression Human Immune V2 panel (NanoString), which includes 579 target and 15 housekeeping genes. A machine learning (ML) algorithm was applied to design a signature associated with DED-MGD.

RESULTS: Forty-five immune genes were found upregulated in DED-MGD vs. controls, involved in eight signaling pathways, IFN I/II, MHC class I/II, immunometabolism, B cell receptor, T Cell receptor, and T helper-17 (Th-17) differentiation. Additionally, statistically significant correlations were found between 31 genes and clinical characteristics of the disease such as lid margin or tear osmolarity (Pearson’s r < 0.05). ML analysis using a recursive feature elimination (RFE) algorithm selected a 4-gene mRNA signature that discriminated DED-MGD from control samples with an area under the ROC curve (AUC ROC) of 0.86 and an accuracy of 77.5%.

CONCLUSIONS: Multiplexed mRNA analysis of conjunctival cells can be used to analyze immune gene expression patterns in patients with DED-MGD and to generate diagnostic signatures.

PMID:37524297 | DOI:10.1016/j.jtos.2023.07.010

Int J Infect Dis. 2023 Jul 29:S1201-9712(23)00681-1. doi: 10.1016/j.ijid.2023.07.031. Online ahead of print.

ABSTRACT

BACKGROUND: A previous review demonstrated that the majority of NTM infections in the Northern Territory (NT) are pulmonary in nature,[1] however skin and soft tissue (SST) are likely the next most common sites of disease. The current epidemiology of NTM SST infections across the NT is not known. We aimed to establish the current and historical incidence rates, and the organisms involved.

METHODS: All NTM cases reported to the Centre for Disease Control in Darwin from 1989-2021 were retrospectively reviewed.

RESULTS: 226 NTM notifications were reviewed. 73 (32%) cases were SST infections. The incidence of SST cases increased over the study period. Female cases were more common (p=0·002). Disease occurred across a wide age range (1-85 years). Only 16% of cases occurred in Aboriginal individuals. Many cases had no clear provocation, but localised trauma was the most common risk factor. The most common organism identified was M. fortuitum (41%). Diagnosis was often delayed, with a median time to diagnosis of 69 days (IQR=31-149). Most cases (60%) underwent surgical intervention with adjunctive anti-mycobacterial medical therapy.

CONCLUSION: NTM SST incidence rates increased over the study period. NTM SST infections are a rare but important differential diagnosis for non-healing cutaneous wounds.

PMID:37524256 | DOI:10.1016/j.ijid.2023.07.031