Development of rabbit models of ventilator-associated bacterial pneumonia produced by carbapenem-resistant Pseudomonas aeruginosa.

Ventilator-associated bacterial pneumonia (VABP) is among the most intractable of carbapenem-resistant Gram-negative bacterial infections. New antimicrobial agents are critically needed for the treatment of VABP. However, current conventionally used animal model systems are inadequate to meet this challenge. We, therefore, developed rabbit models of VABP caused by carbapenem-resistant Pseudomonas aeruginosa. Persistently neutropenic New Zealand White rabbits were used throughout the study. The early-phase intubated model (0-24 h) received mechanical ventilation, while the late-phase intubated model (72-96 h) was ambulatory. The following outcome parameters were studied: survival, residual tissue bacterial burden (CFU/g), residual BAL bacterial burden (CFU/mL), lung weights, pulmonary lesion score, histology, O2 saturation, radiographic imaging, and histology. Each anesthetized rabbit received a predetermined endotracheal bacterial inoculum, and ventilators were set to FiO2 = 40% and PEEP = 8 mmHg. Within the first 12 h post-inoculation, mean bacterial burdens in lung tissue and BAL fluid, respectively, were established at approximately 107 CFU/g and 106 CFU/mL, persisted through 24 h in the early-phase model and increased in the late-phase model to approximately 108 CFU/g and 107 CFU/mL. Mean max SpO2 was ≥98 mmHg, and mean nadir SpO2 was ≥68 mmHg. Serial thoracic radiographs demonstrated progressive multilobar pneumonic infiltrates. Lung histology revealed progressive focal bronchopneumonia, coagulative necrosis, intra-alveolar hemorrhage, alveolar epithelial cell necrosis, and bacterial microcolonies. The new rabbit model of VABP produced by carbapenem-resistant Pseudomonas aeruginosa recapitulates the pathophysiological, microbiological, diagnostic imaging, and histological patterns of human disease by which to assess critically needed new antimicrobial agents against this lethal infection.

Exploring the potential of bis(thiazol-5-yl)phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) represents an alarming global challenge to public health. Infections caused by multidrug-resistant Staphylococcus aureus (S. aureus) pose an emerging global threat. Therefore, it is crucial to develop novel compounds with promising antimicrobial activity against S. aureus especially those with challenging resistance mechanisms and biofilm formation. Series of bis(thiazol-5-yl)phenylmethane derivatives were evaluated against drug-resistant Gram-positive bacteria. The screening revealed an S. aureus-selective mechanism of bis(thiazol-5-yl)phenylmethane derivatives (MIC 2-64 µg/mL), while significantly lower activity was observed with vancomycin-resistant Enterococcus faecalis (MIC 64 µg/mL) (p<0.05). The most active phenylmethane-based (p-tolyl) derivative, 23a, containing nitro and dimethylamine substituents, and the naphthalene-based derivative, 28b, harboring fluorine and nitro substituents, exhibited strong, near MIC bactericidal activity against S. aureus with genetically defined resistance phenotypes such as MSSA, MRSA, and VRSA and their biofilms. The in silico modeling revealed that most promising compounds 23a and 28b were predicted to bind S. aureus MurC ligase. The 23a and 28b formed bonds with MurC residues at binding site, specifically Ser12 and Arg375, indicating consequential interactions essential for complex stability. The in vitro antimicrobial activity of compound 28b was not affected by the addition of 50% serum. Finally, all tested bis(thiazol-5-yl)phenylmethane derivatives showed favorable cytotoxicity profiles in A549 and THP-1-derived macrophage models. These results demonstrated that bis(thiazol-5-yl)phenylmethane derivatives 23a and 28b could be potentially explored as scaffolds for the development of novel candidates targeting drug-resistant S. aureus. Further studies are also warranted to understand in vivo safety, efficacy, and pharmacological bioavailability of bis(thiazol-5-yl)phenylmethane derivatives.

Synthesis of 3-((4-Hydroxyphenyl)amino)propanoic Acid Derivatives as Promising Scaffolds for the Development of Antimicrobial Candidates Targeting Multidrug-Resistant Bacterial and Fungal Pathogens.

Infections caused by multidrug-resistant bacterial and fungal pathogens represent a significant global health concern, contributing to increased morbidity and mortality rates. Therefore, it is crucial to develop novel compounds targeting drug-resistant microbial strains. Herein, we report the synthesis of amino acid derivatives bearing an incorporated 4-hydroxyphenyl moiety with various substitutions. The resultant novel 3-((4-hydroxyphenyl)amino)propanoic acid derivatives 2-37 exhibited structure-dependent antimicrobial activity against both ESKAPE group bacteria and drug-resistant Candida species. Furthermore, these derivatives demonstrated substantial activity against Candida auris, with minimum inhibitory concentrations ranging from 0.5 to 64 µg/mL. Hydrazones 14-16, containing heterocyclic substituents, showed the most potent and broad-spectrum antimicrobial activity. This activity extended to methicillin-resistant Staphylococcus aureus (MRSA) with MIC values ranging from 1 to 8 µg/mL, vancomycin-resistant Enterococcus faecalis (0.5-2 µg/mL), Gram-negative pathogens (MIC 8-64 µg/mL), and drug-resistant Candida species (MIC 8-64 µg/mL), including Candida auris. Collectively, these findings underscore the potential utility of the novel 3-((4-hydroxyphenyl)amino)propanoic acid scaffold for further development as a foundational platform for novel antimicrobial agents targeting emerging and drug-resistant bacterial and fungal pathogens.

Understanding the Immunomodulatory Effects of Bovine Colostrum: Insights into IL-6/IL-10 Axis-Mediated Inflammatory Control.

Bovine colostrum (COL), the first milk secreted by lactating cows postpartum, is a rich source of bioactive compounds that exert a significant role in the survival, growth, and immune development of neonatal calves. This study investigated the immunomodulatory effects of COL on cytokine production in vitro using a Caco-2/THP-1 macrophage co-culture model stimulated with Phorbol 12-myristate 13-acetate (PMA). COL pretreatment significantly reduced IL-6 (241.3 pg/mL) production induced by PMA (p < 0.05), while increasing IL-10 production (45.3 pg/mL), in comparison to PMA control (441.1 and 12.5 pg/mL, respectively). Further investigations revealed that the IL-6 suppressive effect of colostrum was heat-sensitive and associated with components of higher molecular mass (100 kDa). Moreover, colostrum primarily influenced THP-1 macrophages rather than Caco-2 epithelial cells. The effects of colostrum on IL-6 production were associated with reduced NF-κB activation in THP-1 macrophages. In calf-FMT transplanted C57BL/6 murine model, colostrum decreased intestinal permeability, reduced immune cell infiltration and intestinal score, and suppressed IL-6 (142.0 pg/mL) production during S. typhimurium infection, in comparison to control animals (215.2 pg/mL). These results suggest the immunomodulatory activity of bovine colostrum and its potential applications in inflammatory disorders. Further studies are needed to elucidate the underlying mechanisms and validate the findings in bovine models.

Synthesis of 1-(2-Hydroxyphenyl)- and (3,5-Dichloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid Derivatives as Promising Scaffolds for the Development of Novel Antimicrobial and Anticancer Agents.

Increasing antimicrobial resistance among Gram-positive pathogens and pathogenic fungi remains one of the major public healthcare threats. Therefore, novel antimicrobial candidates and scaffolds are critically needed to overcome resistance in Gram-positive pathogens and drug-resistant fungal pathogens. In this study, we explored 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid and its 3,5-dichloro-2-hydroxyphenyl analogue for their in vitro antimicrobial activity against multidrug-resistant pathogens. The compounds showed structure-dependent antimicrobial activity against Gram-positive pathogens (S. aureus, E. faecalis, C. difficile). Compounds 14 and 24b showed promising activity against vancomycin-intermediate S. aureus strains, and favorable cytotoxic profiles in HSAEC-1 cells, making them attractive scaffolds for further development. 5-Fluorobenzimidazole, having a 3,5-dichloro-2-hydroxyphenyl substituent, was found to be four-fold, and hydrazone, with a thien-2-yl fragment, was two-fold stronger than clindamycin against methicillin resistant S. aureus TCH 1516. Moreover, hydrazone, bearing a 5-nitrothien-2-yl moiety, showed promising activity against three tested multidrug-resistant C. auris isolates representing major genetic lineages (MIC 16 µg/mL) and azole-resistant A. fumigatus strains harboring TR34/L98H mutations in the CYP51A gene. The anticancer activity characterization demonstrated that the 5-fluorobenzimidazole derivative with a 3,5-dichloro-2-hydroxyphenyl substituent showed the highest anticancer activity in an A549 human pulmonary cancer cell culture model. Collectively these results demonstrate that 1-(2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives could be further explored for the development of novel candidates targeting Gram-positive pathogens and drug-resistant fungi.

Synthesis of Novel Benzenesulfonamide-Bearing Functionalized Imidazole Derivatives as Novel Candidates Targeting Multidrug-Resistant Mycobacterium abscessus Complex.

Infections caused by drug-resistant (DR) Mycobacterium abscessus (M. abscessus) complex (MAC) are an important public health concern, particularly when affecting individuals with various immunodeficiencies or chronic pulmonary diseases. Rapidly growing antimicrobial resistance among MAC urges us to develop novel antimicrobial candidates for future optimization. Therefore, we have designed and synthesized benzenesulfonamide-bearing functionalized imidazole or S-alkylated derivatives and evaluated their antimicrobial activity using multidrug-resistant M. abscessus strains and compared their antimycobacterial activity using M. bovis BCG and M. tuberculosis H37Ra. Benzenesulfonamide-bearing imidazole-2-thiol compound 13, containing 4-CF3 substituent in benzene ring, showed strong antimicrobial activity against the tested mycobacterial strains and was more active than some antibiotics used as a reference. Furthermore, an imidazole-bearing 4-F substituent and S-methyl group demonstrated good antimicrobial activity against M. abscessus complex strains, as well as M. bovis BCG and M. tuberculosis H37Ra. In summary, these results demonstrated that novel benzenesulfonamide derivatives, bearing substituted imidazoles, could be further explored as potential candidates for the further hit-to-lead optimization of novel antimycobacterial compounds.

The Influence of Feeding with Colostrum and Colostrum Replacer on Major Blood Biomarkers and Growth Performance in Dairy Calves.

Bovine colostrum (BC) is the first milk produced by lactating cows after parturition. BC is rich in various amino acids, proteins, and fats essential for the nutrition of the neonate calves. Despite the evident beneficial effect of BC on calves, the effect of BC on blood biomarkers is poorly understood. Calves that received BC showed significantly higher body mass at days 7 and 30 (38.54 kg and 43.42 kg, respectively) compared to the colostrum replacer group (p = 0.0064). BC induced greater quantities of blood neutrophils (0.27 × 109/L) and monocytes (4.76 × 109/L) in comparison to the colostrum replacer (0.08 and 0.06 × 109/L, respectively) (p = 0.0001). Animals that received BC showed higher levels of total serum protein (59.16 g/L) and albumin (29.96 g/L) in comparison to the colostrum replacer group (44.34 g/L and 31.58 g/L, respectively). In addition, BC induced greater intestinal mucus production in the Wistar rat model. Collectively, these results demonstrate that BC is important for the growth of calves and that it provides a significant beneficial effect on morphological and biochemical blood parameters.

Synthesis and Development of N-2,5-Dimethylphenylthioureido Acid Derivatives as Scaffolds for New Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens.

The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant S. aureus, as well as emerging fungal pathogens. The 4-substituted thiazoles 3h, and 3j with naphthoquinone-fused thiazole derivative 7 with excellent activity against methicillin and tedizolid/linezolid-resistant S. aureus. Moreover, compounds 3h, 3j and 7 showed favourable activity against vancomycin-resistant E. faecium. Compounds 9f and 14f showed broad-spectrum antifungal activity against drug-resistant Candida strains, while ester 8f showed good activity against Candida auris which was greater than fluconazole. Collectively, these data demonstrate that N-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi.

Efficacy of Cefiderocol in Experimental Stenotrophomonas maltophilia Pneumonia in Persistently Neutropenic Rabbits.

Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia. We evaluated the efficacy of cefiderocol in a neutropenic rabbit model of S. maltophilia pneumonia in comparison to trimethoprim-sulfamethoxazole (TMP-SMX). The cefiderocol area under the plasma drug concentration-time curve extrapolated to 8 h (AUC0-8) was lower (423.0 ± 40.9 µg·h/mL versus 713.6 ± 40.1 µg·h/mL) and clearance higher (252.77 ± 38.9 mL/h/kg versus 142.6 ± 32.9 mL/h/kg) in infected versus noninfected rabbits. We studied a clinical bloodstream S. maltophilia isolate with an MIC of 0.03 µg/mL of cefiderocol. Time spent above the MIC of cefiderocol for the majority of S. maltophilia isolates in rabbits recapitulated the plasma concentration-time profile observed in adult humans at the licensed dose of 2 g given intravenously (i.v.). Experimental groups consisted of 120 mg/kg cefiderocol i.v. every 8 hours (q8h); TMP-SMX, 5 mg/kg i.v. Q12h, and untreated controls (UCs). Treatment was administered for 10 days. Survival in cefiderocol-treated rabbits (87%) was greater than that in TMP-SMX-treated (25%; P < 0.05) and UC (0%; P < 0.05) groups. There was no residual bacterial burden in lung tissue or bronchoalveolar lavage (BAL) fluid in the cefiderocol group. Residual bacterial burden was present in lung tissue and BAL fluid in the TMP-SMX group but was decreased in comparison to UCs (P < 0.001). Lung weights (markers of pulmonary injury) were decreased in cefiderocol-treated versus TMP-SMX (P < 0.001) and UC (P < 0.001) groups. Cefiderocol is highly active in treatment of experimental S. maltophilia pneumonia, laying the foundation for future clinical investigations against this lethal infection in immunocompromised patients.

Molecular Epidemiology of Group B Streptococci in Lithuania Identifies Multi-Drug Resistant Clones and Sporadic ST1 Serotypes Ia and Ib.

Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading cause of neonatal infections. Yet, detailed assessment of the genotypic and phenotypic factors associated with GBS carriage, mother-to-baby transmission, and GBS infection in neonates and adults is lacking. Understanding the distribution of GBS genotypes, including the predominance of different serotypes, antimicrobial resistance (AMR) genes, and virulence factors, is likely to help to prevent GBS diseases, as well as inform estimates of the efficacy of future GBS vaccines. To this end, we set out to characterise GBS isolates collected from pregnant and non-pregnant women in Kaunas region in Lithuania. Whole genome sequences of 42 GBS isolates were analysed to determine multi-locus sequence typing (MLST), the presence of acquired AMR and surface protein genes, and the phylogenetic relatedness of isolates. We identified serotypes Ia (42.9%, 18/42), III (33.3%, 14/42), V (21.4%, 9/42), and a single isolate of serotype Ib. Genomic analyses revealed high diversity among the isolates, with 18 sequence types (STs) identified, including three novel STs. 85.7% (36/42) of isolates carried at least one AMR gene: tetM or tetO (35/42), ermB or lsaC (8/42) and ant6-Ia and aph3-III (2/42). This study represents the first genomic analysis of GBS isolated from women in Lithuania and contributes to an improved understanding of the global spread of GBS genotypes and phenotypes, laying the foundations for future GBS surveillance in Lithuania.

Synthesis and Biological Activity Characterization of Novel 5-Oxopyrrolidine Derivatives with Promising Anticancer and Antimicrobial Activity.

The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. The resulted compounds 2 and 4-22 were subjected to the in vitro anticancer and antimicrobial activity determination. The compounds 18-22 exerted the most potent anticancer activity against A549 cells. Furthermore, compound 21 bearing 5-nitrothiophene substituents demonstrated promising and selective antimicrobial activity against multidrug-resistant Staphylococcus aureus strains, including linezolid and tedizolid-resistant S. aureus. These results demonstrate that 5-oxopyrolidine derivatives are attractive scaffolds for the further development of anticancer and antimicrobial compounds targeting multidrug-resistant Gram-positive pathogens.

Low Anterior Resection Syndrome: What Have We Learned Assessing a Large Population?

Our goal was to assess the rate of symptoms commonly included in LARS score in a large general population. The study was based on a population-based design. We disseminated LARS scores through community online platforms and general practitioners throughout Lithuania. We received 8183 responses to the questionnaire. There were 142 (1.74%) participants who were excluded for lack of information. There were 6100 (75.9%) females and 1941 (24.1%) males. After adjusting for sex and age, male participants had a significant average score of 18.4 (SD ± 10.35) and female 20.3 (SD ± 9.74) p < 0.001. There were 36.4% of participants who had minor LARS symptoms, and 14.2% who had major LARS symptoms. Overall, major LARS-related symptoms were significantly related to previous operations: 863 participants in the operated group (71.7%), and 340 in the non-operated group (28.3%; p0.001). In 51−75-year-old patients, major LARS was significantly more prevalent with 22.7% (p < 0.001) and increasing with age, with a higher incidence of females after the age of 75. After excluding colorectal and perineal procedures, the results of multivariate logistic regression analysis indicated the use of neurological drugs and gynaecological operations were independent risk factors for major LARS−odd ratio of 1.6 (p = 0.018, SI 1.2−2.1) and 1.28 (p = 0.018, SI 1.07−1.53), respectively. The symptoms included in the LARS score are common in the general population, and there is a variety of factors that influence this, including previous surgeries, age, sex, comorbidities, and medication. These factors should be considered when interpreting the LARS score following low anterior resection and when considering treatment options preoperatively.

Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity.

Metallo-ß-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P < 0.05). A neutropenic rabbit pneumonia model demonstrated that aztreonam plus ceftazidime-avibactam with or without polymyxin B resulted in similar bacterial killing, and these combination therapies were statistically significantly better than monotherapies (P < 0.05). However, only the polymyxin B-containing combination therapy produced a statistically significant decrease in lung weights (P < 0.05), indicating a decreased inflammatory process. Altogether, adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM- and CTX-M-producing K. pneumoniae improved bacterial killing effects, reduced lung inflammation, suppressed resistance amplification, and limited virulence changes.

Synthesis of Novel Aminothiazole Derivatives as Promising Antiviral, Antioxidant and Antibacterial Candidates.

It is well-known that thiazole derivatives are usually found in lead structures, which demonstrate a wide range of pharmacological effects. The aim of this research was to explore the antiviral, antioxidant, and antibacterial activities of novel, substituted thiazole compounds and to find potential agents that could have biological activities in one single biomolecule. A series of novel aminothiazoles were synthesized, and their biological activity was characterized. The obtained results were compared with those of the standard antiviral, antioxidant, antibacterial and anticancer agents. The compound bearing 4-cianophenyl substituent in the thiazole ring demonstrated the highest cytotoxic properties by decreasing the A549 viability to 87.2%. The compound bearing 4-trifluoromethylphenyl substituent in the thiazole ring showed significant antiviral activity against the PR8 influenza A strain, which was comparable to the oseltamivir and amantadine. Novel compounds with 4-chlorophenyl, 4-trifluoromethylphenyl, phenyl, 4-fluorophenyl, and 4-cianophenyl substituents in the thiazole ring demonstrated antioxidant activity by DPPH, reducing power, FRAP methods, and antibacterial activity against Escherichia coli and Bacillus subtilis bacteria. These data demonstrate that substituted aminothiazole derivatives are promising scaffolds for further optimization and development of new compounds with potential influenza A-targeted antiviral activity. Study results could demonstrate that structure optimization of novel aminothiazole compounds may be useful in the prevention of reactive oxygen species and developing new specifically targeted antioxidant and antibacterial agents.

Hand Assisted Laparoscopic Surgery for Colorectal Cancer: Surgical and Oncological Outcomes from a Single Tertiary Referral Centre.

The aim of this study was to report overall experience, perioperative and long-term survival results in a single tertiary referral center in Lithuania with hand assisted laparoscopic surgery (HALS) for colorectal cancer. A prospectively maintained database included 467 patients who underwent HALS for left-sided colon and rectal cancer, from April 2006 to October 2016. All those operations were performed by three consultant surgeons and nine surgical residents, in all cases assisted by one of the same consultant surgeons. There were 230 (49.25%) females, with an average age of 64 ± 9.7 years (range, 26-91 years). The procedures performed included 170 (36.4%) anterior rectal resections with partial mesorectal excision, 160 (34.26%) sigmoid colectomies, 81 (17.35%) left hemicolectomies, 45 (9.64%) low anterior rectal resections with total mesorectal excision, and 11 (2.25%) other procedures. Stage I colorectal cancer was found in 140 (29.98%) patients, 139 (29.76%) stage II, 152 (32.55%) stage III and 36 (7.71%) stage IV. There were five conversions to open surgery (1.1%). The mean postoperative hospital stay was 6.9 ± 3.4 days (range, 1-30 days). In total, 33 (7.06%) patients developed postoperative complications. The most common complications were small bowel obstruction (n = 6), anastomotic leakage (n = 5), intraabdominal abscess (n = 4) and dysuria (n = 4). There were two postoperative deaths (0.43%). Overall, 5-year survival for all TNM stages was 85.7%, 93.2% for stage I, 88.5% for stage II and 76.3% for stage III. Hand assisted colorectal surgery for left-sided colon and rectal cancer in a single tertiary referral center was feasible and safe, having all the advantages of minimally invasive surgery, with good perioperative parameters, adequate oncological quality and excellent survival.

Synthesis, Biological Activity, and Molecular Modelling Studies of Naphthoquinone Derivatives as Promising Anticancer Candidates Targeting COX-2.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-associated mortalities worldwide. Therefore, it is crucial to develop a novel therapeutic option targeting localized and metastatic NSCLC. In this paper, we describe the synthesis and biological activity characterization of naphthoquinone derivatives bearing selective anticancer activity to NSCLC via a COX-2 mediated pathway. The biological evaluation of compounds 9−16 showed promising structure-dependent anticancer activity on A549 cells in 2D and 3D models. Compounds were able to significantly (p < 0.05) reduce the A549 viability after 24 h of treatment in comparison to treated control. Compounds 9 and 16 bearing phenylamino and 4-hydroxyphenylamino substituents demonstrated the most promising anticancer activity and were able to induce mitochondrial damage and ROS formation. Furthermore, most promising compounds showed significantly lower cytotoxicity to non-cancerous Vero cells. The in silico ADMET properties revealed promising drug-like properties of compounds 9 and 16. Both compounds demonstrated favorable predicted GI absorption values, while only 16 was predicted to be permeable through the blood−brain barrier. Molecular modeling studies identified that compound 16 is able to interact with COX-2 in arachidonic acid site. Further studies are needed to better understand the safety and in vivo efficacy of compounds 9 and 16.

Short-term clinical and functional results of rectal wall suture defect after transanal endoscopic microsurgery-a prospective cohort study.

PURPOSE: Our goal was to assess the outcomes of rectal wall suture during the early and late periods after transanal endoscopic microsurgery (TEM) and long-term bowel function. METHODS: Patients who underwent TEM for rectal neoplasms from May 2017 to March 2021 were prospectively included. A total of 70 patients were enrolled. Seven to 10 days after TEM, clinical data were recorded, and digital rectal examination and rigid proctoscopy were performed. After at least 6 months, bowel function was evaluated using low anterior resection syndrome (LARS) and Wexner questionnaires. RESULTS: Forty-five men with an average age of 67 ± 10.1 (40-85) were included. TEM sutures were recorded as intact in 48/70 (68%) and as dehiscent in 22/70 (32%). It did not have any significant clinical manifestation and was not related with longer postoperative stay or incidence of postoperative complications. Eight of 22 (36.4%) patients with suture dehiscence had per rectal bleeding or febrile temperature without any need for intervention or treatment. The only risk factor for wound dehiscence was a posteriorly located defect. In late postoperative period, there was no difference between groups in LARS or Wexner questionnaire (p value 0.72 and 0.85, respectively). CONCLUSIONS: Our study suggests that 1/3 of the patients' rectal wall defect after TEM will undergo dehiscence in early postoperative period and will not transfer to clinically significant manifestation (without a need of hospitalization or prolonging it). In late postoperative period, there is no difference in bowel function.

Trends in Pancreatic Cancer Incidence and Mortality in Lithuania, 1998-2015.

BACKGROUND: Pancreatic cancer is one of the deadliest cancers worldwide, and its incidence is increasing. The aim of this study was to examine the time trends in the incidence and mortality rates of pancreatic cancer for the period of 1998-2015 for the first time in Lithuania by sex, age, subsite, and stage. METHODS: This study was based on all cases (deaths) of pancreatic cancer diagnosed between 1998 and 2015. Age-standardized incidence (mortality) rates and group-specific rates were calculated for each sex using the direct method (European Standard). TNM classification-based information reported to the cancer registry was grouped into three categories: (1) localized cancer: T1-3/N0/M0; (2) cancer with regional metastasis: any 1-3/N+/M0; (3) advanced cancer: any T/any N/M+. Joinpoint regression was used to provide annual percentage changes (APCs) and to detect points in time where statistically significant changes in the trends occurred. RESULTS: Overall, 8514 pancreatic cancer cases (4364 in men and 3150 in women) were diagnosed and 7684 persons died from cancer of the pancreas. Pancreatic cancer incidence rates were considerably lower for women than for men, with a female:male ratio of 1:2. Incidence rates changed during the study period from 14.2 in 1998 to 15.0/100,000 in the year 2015 in men, and from 6.7 to 9.8/100,000 in women. Incidence rates over the study period were stable for men (APC = 0.1%) and increasing for women by 1.1% per year. Similarly, mortality rates increased in women by 0.9% per year, and were stable in men. During the study period, incidence and mortality rates of pancreatic cancer were close. For the entire study period, rates increased significantly in the 50-74 years age group; only cancer of the head of pancreas showed a decline by 0.9%, while tail and not-specified pancreatic cancer incidence increased by 11.4% and 4.51%, respectively. CONCLUSIONS: The increasing pancreatic cancer incidence trend in the Lithuanian population may be related to the prevalence of its main risk factors (smoking, obesity, physical inactivity, diet, and diabetes).

The Role of Traditional Acupuncture in Low Anterior Resection Syndrome Treatment: A Pilot Study.

BACKGROUND: There is limited evidence on the efficacy of acupuncture in bowel dysfunction treatment. OBJECTIVE: The aim of this pilot study was to investigate the potential value of acupuncture in the treatment of low anterior resection syndrome. DESIGN: This was an open-design pilot study. SETTINGS: This was a single-center study. PATIENTS: Nine (5 female) patients with major low anterior resection syndrome were included. INTERVENTIONS: All patients underwent acupuncture by a trained specialist once a week for 10 weeks. MAIN OUTCOME MEASURES: Bowel function was assessed by using the low anterior resection syndrome score and the Memorial Sloan-Kettering Cancer Center bowel function instrument before the procedure, just after finishing the course of acupuncture, and 6 months after the treatment. RESULTS: The average age was 56.44 (50-65; SD ±5.4). Median age was 56 years. At the end of the procedure, all patients reported significant improvement in low anterior resection syndrome symptoms: the average low anterior resection syndrome score before acupuncture was 39 (±2.7), after acupuncture it was 30.3 (±10.6), and 6 months after acupuncture it was 7.22 (±10.244; p < 0.000). The average Memorial Sloan-Kettering Cancer Center bowel function instrument score before acupuncture was 55.33 (±11.55), after the procedure it was 60 (±14.97), and 6 months later it was 70.22 (±12.2; p < 0.000). LIMITATIONS: The small sample size and the fact that this is a single-center nonblinded study are limitations of this work. CONCLUSIONS: Acupuncture may be effective in low anterior resection syndrome treatment and needs further evaluation. The procedure is safe and feasible. See Video Abstract at http://links.lww.com/DCR/B700. REGISTRATION: ClinicalTrials.gov: NCT03916549. EL PAPEL DE LA ACUPUNTURA TRADICIONAL EN EL TRATAMIENTO DEL SNDROME DE RESECCIN ANTERIOR BAJA UN ESTUDIO PILOTO: ANTECEDENTES:Existe evidencia limitada sobre la eficacia de la acupuntura para el tratamiento de la disfunción intestinal.OBJETIVO:El objetivo de este estudio piloto fue investigar el valor potencial de la acupuntura en el tratamiento del síndrome de resección anterior baja.DISEÑO:Este fue un estudio piloto de diseño abiertoAJUSTES:Este fue un estudio en un solo centroPACIENTES:Fueron incluidos nueve pacientes con síndrome de resección anterior baja (muy sintomáticos), cinco de ellos eran mujeresINTERVENCIONES:Todos los pacientes fueron tratados con acupuntura, una vez a la semana durante diez semanas por un especialista capacitado.PRINCIPALES MEDIDAS DE RESULTADO:La función intestinal fue evaluada, antes del procedimiento, justo al finalizar el ciclo de acupuntura y a los seis meses, utilizando la puntuación (score) para el síndrome de resección anterior baja y el instrumento de función intestinal del Memorial Sloan-Kettering Cancer Center.RESULTADOS:La edad media fue 56,44 (50 - 65) (DE ± 5,4). Edad mediana 56 años. Al final del procedimiento, todos los pacientes manifestaron una mejoría significativa de los síntomas del síndrome de resección anterior baja: La puntuación promedio del síndrome de resección anterior baja antes de la acupuntura fue 39 (± 2,7), después de - 30,3 (± 10,6) y 6 meses después de 7,22 (± 10,244) (p <0,000). El puntaje promedio del instrumento de función intestinal del Memorial Sloan-Kettering Cancer Center antes de la acupuntura fue 55.33 (± 11.55), después del procedimiento 60 (± 14.97) y 6 meses después 70.22 (± 12.2) (p <0,000).LIMITACIONES:Tamaño de muestra pequeño, estudio no cegado en un solo centro.CONCLUSIONES:La acupuntura puede ser eficaz en el tratamiento del síndrome de resección anterior baja, pero es necesario continuar evaluando su utilidad. El procedimiento es seguro y factible. Consulte Video Resumen en http://links.lww.com/DCR/B700.

Pharmacokinetics, Tissue Distribution, and Efficacy of VIO-001 (Meropenem/Piperacillin/Tazobactam) for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia in Immunocompetent Rabbits with Chronic Indwelling Vascular Catheters.

Methicillin-resistant Staphylococcus aureus (MRSA) infections of surgically implanted subcutaneous vascular catheters (SISVCs) cause serious morbidity in patients with chronic illnesses. Previous in vitro and murine models demonstrated the synergistic interaction of equimolar concentrations of meropenem/piperacillin/tazobactam (MPT) (VIO-001) against MRSA infection. We investigated the pharmacokinetics (PK) and efficacy of VIO-001 for the treatment of MRSA bacteremia in immunocompetent rabbits with SISVCs. In PK studies, we determined that optimal dosing to achieve a time above 4× MIC (T>4×MIC) of a duration of 3 to 3.30 h required a 1-h infusion with every-4-h (Q4h) dosing. Study groups in efficacy experiments consisted of MPT combinations of 100/150/100 mg/kg of body weight (MPT100), 200/300/200 mg/kg (MPT200), and 400/600/400 mg/kg (MPT400); vancomycin (VAN) at 15 mg/kg; and untreated controls (UC). The inoculum of MRSA isolate USA300-TCH1516 (1 × 103 organisms) was administered via the SISCV on day 1 and locked for 24 h. The 8-day therapy started at 24 h postinoculation. There was a significant reduction of MRSA in blood cultures from the SISVCs in all treatment groups, with full clearance on day 4, versus UCs (P < 0.05). Consistent with the clearance of SISVC-related infection, full eradication of MRSA was achieved in lungs, heart, liver, spleen, and kidneys at the end of the study versus UC (P < 0.01). These results strongly correlated with time-kill data, where MPT in the range of 4/6/4 µg/ml to 32/48/32 µg/ml demonstrated a significant 6-log decrease in the bacterial burden versus UC (P < 0.01). In summary, VIO-001 demonstrated a favorable PK/pharmacodynamic (PD) profile and activity against SISCV MRSA infection, bacteremia, and disseminated infection. This rabbit model provides a new system for understanding new antimicrobial agents against MRSA SISVC-related infection, and these data provide a basis for future clinical investigation.