The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

The core phageome and its interrelationship with preterm human milk lipids

\ua9 2023 The AuthorsPhages and lipids in human milk (HM) may benefit preterm infant health by preventing gastrointestinal pathobiont overgrowth and microbiome modulation. Lipid association may promote vertical transmission of phages to the infant. Despite this, interrelationships between lipids and phages are poorly characterized in preterm HM. Shotgun metagenomics and untargeted lipidomics of phage and lipid profiles from 99 preterm HM samples reveals that phages are abundant and prevalent from the first week and throughout the first 100 days of lactation. Phage-host richness of preterm HM increases longitudinally. Core phage communities characterized by Staphylococcus- and Propionibacterium-infecting phages are significantly correlated with long-chain fatty acid abundances over lactational age. We report here a phage-lipid interaction in preterm HM, highlighting the potential importance of phage carriage in preterm HM. These results reveal possible strategies for phage carriage in HM and their importance in early-life microbiota development

Intramuscular myxoid lipoma in the proximal forearm presenting as an olecranon mass with superficial radial nerve palsy: a case report

<p>Abstract</p> <p>Background</p> <p>Extremity lipomas may occur in any location, including the proximal forearm. We describe a case of a patient with an intramuscular lipoma presenting as an unusual posterior elbow mass.</p> <p>Case presentation</p> <p>We discuss the case of a 57-year-old Caucasian man who presented with a tender, posterior elbow mass initially diagnosed as chronic olecranon bursitis. A minor sensory disturbance in the distribution of the superficial radial nerve was initially thought to be unrelated, but was likely caused by mass effect from the lipoma. No pre-operative advanced imaging was obtained because the diagnosis was felt to have already been made. At the time of surgery, a fatty mass originating in the volar forearm muscles was found to have breached the dorsal forearm fascia and displaced the olecranon bursa. Tissue diagnosis was made by histopathology as a myxoid lipoma with no aggressive features. Post-operative recovery was uneventful.</p> <p>Conclusion</p> <p>We present a case of an unusual elbow mass presenting with symptoms consistent with chronic olecranon bursitis, a relatively common condition. The only unexplained pre-operative finding was the non-specific finding of a transient superficial radial nerve deficit. We remind clinicians to be cautious when diagnosing soft tissue masses in the extremities when unexplained physical findings are present.</p

Passive heating and glycaemic control in non-diabetic and diabetic individuals: a systematic review and meta-analysis

Objective: Passive heating (PH) has begun to gain research attention as an alternative therapy for cardio-metabolic diseases. Whether PH improves glycaemic control in diabetic and non-diabetic individuals is unknown. This study aims to review and conduct a meta-analysis of published literature relating to PH and glycaemic control. Methods: Electronic data sources, PubMed, Embase and Web of Science from inception to July 2018 were searched for randomised controlled trials (RCT) studying the effect of PH on glycaemic control in diabetic or non-diabetic individuals. To measure the treatment effect, standardised mean differences (SMD) with 95 % confidence intervals (CI) were calculated. Results: Fourteen articles were included in the meta-analysis. Following a glucose load, glucose concentration was greater during PH in non-diabetic (SMD 0.75, 95 % CI 1.02 to 0.48, P 0.050) and a glucose challenge given within 24 hours post-heating (SMD 0.30, 95 % CI 0.62 to -0.02, P > 0.050). Conclusion: PH preceded by a glucose load results in acute glucose intolerance in non-diabetic and diabetic individuals. However, heating a non-diabetic individual without a glucose load appears not to affect glycaemic control. Likewise, a glucose challenge given within 24 hours of a single-bout of heating does not affect glucose tolerance in non-diabetic individuals. Despite the promise PH may hold, no short-term benefit to glucose tolerance is observed in non-diabetic individuals. More research is needed to elucidate whether this alternative therapy benefits diabetic individuals

Different Successful Management Strategies for Obstructing Renal Parapelvic Cysts

Parapelvic cysts originate in the renal parenchyma and extend into the renal sinus. A series of 3 patients with symptomatic obstructing parapelvic cysts is described, 2 with acute presentations, and 1 with chronic symptoms. In 2 of the 3 cases, there was a significant delay in establishing a diagnosis. Although one individual was successfully managed by image-guided cyst aspiration, the second patient required repeated aspiration due to cyst re-accumulation. A high index of clinical suspicion and a combination of imaging modalities, including serial ultrasound, excretory-phase CT, and MAG3 renogram, are necessary to establish the diagnosis and monitor response to treatment

A Decision Analysis Evaluating Screening for Kidney Cancer Using Focused Renal Ultrasound

Background Screening for renal cell carcinoma (RCC) has been identified as a key research priority; however, no randomised control trials have been performed. Value of information analysis can determine whether further research on this topic is of value. Objective To determine (1) whether current evidence suggests that screening is potentially cost effective and, if so, (2) in which age/sex groups, (3) identify evidence gaps, and (4) estimate the value of further research to close those gaps. Design, setting, and participants A decision model was developed evaluating screening in asymptomatic individuals in the UK. A National Health Service perspective was adopted. Intervention A single focused renal ultrasound scan compared with standard of care (no screening). Outcome measurements and statistical analysis Expected lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER), discounted at 3.5% per annum. Results and limitations Given a prevalence of RCC of 0.34% (0.18–0.54%), screening 60-yr-old men resulted in an ICER of £18 092/QALY (€22 843/QALY). Given a prevalence of RCC of 0.16% (0.08–0.25%), screening 60-yr-old women resulted in an ICER of £37 327/QALY (€47 129/QALY). In the one-way sensitivity analysis, the ICER was <£30 000/QALY as long as the prevalence of RCC was ≥0.25% for men and ≥0.2% for women at age 60 yr. Given the willingness to pay a threshold of £30 000/QALY (€37 878/QALY), the population-expected values of perfect information were £194 million (€244 million) and £97 million (€123 million) for 60-yr-old men and women, respectively. The expected value of perfect parameter information suggests that the prevalence of RCC and stage shift associated with screening are key research priorities. Conclusions Current evidence suggests that one-off screening of 60-yr-old men is potentially cost effective and that further research into this topic would be of value to society. Patient summary Economic modelling suggests that screening 60-yr-old men for kidney cancer using ultrasound may be a good use of resources and that further research on this topic should be performed

Cholestatic hepatitis as a possible new side-effect of oxycodone: a case report

<p>Abstract</p> <p>Introduction</p> <p>Oxycodone is a widely-used semisynthetic opioid analgesic that has been used for over eighty years. Oxycodone is known to cause side effects such as nausea, pruritus, dizziness, constipation and somnolence. As far as we are aware cholestatic hepatitis as a result of oxycodone use has not been reported so far in the world literature.</p> <p>Case presentation</p> <p>A 34-year-old male presented with cholestatic jaundice and severe pruritus after receiving oxycodone for analgesia post-T11 vertebrectomy. Extensive laboratory investigations and imaging studies did not reveal any other obvious cause for his jaundice and a liver biopsy confirmed canalicular cholestatis suggestive of drug-induced hepatotoxicity. The patient's symptoms and transaminases normalised on withdrawal of oxycodone confirming that oxycodone was the probable cause of the patient's hepatotoxicity.</p> <p>Conclusion</p> <p>We conclude that cholestatic hepatitis is possibly a rare side effect of oxycodone use. Physicians should be aware of the possibility of this potentially serious picture of drug-induced hepatotoxicity.</p

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

Wake up, wake up! It's me! It's my life! patient narratives on person-centeredness in the integrated care context: a qualitative study

Person-centered care emphasizes a holistic, humanistic approach that puts patients first, at the center of medical care. Person-centeredness is also considered a core element of integrated care. Yet typologies of integrated care mainly describe how patients fit within integrated services, rather than how services fit into the patient's world. Patient-centeredness has been commonly defined through physician's behaviors aimed at delivering patient-centered care. Yet, it is unclear how 'person-centeredness' is realized in integrated care through the patient voice. We aimed to explore patient narratives of person-centeredness in the integrated care context