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Abstract Purpose The Knee Society Scoring System (KSS) is a frequently used outcome score which quantifies functional patients' outcomes before and after total knee arthroplasty (TKA). Several problems arise when trying to implement KSS for obtaining postoperative outcomes after more personalised aligned TKAs. Scoring for valgus femorotibial angle (FTA) intervals outside moderate ranges is often poorly explained, the specific version of KSS used for outcome collection is frequently unclear and the exact measuring methods are typically not described in the literature. The aims of this systematic review were to investigate the latest user practice, the application of KSS and its limitations after kinematically aligned (KA) TKA. Methods A systematic literature search following PRISMA guidelines was conducted on PubMed, Embase, Medline and Scopus to identify potentially relevant articles for this review, published from the beginning of January 2013 until the end of January 2023. Broad Mesh terms such as ‘kinematic alignment’, ‘total knee arthroplasty’ and ‘knee society score’ were used for building search strategy in each database accordingly. Articles reporting postoperative values of the objective surgeon‐assessed KSS after KA TKA or KA and mechanically aligned TKA were included. For assessing included randomised control trials (RCTs), an Agency for Healthcare Research and Quality's design‐specific scale for assessing RCTs was used. The non‐RCTs were assessed by using the Joanna Briggs Institute Critical Appraisal Tool. The Ottawa–Newcastle Score system was also used. Studies were additionally evaluated for their radiological methodology by using a five‐question checklist (Radiological Assessment Qualit criteria). Results The initial search identified 167 studies, of which 129 were considered for screening. Ten studies reporting outcomes after KA TKA did not use the objective surgeon‐assessed part of KSS for clinical outcome measurement, and 30 studies reporting outcomes after KA TKA did not use KSS at all for clinical and/or functional outcomes. From the 10 included studies, only six have used the latest KSS score (2011), the rest using its 1989 variant; and out of these six studies, only two presented values of the FTA, which is needed for calculating the KSS's ‘alignment’ subcomponent, the rest presenting hip–knee–ankle angle (HKA) values. Additionally, when converting these HKA values to FTA intervals, the authors of this systematic review found that KA TKA FTA intervals display limits, which tend to be outside the ‘well‐scored’ KSS anatomical alignment interval. Conclusion The inconsistent and nonstandardised use of the surgeon‐assessed KSS across studies reviewed compromises assessment reliability and patient outcome scores. To enhance precision and comparability, it is crucial to standardise the KSS application, incorporating personalised alignment strategies for more accurate patient evaluations. Level of Evidence Level III.

Opnurasib (JDQ443) is a newly developed oral KRASG12C inhibitor, with a binding mechanism distinct from the registered KRASG12C inhibitors sotorasib and adagrasib. Phase I and II clinical trials for opnurasib in NSCLC are ongoing. We evaluated the pharmacokinetic roles of the ABCB1 (P-gp/MDR1) and ABCG2 (BCRP) efflux and OATP1 influx transporters, and of the metabolizing enzymes CYP3A and CES1 in plasma and tissue disposition of oral opnurasib, using genetically modified cell lines and mouse models. In vitro, opnurasib was potently transported by human (h)ABCB1 and slightly by mouse (m)Abcg2. In Abcb1a/b- and Abcb1a/b;Abcg2-deficient mice, a significant ∼100-fold increase in brain-to-plasma ratios was observed. Brain penetration was unchanged in Abcg2-/- mice. ABCB1 activity in the blood-brain barrier may therefore potentially limit the efficacy of opnurasib against brain metastases. The Abcb1a/b transporter activity could be almost completely reversed by co-administration of elacridar, a dual ABCB1/ABCG2 inhibitor, increasing the brain penetration without any behavioral or postural signs of acute CNS-related toxicity. No significant pharmacokinetic roles of the OATP1 transporters were observed. Transgenic human CYP3A4 did not substantially affect the plasma exposure of opnurasib, indicating that opnurasib is likely not a sensitive CYP3A4 substrate. Interestingly, Ces1-/- mice showed a 4-fold lower opnurasib plasma exposure compared to wild-type mice, whereas no strong effect was seen on the tissue distribution. Plasma Ces1c therefore likely binds opnurasib, increasing its retention in plasma. The obtained pharmacokinetic insights may be useful for further optimization of the clinical efficacy and safety of opnurasib, and might reveal potential drug-drug interaction risks.

Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1-/-, Abcb1a/1b;Abcg2-/- and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2-/- << Slco1a/1b/2b1-/- < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1-/- and Abcb1a/1b;Abcg2-/- mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2-/- or Slco1a/1b/2b1-/- mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.

Abstract Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.

Abstract Background Psychosocial interventions such as psychoeducation are increasingly being used to treat adult ADHD, both as an alternative and as a supplement to pharmacotherapy. A thorough overview of the literature on psychoeducation for adult ADHD is lacking. The objectives of this scoping review were therefore to identify the characteristics of psychoeducation interventions designed for adults with ADHD, examine how the patient experience or perspective is considered during the intervention’s development and implementation, determine the typical themes covered, and explore how ‘psychoeducation’ is defined in these interventions. Methods A comprehensive search was performed to identify records in MEDLINE, Embase, PsycINFO, Web of Science, Cochrane CENTRAL, AMED, and ClinicalTrials.gov. Two or more reviewers were included in every step of the screening process and the final selection of included studies. The Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist (Supplementary Material 1) was used to report the results, and the framework developed by Arksey and O’Malley was used as a guide throughout the scoping process. Results A total of 2121 records were identified through the literature search. After screening and full-text analysis, ten studies were included for final analysis. Most studies were conducted in Europe and followed a group format. Seven main themes were identified: Information about the diagnosis, treatment options, somatic health and ADHD, the insider perspective, ADHD and social life, coping and psychological skills, and ADHD and work. There was significant overlap in themes covered, but coverage of each theme varied. Themes deemed important by newer research, such as sexuality and gender-specific issues, were missing. Only one intervention involved patients in its development and implementation, and two interventions involved family members. There was variation in how psychoeducation was defined in the included studies, and the implications of this are discussed. Conclusion The literature on psychoeducation for adult ADHD is not ready for any systematic effect estimation. Before such estimations are conducted, a shared understanding and definition of psychoeducation are needed. The involvement of end users in the development and delivery of interventions may aid reach this goal but results from this review indicate that such practices are rare.

Introduction: Pralsetinib is used to treat metastatic RET fusion-positive non-small cell lung cancer. Preclinical studies of pralsetinib have shown blood-brain barrier (BBB) penetration and intracranial activity. The intracranial efficacy of pralsetinib in patients with brain metastasis is considered to be greater compared to older multikinase tyrosine kinase inhibitors. However, CSF concentrations of pralsetinib in patients are not well described in the literature. Case Presentation: We report a case of a patient with RET fusion-positive NSCLC treated with pralsetinib. Despite extracranial clinical and radiological remission, the patient developed progressive brain metastasis during treatment with pralsetinib. We measured the pralsetinib concentration in plasma and in CSF to determine the CSF-to-unbound plasma ratio. The measured pralsetinib concentrations in plasma and CSF were 1,951 ng/mL (∼57 unbound) and 14 ng/mL, respectively, reflecting a CSF-to-unbound plasma concentration ratio of 0.25. Our findings were compared with data from the literature. Conclusion: We showed that pralsetinib penetrates the CSF well and is expected to be an effective treatment for brain metastasis of RET fusion-positive NSCLC. Lack of intracranial efficacy is more likely to be caused by intrinsic or acquired tumor resistance instead of suboptimal exposure of pralsetinib in the brain.

Adagrasib (Krazati™) is the second FDA-approved specific KRASG12C inhibitor for non-small cell lung cancer (NSCLC) patients harboring this mutation. The impact of the drug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing enzymes CYP3A and carboxylesterase 1 (CES1) on the pharmacokinetics of oral adagrasib were studied using genetically modified mouse models. Adagrasib was potently transported by human ABCB1 and modestly by mouse Abcg2 in vitro. In Abcb1a/b-/- and Abcb1a/b;Abcg2-/- mice, the brain-to-plasma ratios were enhanced by 33- and 55-fold, respectively, compared to wild-type mice, whereas ratios in Abcg2-/- mice remained unchanged. The influence of ABC transporters was completely reversed by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, increasing the brain penetration in wild-type mice by 41-fold while no signs of acute CNS toxicity were observed. Tumor ABCB1 overexpression may thus confer adagrasib resistance. Whereas the ABC transporters did not affect adagrasib plasma exposure, CYP3A and Ces1 strongly impacted its apparent oral availability. The plasma AUC0–8 h was significantly enhanced by 2.3-fold in Cyp3a-/- compared to wild-type mice, and subsequently 4.3-fold reduced in transgenic CYP3A4 mice, indicating substantial CYP3A-mediated metabolism. Adagrasib plasma exposure was strongly reduced in Ces1-/- compared to wild-type mice, but tissue exposure was slightly increased, suggesting that adagrasib binds to plasma Ces1c in mice and is perhaps metabolized by Ces1. This binding could complicate interpretation of mouse studies, especially since humans lack circulating CES1 enzyme(s). Our results may be useful to further optimize the clinical safety and efficacy of adagrasib, and give more insight into potential drug-drug interactions risks.

A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (-)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (-)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.

BackgroundPatients with substance use disorders (SUDs) are at increased risk for symptom deterioration following treatment, with up to 60% resuming substance use within the first year posttreatment. Substance use craving together with cognitive and mental health variables play important roles in the understanding of the trajectories from abstinence to substance use. ObjectiveThis prospective observational feasibility study aims to improve our understanding of specific profiles of variables explaining SUD symptom deterioration, in particular, how individual variability in mental health, cognitive functioning, and smartphone use is associated with craving and substance use in a young adult clinical population. MethodsIn this pilot study, 26 patients with SUDs were included at about 2 weeks prior to discharge from inpatient SUD treatment from 3 different treatment facilities in Norway. Patients underwent baseline neuropsychological and mental health assessments; they were equipped with smartwatches and they downloaded an app for mobile sensor data collection in their smartphones. Every 2 days for up to 8 weeks, the patients were administered mobile ecological momentary assessments (EMAs) to evaluate substance use, craving, mental health, cognition, and a mobile Go/NoGo performance task. Repeated EMAs as well as the smartphone’s battery use data were averaged across all days per individual and used as candidate input variables together with the baseline measures in models of craving intensity and the occurrence of any substance use episodes. ResultsA total of 455 momentary assessments were completed out of a potential maximum of 728 assessments. Using EMA and baseline data as candidate input variables and craving and substance use as responses, model selection identified mean craving intensity as the most important predictor of having one or more substance use episodes and with variabilities in self-reported impulsivity, mental health, and battery use as significant explanatory variables of craving intensity. ConclusionsThis prospective observational feasibility study adds novelty by collecting high-intensity data for a considerable period of time, including mental health data, mobile cognitive assessments, and mobile sensor data. Our study also contributes to our knowledge about a clinical population with the most severe SUD presentations in a vulnerable period during and after discharge from inpatient treatment. We confirmed the importance of variability in cognitive function and mood in explaining variability in craving and that smartphone usage may possibly add to this understanding. Further, we found that craving intensity is an important explanatory variable in understanding substance use episodes.

Protein CK2 has gained much interest as an anticancer drug target in the past decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino)benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2-yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC50 = 0.6 μM). Furthermore, 27 induced apoptosis and cell death in 786-O renal cell carcinoma cells (EC50 = 5 μM) and inhibited STAT3 activation even more potently than the ATP-competitive drug candidate CX-4945 (EC50 of 1.6 μM vs 5.3 μM). Notably, the potencies of our allosteric ligands to inhibit CK2 varied depending on the individual substrate. Altogether, the novel allosteric pocket was proved a druggable site, offering an excellent perspective to develop efficient and selective allosteric CK2 inhibitors.

CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non-ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD NMR, circular dichroism spectroscopy, and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the αC helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC50 of 3.4 μM against purified CK2α in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into anticancer drugs.

Organic anion transporting polypeptide 2B1 (OATP2B1/SLCO2B1) facilitates uptake transport of structurally diverse endogenous and exogenous compounds. To investigate the roles of OATP2B1 in physiology and pharmacology, we established and characterized Oatp2b1 knockout (single Slco2b1-/- and combination Slco1a/1b/2b1-/-) and humanized hepatic and intestinal OATP2B1 transgenic mouse models. While viable and fertile, these strains exhibited a modestly increased body weight. In males, unconjugated bilirubin levels were markedly reduced in Slco2b1-/- compared to wild-type mice, whereas bilirubin monoglucuronide levels were modestly increased in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice. Single Slco2b1-/- mice showed no significant changes in oral pharmacokinetics of several tested drugs. However, markedly higher or lower plasma exposure of pravastatin and the erlotinib metabolite OSI-420, respectively, were found in Slco1a/1b/2b1-/- compared to Slco1a/1b-/- mice, while oral rosuvastatin and fluvastatin behaved similarly between the strains. In males, humanized OATP2B1 strains showed lower conjugated and unconjugated bilirubin levels than control Slco1a/1b/2b1-deficient mice. Moreover, hepatic expression of human OATP2B1 partially or completely rescued the impaired hepatic uptake of OSI-420, rosuvastatin, pravastatin, and fluvastatin in Slco1a/1b/2b1-/- mice, establishing an important role in hepatic uptake. Expression of human OATP2B1 in the intestine was basolateral and markedly reduced the oral availability of rosuvastatin and pravastatin, but not of OSI-420 and fluvastatin. Neither lack of Oatp2b1, nor overexpression of human OATP2B1 had any effect on fexofenadine oral pharmacokinetics. While these mouse models still have limitations for human translation, with additional work we expect they will provide powerful tools to further understand the physiological and pharmacological roles of OATP2B1.

Purpose: To identify gender differences in (1) the coronal alignment of functional knee phenotypes and (2) the JLCA (joint line convergence angle) in relation to the phenotype classification. Methods: This study is a retrospective data analysis, including 12,099 osteoarthritic knee computed tomography (5025 male, 7074 female) analysed by Medacta software for hip‐knee‐ankle angle (HKA), femoral mechanical angle (FMA), tibial mechanical angle (TMA) and JLCA. The data were grouped into genders and combined according to the Functional Knee Phenotypes Classification. Results: Out of 127 phenotypes for males and 131 for females, 17 common phenotypes were reported. The commonest four were similar for both genders with VARHKA177° NEUFMA93° NEUTMA87° (9.8% males, 9.50% females), followed by VARHKA174° NEUFMA93°VARTMA84° (7.1%) and VARHKA174°VARFMA90° NEUTMA87° (7.0%) for males and VARHKA174° NEUFMA93° NEUTMA87° (6.1%), VARHKA174° NEUFMA93°VARTMA84° (5.1%) for females. The commonest FMA and TMA (91.5° to 94.5° and 85.5° to 88.5°, respectively) were the same for both genders, however, the rest of the male population observed greater femoral varus than the female population (p < 0.001). JLCA values ranged from −28.4° to 8.2° in the overall study population. Males and females had a mean JLCA of −2.96° (±2.6° SD) and −2.66° (±2.8°7 SD), respectively, p < 0.001. Conclusions: Gender differences exist within the osteoarthritic knee phenotype. The male varus phenotype is influenced by FMA, while TMA values are similar across genders. JLCA variations show similarities to both TMA and FMA, suggesting JLCA is influenced by bone morphology more than by gender. These differences inform surgical decision‐making for the personalised approach to the primary TKA. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Recently, we identified biallelic mutations of SLC25A46 in patients with multiple neuropathies. Functional studies revealed that SLC25A46 may play an important role in mitochondrial dynamics by mediating mitochondrial fission. However, the cellular basis and pathogenic mechanism of the SLC25A46-related neuropathies are not fully understood. Thus, we generated a Slc25a46 knock-out mouse model. Mice lacking SLC25A46 displayed severe ataxia, mainly caused by degeneration of Purkinje cells. Increased numbers of small, unmyelinated and degenerated optic nerves as well as loss of retinal ganglion cells indicated optic atrophy. Compound muscle action potentials in peripheral nerves showed peripheral neuropathy associated with degeneration and demyelination in axons. Mutant cerebellar neurons have large mitochondria, which exhibit abnormal distribution and transport. Biochemically mutant mice showed impaired electron transport chain activity and accumulated autophagy markers. Our results suggest that loss of SLC25A46 causes degeneration in neurons by affecting mitochondrial dynamics and energy production.