Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Benefit and Expedited Approval of Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia

PURPOSE: Regulatory agencies have sought to speed up the review of new cancer medicines and reduce delays in approval between countries. We examined trends in regulatory review times and association with clinical benefit for new cancer medicines in six jurisdictions: United States (Food and Drug Administration [FDA]), European Union (European Medicines Agency [EMA]), Switzerland (Swissmedic), Japan (Pharmaceuticals and Medical Devices Agency [PMDA]), Canada (Health Canada), and Australia (Therapeutic Goods Administration). METHODS: We studied all new cancer drugs approved in the six aforementioned jurisdictions from 2007 to 2020. We extracted all applicable expedited programs, total regulatory review times, and, for drugs first approved by the FDA, times to subsequent regulatory approval. Clinical benefit was assessed using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale value framework and ASCO-Cancer Research Committee's targets. Nonparametric Kruskal-Wallis test was used to compare total review times for high versus low clinical benefit drugs. RESULTS: One hundred and twenty eight drugs received initial approval in at least one of the six included jurisdictions. Most drugs approved by the FDA (91%) and Health Canada (59%) qualified for at least one expedited program within those jurisdictions, compared with 46% of EMA approvals and 18% of PMDA approvals. The FDA was the first regulator to approve 102 (80%) drugs. Delays in submission accounted for a median of 20.2% (EMA) to 83.8% (PMDA) of the time to subsequent approval. There was no association between high clinical benefit and shorter total review times. CONCLUSION: Most new cancer therapies were approved first by the FDA, and delays in submission of regulatory applications accounted for substantial delays in approving cancer drugs in other countries. Regulators should prioritize faster review for drugs with high clinical benefit.
Antimicrobial safety considerations in critically ill patients: part I: focused on acute kidney injury

ABSTRACT Introduction Antibiotic prescription is a challenging issue in critical care settings. Different pharmacokinetic and pharmacodynamic properties, polypharmacy, drug interactions, and high incidence of multidrug-resistant microorganisms in this population can influence the selection, safety, and efficacy of prescribed antibiotics. Areas covered In the current article, we searched PubMed, Scopus, and Google Scholar for estimating renal function in acute kidney injury, nephrotoxicity of commonly used antibiotics, and nephrotoxin stewardship in intensive care units. Expert opinion Early estimation of kidney function with an accurate method may be helpful to optimize antimicrobial treatment in critically ill patients. Different antibiotic dosing regimens may be required for patients with acute kidney injury. In many low-resource settings, therapeutic drug monitoring is not available for antibiotics. Acute kidney injury may influence treatment effectiveness and patient outcome.
Kinetic diffusion–controlled synthesis of twinned intermetallic nanocrystals for CO-resistant catalysis

Intermetallic catalysts are of immense interest, but how heterometals diffuse and related interface structure remain unclear when there exists a strong metal-support interaction. Here, we developed a kinetic diffusion–controlled method and synthesized intermetallic Pt2Mo nanocrystals with twin boundaries on mesoporous carbon (Pt2Mo/C). The formation of small-sized twinned intermetallic nanocrystals is associated with the strong Mo-C interaction–induced slow Mo diffusion and the heterogeneity of alloying, which is revealed by an in situ aberration-corrected transmission electron microscope (TEM) at high temperature. The twinned Pt2Mo/C constitutes a promising CO-resistant catalyst for highly selective hydrogenation of nitroarenes. Theoretical calculations and environmental TEM suggest that the weakened CO adsorption over Pt sites of Pt2Mo twin boundaries and their local region endows them with high CO resistance, selectivity, and reusability. The present strategy paves the way for tailoring the interface structure of high–melting point Mo/W-based intermetallic nanocrystals that proved to be important for the industrially viable reactions.
Abnormal white‐matter rich‐club organization in obsessive–compulsive disorder

Rich‐club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher‐order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive–compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich‐club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion‐weighted imaging and probabilistic tractography. Topological and weighted measures of rich‐club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich‐club organization, allocating a smaller fraction of all connection weights to the rich‐club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three‐group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich‐club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network‐based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.
TEB/POLQ plays dual roles in protecting Arabidopsis from NO-induced DNA damage

Abstract Nitric oxide (NO) is a key player in numerous physiological processes. Excessive NO induces DNA damage, but how plants respond to this damage remains unclear. We screened and identified an Arabidopsis NO hypersensitive mutant and found it to be allelic to TEBICHI/POLQ, encoding DNA polymerase θ. The teb mutant plants were preferentially sensitive to NO- and its derivative peroxynitrite-induced DNA damage and subsequent double-strand breaks (DSBs). Inactivation of TEB caused the accumulation of spontaneous DSBs largely attributed to endogenous NO and was synergistic to DSB repair pathway mutations with respect to growth. These effects were manifested in the presence of NO-inducing agents and relieved by NO scavengers. NO induced G2/M cell cycle arrest in the teb mutant, indicative of stalled replication forks. Genetic analyses indicate that Polθ is required for translesion DNA synthesis across NO-induced lesions, but not oxidation-induced lesions. Whole-genome sequencing revealed that Polθ bypasses NO-induced base adducts in an error-free manner and generates mutations characteristic of Polθ-mediated end joining. Our experimental data collectively suggests that Polθ plays dual roles in protecting plants from NO-induced DNA damage. Since Polθ is conserved in higher eukaryotes, mammalian Polθ may also be required for balancing NO physiological signaling and genotoxicity.
Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study

Abstract Background Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug’s area under the concentration-time curve over 24 hours (AUC0–24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0–24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0–24/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0–24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21–11.56; P = .022); levofloxacin AUC0–24/MIC of 118.3, clofazimine AUC0–24/MIC of 50.5, and pyrazinamide AUC0–24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0–24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. Conclusions Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive and should be optimized to improve clinical outcome. Clinical Trials Registration NCT03559582.
Insulin Resistance and Metabolic Comorbidities in Alzheimer’s Disease

Alzheimer’s disease affects 50 million people worldwide and just like any modern lifestyle disease, it is steadily increasing. Unfortunately, a cure has not yet been found, despite decades of research. The pathophysiology of Alzheimer’s disease is extraordinarily complex and involves many different factors. Despite it being a protein misfolding disease, a lot of evidence currently point to insulin resistance, impaired glucose metabolism and comorbidities with other metabolic disorders such as obesity, elevated blood lipids, and non-alcoholic fatty liver disease, as a potential root cause. Genetics aside, it seems like poor metabolic functioning affects the brain and central nervous system a great deal: affecting mood, behaviour, and cognitive performance. Even mood disorders are interlinked with metabolic disorders and increase the risk for Alzheimer’s disease later in life. This is a summary of objectively chosen original research articles, published between 2011-2021 and with insulin resistance as the main objective for cognitive impairment and Alzheimer’s disease.
Part 2. Veterinary medicine CELLuLAR AND HumORAL mEDIATED ImmuNITY AND DISTRIBuTION Of VIRAL ANTIGENS IN CHICKENS AfTER INfECTION wITH A LOw PATHOGENIC AVIAN INfLuENZA VIRuS (LPAIV H4N6) ISOLATED fROm wILD DuCKS

Summary. Four-week-old commercial chickens were intranasally inoculated with a H4N6 low pathogenic avian influenza virus (LPAIV) isolated from a garganey in Ukraine. The virus did not cause disease in chickens and no pathological changes were observed in inoculated birds. No virus was isolated from internal organs, but 3 chickens of 5 showed antibodies to influenza virus at intranasal infection. Cecum, spleen, lung, and trachea samples were collected from LPAIV-infected chickens from 1 to 14 days post inoculation (dpi) and examined by immunohistochemical techniques to determine the distribution of LPAIV and evaluate the host immune response using various immune markers. From 7 to 14 dpi, a sharp increase of the number of cells bearing CD4, IgM, IgG, and IgA was observed. In spleen, the number of CD4 T lymphocytes and macrophages were increased in immunohistochemical staining when compared to controls. In the lung, B lymphocytes expressing IgM (6.8±0.5%), IgG (9.4±1.3%), and IgA (8.6±0.1%) were detected in higher numbers than in controls. High levels of IFN-γ, IL-2, IL-15 were present on 7 dpi. We also found LPAIV nucleoprotein (NP) staining in the trachea observed on 10 dpi (2.7±0.4% of antibody-stained areas) as well as in the spleen on 5 dpi (3.3±0.2%). There was no NP antigen in other organs. In conclusion, although infection with a LPAIV did not cause obvious clinical disease, viral replication was seen in the trachea and spleen and both local and systemic cellular and humoral immune responses were elicited in these LPAIV-infected chickens.
The (dis) pleasures of creativity

Previous research has demonstrated that individual differences in affect and motivation predict divergent and convergent thinking performance, two thinking processes involved in creative idea generation. Individual differences in affect and motivation also predict spontaneous eye blink rate (sEBR) during divergent and convergent thinking; and sEBR predicts divergent and convergent thinking performance. This study investi-gates experimentally whether the relationship between sEBR and divergent and convergent thinking depends on individual differences in affect and motivation. Eighty-two participants completed the Emotion/motiva-tion-related Divergent and Convergent thinking styles Scale (EDICOS; G. Soroa et al., 2015), performed the alternative uses task (AUT; divergent thinking) or the remote associates task (RAT; convergent thinking), while their sEBR was captured with an eye-tracker. The results showed that individual differences in positive affect positively correlated with sEBR for the AUT, whereas individual differences in negative affect positively correlated with sEBR for the RAT. Furthermore, the interaction between individual differences in posi- tive and negative affect and sEBR predicted divergent and convergent thinking performance. The contribution of our study is therefore that individual differences in positive and negative affect can both positively correlate with sEBR during divergent and convergent thinking; and that this predicts divergent and convergent thinking performance. alpha. EDICOS was translated from Spanish into Dutch by the joint efforts of a bilingual Spanish-Dutch speaker and a Dutch-Spanish language professional. The distributions of the four EDICOS factors obtained in this study are presented in Appendix A. Assessment of divergent and convergent p = . 188. Taken together, these results suggest that the degree to which people self-report to experience positive affect when they engage in a divergent thinking task (divergent pleas- ant), positively correlates with sEBR, but only for the AUT; whereas the degree to which people self-report to experience negative affect when they engage in a convergent thinking task (convergent unpleasant), posi- tively correlates with sEBR, but only for the RAT. and divergent thinking. Speculatively, the implications of these ﬁndings are that sEBR can represent multiple relationships between (individual differences in) affect and cognitive control, where increases in sEBR associate with: (a) a relation- ship between positive affect and cognitive ﬂexibility during divergent thinking, and (b) a relationship between negative affect and cognitive stability during convergent thinking. That is, the results showed that the interac- tion of individual differences in positive affect with sEBR negatively correlates with convergent thinking performance. In previous studies, this has been attributed to a negative effect of cognitive ﬂexibility on convergent thinking; while previous studies
Relative Importance of H 2 and H 2 S as Energy Sources for Primary Production in Geothermal Springs (cid:1) †

Geothermal waters contain numerous potential electron donors capable of supporting chemolithotrophy- based primary production. Thermodynamic predictions of energy yields for speciﬁc electron donor and acceptor pairs in such systems are available, although direct assessments of these predictions are rare. This study assessed the relative importance of dissolved H 2 and H 2 S as energy sources for the support of chemolithotrophic metabolism in an acidic geothermal spring in Yellowstone National Park. H 2 S and H 2 concen- tration gradients were observed in the outﬂow channel, and vertical H 2 S and O 2 gradients were evident within the microbial mat. H 2 S levels and microbial consumption rates were approximately three orders of magnitude greater than those of H 2 . Hydrogenobaculum -like organisms dominated the bacterial component of the micro- bial community, and isolates representing three distinct 16S rRNA gene phylotypes (phylotype (cid:1) 100% identity) were isolated and characterized. Within a phylotype, O 2 requirements varied, as did energy source utilization: some isolates could grow only with H 2 S, some only with H 2 , while others could utilize either as an energy source. These metabolic phenotypes were consistent with in situ geochemical conditions measured using aqueous chemical analysis and in-ﬁeld measurements made by using gas chromatography and microelectrodes. Pure-culture experiments with an isolate that could utilize H 2 S and H 2 and that represented the dominant phylotype (70% of the PCR clones) showed that H 2 S and H 2 were used simultaneously, without evidence of induction or catabolite repression, and at relative rate differences comparable to those measured in ex situ ﬁeld assays. Under in situ-relevant concentrations, growth of this isolate with H 2 S was better than that with H 2 . The major conclusions drawn from this study are that phylogeny may not necessarily be reliable for predicting physiology and that H 2 S can dominate over H 2 as an energy source in terms of availability, apparent in situ consumption rates, and growth-supporting energy.
Extracellular Vesicle Functionalised Melt Electrowriting Scaffolds for Bone Tissue Engineering

Mechanobiological cues arising directly via tissue/scaffold mechanics or indirectly via mechanically activated cell secretomes represent potent stimuli that mediate cell behaviour and tissue adaptation. Exploiting these cues in regeneration strategies holds great promise for tissue repair. In this study, we harness indirect biophysical cues originating from osteocytes in a combination with direct biophysical cues from melt electrowriting (MEW) scaffolds to form a single engineered construct with the aim of synergistically enhancing osteogenesis. The secretome of mechanically activated osteocytes was collected within conditioned media (CM) and extracellular vesicles (EV) were subsequently isolated. Building on MEW micro-fibrous scaffolds with controlled microarchitecture and mineral nanotopography optimised for bone repair, a protocol was developed to functionalise these materials with CM or EVs. Human MSC proliferation was enhanced in both CM and EV functionalised scaffolds. EV functionalised scaffolds were further found to significantly enhance MSC osteogenesis, with enhanced alkaline phosphatase expression, collagen production, and mineralisation compared to control scaffolds. Furthermore, enhanced formation of mineralised nodules was identified in EV functionalised materials. Combining direct cultured up to 21 days before evaluating collagen content. Cell-scaffold constructs were rinsed in PBS, fixed in 10% neutral buffered formalin for 15 min and rinsed again in PBS before storage at -20°C. Scaffolds were stained with 200μl of 1mg/ml of Direct Red 80 (Sigma Aldrich, 365548) in a saturated aqueous picric acid solution for 1 h with shaking at 150 rpm. Scaffolds were then washed twice with 0.5% acetic acid and allowed to dry overnight before imaging. To quantify collagen content, 500µl 0.5M NaOH was added to wells under shaking until stain was dissolved, and solutions were added to 1.5 ml tubes. Tubes were centrifuged at 14,000g for 10 min to pellet debris. Standards were made by adding direct red staining solution to 8µl of collagen I (Corning, #354249) before centrifuging at 14,000g for 10 min and re-suspending the collagen in 500µl 0.5M NaOH. The absorbance of samples and standards were read at 490 nm in 96-well plates.
Editor’s Choice Economic incentives to target species and ﬁsh size: prices and ﬁne-scale product attributes in Norwegian ﬁsheries

size:prices andﬁne-scaleproduct attributes Improved ﬁsheries management provides ﬁshers with more opportunities to maximize harvest value by accounting for valuable attributes of the harvest such asspecies, harvest timing, ﬁsh size, productform, and landing location. Harvestvalues can alsovaryby vessel andgear type. Moreover, theextentoftargetingcaninﬂuencetheecosysteminwhichtheﬁshersoperateandprovideimportantmanagementchallenges. Weutilizeauniquedatasetcontainingdailyvessel-levelﬁshlandingsinoneregionofNorwayin2010toinvestigatethevalueofanarrayofattributes,includingspecies,productform,productcondition,timing,ﬁshsize,vesseltype,geartype,andlandinglocationforcodandotherwhiteﬁshspecies,aswellaskingcrab.Wealsoinvestigatetowhatextentlandedvaluediffersacrossdifferentcommunities,ﬁrms,andplants.Theresultsindicatesubstantialvariationforallattributes,highlightingopportunitiesforﬁshersaswellaspotentialmanagementchallenges. Forwhiteﬁsh,thespecieslandedaccountsforthree-quartersofthevariationinprices.Forcodinparticular,theﬁshsizeaccountsfornearlyallvariationinprices. Intheseﬁsheries,marketconditions justify management focus on the biological composition of the catch.
A cross-sectional study on spouse and parent differences in caregiving experiences of people living with schizophrenia in rural China CURRENT

Background: Conflicting evidence exists on whether parent or spouse caregivers experience better outcomes when caring for family members with schizophrenia. The current study aims to examine relative caregiving experiences and impacts of spouse and parent caregivers for people living with schizophrenia (PLS) in China. Methods: A cross-sectional study was conducted in a sample of 264 community-dwelling primary family caregivers of PLS. Face-to-face interviews were conducted to collect information on family caregiving activities; objective and subjective burden; caregiver psychological distress, such as depression and anxiety; positive caregiving impact, such as caregiving rewarding feelings; and family functioning for spouse and parent caregivers. Results: Both types of caregivers report engaging in similar caregiving activities and report comparable levels of objective burden. However, parent caregivers report significantly higher subjective burden than spouse caregivers ( b =7.94, 95% CI :2.08, 13.80, P <0.01), which is also reflected in significantly higher depression ( b =3.88, 95% CI :1.35, 6.41, P <0.01) and anxiety ( b =2.53, 95% CI : 0.22, 4.84, P <0.05), and lower family functioning ( b =-1.71, 95% CI : -2.73, -0.49, P <0.01). Despite these differences, both groups of caregivers report comparable rewarding feelings about caregiving. Conclusions: Our findings have implications for family caregivers globally, but especially for countries that adhere to Confusion cultural values, and provide guidance for future family intervention programs. Such programs may do well to incorporate cultural values and beliefs in understanding caregiving and kinship family dynamics so as support family caregivers, and in particular, the specific vulnerabilities of parent caregivers. that caregivers may have during caregiving. Each “yes” response was scored 1 and “no” responses 0, with total scores ranging from 0 to 12; higher scores indicate more positive feelings in caregiving. For the present study, CRF was administered by the research team to primary caregivers and the Chinese version of CRF showed acceptable reliability with a Cronbach's alpha of 0.77.