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Introduction: Pralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, RET fusion-positive NSCLC. Objective: To assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC. Design: Retrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021. Participants: A total of 41 patients with advanced, refractory, RET fusion-positive NSCLC were included. Pralsetinib was administered at a daily dose of 400 mg based on safety and pharmacokinetic outcomes from previous phase 1/2 study. Results: Pralsetinib was administered as second line in 23 patients (56%) and as third line and beyond in 15 patients (37%). After a median follow-up of 26.3 months, pralsetinib was ongoing in 13 patients. Median real-world progression-free survival was 11.8 (95% confidence interval [CI]: 9.3–15.5) months. Objective response rate was 68% (95% CI: 50%–82%), and disease control rate was 89% (95% CI: 75%–97%). Subsequent line of systemic therapy was initiated in 11 patients. Median overall survival from pralsetinib initiation was 23.8 (95% CI: 16.5–not reached) months. Conclusion: In this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression.

Summary: Antibody-oligonucleotide conjugates (AOCs) are a fast-expanding modality for targeted delivery of therapeutic oligonucleotides to tissues. Here, we present a protocol to generate, purify, and analyze AOCs from off-the-shelf antibodies. We describe steps to conjugate single/double-stranded oligonucleotides bearing amine handles to linkers and, then, to antibodies using well-established chemistry. In addition, we provide details regarding the purification techniques and analytical methods suitable for AOC. This protocol can be applied for several purposes where AOC is a modality of interest.For complete details on the use and execution of this protocol, please refer to Rady et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

I en tid med stigende skolefravær i hele Norden giver denne artikel elevperspektiverende bud på, hvornår og hvorfor skole vælges til og fra eller bliver en umulighed. Med inspiration fra sociokulturelle læringsteoretikere som Jean Lave, Etienne Wenger og Jerome Bruner undersøges elevernes relationelle og sociale forhold, herunder hvad der skaber meningsfuldhed og meningsløshed knyttet til skolegang. Det empiriske grundlag er udsagn fra og interviews med børn og unge indsamlet igennem de senere år af artiklens tre forfattere. Nogle interviews er foretaget i forbindelse med terapeutiske børne- og ungesamtaler, andre interviews er gennemført i forbindelse med skolebesøg og andre igen i forbindelse med kvalitative studier af fravær. De analytiske fund her i artiklen centrerer sig om oplevelse af skolen som utryg, kedelig, ekskluderende og til tider skræmmende, og dette forbindes ofte med sociale, relationelle og faglige vilkår. Omvendt forbindes det at vælge skolen positivt til med oplevelser af at kunne deltage og bidrage med noget, når undervisningen findes spændende, nærværende og inviterende, når fællesskabet fungerer, og når der forefindes tillidsfulde relationer. At have længerevarende skolefravær kan både komme af – og skabe – manglende oplevelse af at høre til i skolen. Begrebsparret skolefravær-skoletilvær (Hansen, 2019) er et analytisk par, hvori skolefravær forstås ved at samlæse perspektiver på såvel at have skolefravær, som det at vælge skole proaktiv til, altså skoletilvær. Samlet set og på tværs af negative og positive elevreflektioner over skolen som social lokation fører analysen til, at løsningsretninger må handle om at genoprette tillid, skabe tilhør og relationer og at møde børn og unges differentierede undervisningsbehov.

Dilek Gogas Yavuz,1 Omar Akhtar,2 Kaywei Low,2 Adrien Gras,2 Batu Gurser,3 Esra Safak Yilmaz,4 Amaury Basse5 1School of Medicine, Marmara University, Section of Endocrinology and Metabolism, Istanbul, Turkey; 2Healthcare Market Access, Ipsos, Singapore; 3Novo Nordisk, İstanbul, Türkiye; 4Novo Nordisk, Ankara, Türkiye; 5Novo Nordisk, Novo Nordisk Region South East Europe, Middle East & Africa, Zurich, SwitzerlandCorrespondence: Amaury Basse, Email aayb@novonordisk.comBackground: Turkey currently has the highest obesity prevalence among its European counterparts. 32% and 61% of the population live with obesity and overweight, respectively. Overweight and obesity are linked to non-communicable diseases that incur incremental health and economic costs. The significant public health concern warrants an assessment of the cost of obesity.Methods: A micro-costing approach from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Turkey. Clinical practice guidelines and a systematic literature review informed ORCs and the respective cost categories. This was subsequently validated by a steering committee comprising seven experts. Seventy public sector physicians were surveyed to estimate healthcare resource use. Unit costs were derived from Social Security Institute’s Healthcare Implementation Communique. Cost items were summed to determine the annual cost per patient per ORC, which was validated by the steering committee. Medical inflation was considered in a scenario analysis that varied resource unit costs.Results: Chronic kidney disease, heart failure and type 2 diabetes are the costliest ORCs, incurring an annual cost of 28,600 TRY, 16,639 TRY and 11,993 TRY, respectively. Individuals in Turkey with any ORC triggered direct healthcare costs ranging 1857– 28,600 TRY annually. Costs were driven by tertiary care resources arising from treatment-related adverse events, disease complications and inpatient procedures. In the scenario analysis, medical resource unit costs were inflated by 18.7% and 39.4%, triggering an average increase in cost across all ORCs of 1998 TRY and 4210 TRY, respectively.Conclusion: Our findings confirm that obesity and its complications result in significant financial burden to the public healthcare system. By quantifying the burden of obesity across a comprehensive spectrum of ORCs, our study aims to support the economic case for investing in appropriate obesity interventions.Keywords: obesity, micro-costing, cost of illness, burden of illness, healthcare resource utilization

Cervical dystonia is the most common focal dystonia affecting adults. It frequently causes postural control problems, neck pain and spasm attacks of the cervical musculature. One of the surgical options available is selective cervical denervation. We report the case of a 32-year-old patient with cervical dystonia refractory to conservative treatment and an injection of botulinum toxin A, which was finally completed by bilateral selective cervical denervation, with considerable regression of cervical spasm at 16 months post-operatively.The clinical presentation of cervical dystonia includes abnormal movements or postural changes of the head, neck and shoulders caused by involuntary contractions of the cervical muscles. When the spasmodic attacks are recurrent, they can cause real handicaps for the patient. The causes of the disease and its pathophysiological mechanism are still poorly understood. There are a number of treatment options, including pharmacological therapy and surgery in cases of therapeutic failure. Repeated intramuscular injections of botulinum toxin are the first-line treatment. Some conservative measures such as physiotherapy are also used, although there is little literature on these approaches.Selective peripheral denervation is currently the main surgical treatment for refractory cervical dystonia. A combination of conservative treatment with BT-A injection and denervation appears to be an effective treatment option.

Background: Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor ( EGFR ) mutations. The main objective of this study was to describe, in the real-world setting, these patients’ incidence, clinical, and tumoral characteristics. Methods: The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery. Results: The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36–88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1–49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 ( L858R )/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6–33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%. Conclusion: This real-world analysis provides the incidence and outcomes of resected EGFR -mutated NSCLCs in a European patient cohort.

Oncogenic forms of KRAS proteins are known to be drivers of pancreatic, colorectal, and lung cancers. The goal of this study is to identify chemical leads that inhibit oncogenic KRAS signaling. We first developed an isogenic panel of mouse embryonic fibroblast (MEF) cell lines that carry wild-type RAS, oncogenic KRAS, and oncogenic BRAF. We validated these cell lines by screening against a tool compound library of 1402 annotated inhibitors in an adenosine triphosphate (ATP)-based cell viability assay. Subsequently, this MEF panel was used to conduct a high-throughput phenotypic screen in a cell viability assay with a proprietary compound library. All 126 compounds that exhibited a selective activity against mutant KRAS were selected and prioritized based on their activities in secondary assays. Finally, five chemical clusters were chosen. They had specific activity against SW620 and LS513 over Colo320 colorectal cancer cell lines. In addition, they had no effects on BRAFV600E, MEK1, extracellular signal-regulated kinase 2 (ERK2), phosphoinositide 3-kinase alpha (PI3Kα), AKT1, or mammalian target of rapamycin (mTOR) as tested in in vitro enzymatic activity assays. Biophysical assays demonstrated that these compounds did not bind directly to KRAS. We further identified the mechanism of action and showed that three of them have CDK9 inhibitory activity. In conclusion, we have developed and validated an isogenic MEF panel that was used successfully to identify RAS oncogenic or wild-type allele-specific vulnerabilities. Furthermore, we identified sensitivity of oncogenic KRAS-expressing cells to CDK9 inhibitors, which warrants future studies of treating KRAS-driven cancers with CDK9 inhibitors.

We previously reported that dendritic cell (DC)-based vaccines targeting antigens expressed by tumor-associated vascular endothelial cells (VECs) and pericytes effectively control tumor growth in translational mouse tumor models. In the current report, we examined whether the therapeutic benefits of such tumor blood vessel antigen (TBVA)-targeted vaccines could be improved by the cotargeting of tumor antigens in the s.c. B16 melanoma model. We also evaluated whether combination vaccines incorporating anti-PD-L1 checkpoint blockade and/or a chemokine-modulating (CKM; IFNα + TLR3-L [rintatolimod] + Celecoxib) regimen would improve T cell infiltration/functionality in tumors yielding enhanced treatment benefits. We report that DC–peptide or DC–tumor lysate vaccines coordinately targeting melanoma antigens and TBVAs were effective in slowing B16 growth in vivo and extending survival, with superior outcomes observed for DC–peptide-based vaccines. Peptide-based vaccines that selectively target either melanoma antigens or TBVAs elicited a CD8+ T cell repertoire recognizing both tumor cells and tumor-associated VECs and pericytes in vitro, consistent with a treatment-induced epitope spreading mechanism. Notably, combination vaccines including anti-PD-L1 + CKM yielded superior therapeutic effects on tumor growth and animal survival, in association with the potentiation of polyfunctional CD8+ T cell reactivity against both tumor cells and tumor-associated vascular cells and a pro-inflammatory TME.

L’élevage intensif de moutons Ladoum, race ovine considérée par les éleveurs comme étant la plus performante, connaît un essor considérable ces dernières décennies au Sénégal. Ce travail a eu pour objectif de comparer les performances d’embouche de trois principales races d’agneaux. Il a porté sur 31 agneaux (12 Ladoum, 8 Touabire et 11 Peul-peul) de trois mois d’âge ayant un poids vif (PV) initial de 25,4 kg et élevés durant sept mois où ils ont été alimentés ad libitum avec de la fane d’arachide, un concentré, de l’eau potable et des pierres à lécher. Les PV, consommations d’aliments (CAI) et d’eau (CE), gains moyens quotidiens (GMQ), indice de conversion alimentaire (IC), poids de carcasse chaude (PC), rendement commercial (RC) et des éléments du 5e quartier (REQ), proportions de viande maigre (PMC) et du gras (PGC) des carcasses par race ont été étudiés. Les résultats ont révélé que les PV, GMQ, CAI, IC, PC, RC, REQ, PMC et PGC ont été semblables (p > 0,05) entre les trois races d’agneaux. Les consommations de concentré par rapport au fourrage et les rendements des abats blancs chez les Ladoum (72,5 % CAI et 5,5 %) ont été plus faibles (p < 0,05) comparés à ceux des Touabire (77,14 % CAI et 6,77 %) et Peul-peul (78 % CAI et 6,1 %) qui sont restés identiques, contrairement à la CE (4 vs. 3 litres/j). Les épaisseurs de tissu total (GR), du longissimus dorsi, du gras dorsal mesurées de la 3e à la dernière semaine ante-mortem, ont été similaires (p > 0,05) pour ces trois races, excepté la GR qui a été significativement réduite à la 3e semaine ante-mortem chez les Ladoum. Il ressort que les races ovines sénégalaises disposent d’un réel potentiel génétique qui pourrait mieux s’extérioriser dans de bonnes conditions d’élevage, pour une amélioration du revenu des éleveurs au Sénégal.

Background The role of positive pressure ventilation, central venous pressure (CVP) and inflammation on the occurrence of acute kidney injury (AKI) have been poorly described in mechanically ventilated patient secondary to coronavirus disease 2019 (COVID-19). Methods This was a monocenter retrospective cohort study of consecutive ventilated COVID-19 patients admitted in a French surgical intensive care unit between March 2020 and July 2020. Worsening renal function (WRF) was defined as development of a new AKI or a persistent AKI during the 5 days after mechanical ventilation initiation. We studied the association between WRF and ventilatory parameters including positive end-expiratory pressure (PEEP), CVP, and leukocytes count. Results Fifty-seven patients were included, 12 (21%) presented WRF. Daily PEEP, 5 days mean PEEP and daily CVP values were not associated with occurrence of WRF. 5 days mean CVP was higher in the WRF group compared to patients without WRF (median [IQR], 12 mm Hg [11-13] vs. 10 mm Hg [9–12]; P=0.03). Multivariate models with adjustment on leukocytes and Simplified Acute Physiology Score (SAPS) II confirmed the association between CVP value and risk of WRF (odd ratio, 1.97; 95% confidence interval, 1.12–4.33). Leukocytes count was also associated with occurrence of WRF in the WRF group (14 G/L [11–18]) and the no-WRF group (9 G/L [8–11]) (P=0.002). Conclusions In mechanically ventilated COVID-19 patients, PEEP levels did not appear to influence occurrence of WRF. High CVP levels and leukocytes count are associated with risk of WRF.