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Integrating weightbearing CT findings into evaluation of conventional radiographs in progressive collapsing foot deformity
No full textBackgroundProgressive collapsing foot deformity (PCFD) remains challenging to treat. Surgical planning depends on the amount and complexity of the deformity, which requires accurate differentiation through precise imaging. Weightbearing CT (WBCT) imaging has enhanced the three-dimensional (3D) assessment of PCFD. However, it remains unclear how PCFD findings on WBCT are related to the evaluation of conventional weightbearing radiographs. Therefore, we aimed to (1) compare specific X-ray measurements to corresponding WBCT measurements; (2) evaluate the reliability of X-ray measurements of interest; and (3) investigate whether X-ray measurements can infer osseous impingement in the subtalar joint region identified through WBCT.MethodsTwo clinically established measurements were assessed on standardized weightbearing radiographs (manually) as well as on the WBCT datasets (auto-generated): (1) talo-calcaneal overlap (TCO, mm) and (2) talo-navicular coverage (TNC, °). In addition to the measurements, osseous impingement in the subtalar joint region was assessed on WBCT using three criteria, compared both inter- and intra-rater: (1) joint obliteration; (2) cyst formation; and (3) signs of secondary instability. Two of the criteria needed to be fulfilled to confirm subtalar impingement.ResultsWhile no significant difference between X-ray and WBCT measurements was evident for TCO, significant differences were found for TNC. Inter- and intra-observer reliability was with an intraclass correlation coefficient > 0.9 excellent for both measurements on X-rays. The mean bias of measurement (between X-ray and WBCT) was 0.2 mm for TCO and −22 degrees for TNC. Cohen’s Kappa for inter- and intra-rater reliability to assess patients for subtalar instability was > 0.9. The probability to infer subtalar impingement was ≥ 0.85 if TCO was > 15 mm or TNC was > 25 degrees on X-ray.ConclusionThe examined imaging parameters are reliably assessable through conventional radiographs (TCO/TNC) or WBCT (osseous subtalar impingement). In situations where WBCT is unavailable, X-ray-assessed TCO and TNC can serve as predictors for osseous sinus tarsi impingement. This finding plays a pivotal role in evaluating PCFD patients, aiding in the surgical decision-making process between joint-preserving interventions (e.g., osteotomies) and joint-sacrificing procedures (e.g., realignment fusion).Level of EvidenceLevel IV, observational studyBackgroundProgressive collapsing foot deformity (PCFD) remains challenging to treat. Surgical planning depends on the amount and complexity of the deformity, which requires accurate differentiation through precise imaging. Weightbearing CT (WBCT) imaging has enhanced the three-dimensional (3D) assessment of PCFD. However, it remains unclear how PCFD findings on WBCT are related to the evaluation of conventional weightbearing radiographs. Therefore, we aimed to (1) compare specific X-ray measurements to corresponding WBCT measurements; (2) evaluate the reliability of X-ray measurements of interest; and (3) investigate whether X-ray measurements can infer osseous impingement in the subtalar joint region identified through WBCT.MethodsTwo clinically established measurements were assessed on standardized weightbearing radiographs (manually) as well as on the WBCT datasets (auto-generated): (1) talo-calcaneal overlap (TCO, mm) and (2) talo-navicular coverage (TNC, °). In addition to the measurements, osseous impingement in the subtalar joint region was assessed on WBCT using three criteria, compared both inter- and intra-rater: (1) joint obliteration; (2) cyst formation; and (3) signs of secondary instability. Two of the criteria needed to be fulfilled to confirm subtalar impingement.ResultsWhile no significant difference between X-ray and WBCT measurements was evident for TCO, significant differences were found for TNC. Inter- and intra-observer reliability was with an intraclass correlation coefficient > 0.9 excellent for both measurements on X-rays. The mean bias of measurement (between X-ray and WBCT) was 0.2 mm for TCO and −22 degrees for TNC. Cohen’s Kappa for inter- and intra-rater reliability to assess patients for subtalar instability was > 0.9. The probability to infer subtalar impingement was ≥ 0.85 if TCO was > 15 mm or TNC was > 25 degrees on X-ray.ConclusionThe examined imaging parameters are reliably assessable through conventional radiographs (TCO/TNC) or WBCT (osseous subtalar impingement). In situations where WBCT is unavailable, X-ray-assessed TCO and TNC can serve as predictors for osseous sinus tarsi impingement. This finding plays a pivotal role in evaluating PCFD patients, aiding in the surgical decision-making process between joint-preserving interventions (e.g., osteotomies) and joint-sacrificing procedures (e.g., realignment fusion).Level of EvidenceLevel IV, observational studyA
Mitotic inter-homolog recombination: from reverse to forward genetics in diatoms
No full textPublic defense: 2025-04-10
De kracht van bescheidenheid in de zorg
No full textDe zorgsector staat onder druk: een chronisch tekort aan verpleegkundigen en de daarbij horende hoge werkdruk zorgen voor nog meer uitval en verloop. Zorginstellingen zijn dan ook op zoek naar manieren om verdere uitstroom te voorkomen. Volgens eerder onderzoek kan het versterken van de verbondenheid en betrokkenheid van verpleegkundigen daarbij helpen. Maar hoe kunnen ziekenhuizen daar concreet op inzetten? Ons onderzoek toont aan dat bescheiden leiderschapsgedrag van hoofdverpleegkundigen een sleutelrol speelt.De zorgsector staat onder druk: een chronisch tekort aan verpleegkundigen en de daarbij horende hoge werkdruk zorgen voor nog meer uitval en verloop. Zorginstellingen zijn dan ook op zoek naar manieren om verdere uitstroom te voorkomen. Volgens eerder onderzoek kan het versterken van de verbondenheid en betrokkenheid van verpleegkundigen daarbij helpen. Maar hoe kunnen ziekenhuizen daar concreet op inzetten? Ons onderzoek toont aan dat bescheiden leiderschapsgedrag van hoofdverpleegkundigen een sleutelrol speelt.
Exploring the tomato root protein network exploited by core type 3 effectors from the Ralstonia solanacearum species complex
No full textProteomics has become a powerful approach for the identification and characterization of type III effectors (T3Es). Members of the Ralstonia solanacearum species complex (RSSC) deploy T3Es to manipulate host cells and to promote root infection of, among others, a wide range of solanaceous plants such as tomato, potato, and tobacco. Here, we used TurboID-mediated proximity labeling (PL) in tomato hairy root cultures to explore the proxeomes of the core RSSC T3Es RipU, RipD, and RipB. The RipU proxeome was enriched for multiple protein kinases, suggesting a potential impact on the two branches of the plant immune surveillance system, being the membrane-localized PAMP-triggered immunity (PTI) and the RIN4-dependent effector-triggered immunity (ETI) complexes. In agreement, a transcriptomics analysis in tomato revealed the potential involvement of RipU in modulating reactive oxygen species (ROS) signaling. The proxeome of RipB was putatively enriched for mitochondrial and chloroplast proteins and that of RipD for proteins potentially involved in the endomembrane system. Together, our results demonstrate that TurboID-PL in tomato hairy roots represents a promising tool to study Ralstonia T3E targets and functioning and that it can unravel potential host processes that can be hijacked by the bacterial pathogen.Proteomics has become a powerful approach for the identification and characterization of type III effectors (T3Es). Members of the Ralstonia solanacearum species complex (RSSC) deploy T3Es to manipulate host cells and to promote root infection of, among others, a wide range of solanaceous plants such as tomato, potato, and tobacco. Here, we used TurboID-mediated proximity labeling (PL) in tomato hairy root cultures to explore the proxeomes of the core RSSC T3Es RipU, RipD, and RipB. The RipU proxeome was enriched for multiple protein kinases, suggesting a potential impact on the two branches of the plant immune surveillance system, being the membrane-localized PAMP-triggered immunity (PTI) and the RIN4-dependent effector-triggered immunity (ETI) complexes. In agreement, a transcriptomics analysis in tomato revealed the potential involvement of RipU in modulating reactive oxygen species (ROS) signaling. The proxeome of RipB was putatively enriched for mitochondrial and chloroplast proteins and that of RipD for proteins potentially involved in the endomembrane system. Together, our results demonstrate that TurboID-PL in tomato hairy roots represents a promising tool to study Ralstonia T3E targets and functioning and that it can unravel potential host processes that can be hijacked by the bacterial pathogen.A
Glofitamab in relapsed/refractory mantle cell lymphoma : results from a phase I/II study
No full textPURPOSEPatients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL.METHODSEligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR.RESULTSOf 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade >= 2, 22.7%]) versus 1,000 mg (87.5%; grade >= 2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections).CONCLUSIONFixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.PURPOSEPatients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have a poor prognosis. The phase I/II NP30179 study (ClinicalTrials.gov identifier: NCT03075696) evaluated glofitamab monotherapy in patients with R/R B-cell lymphomas, with obinutuzumab pretreatment (Gpt) to mitigate the risk of cytokine release syndrome (CRS) with glofitamab. We present data for patients with R/R MCL.METHODSEligible patients with R/R MCL (at least one previous therapy) received Gpt (1,000 or 2,000 mg) 7 days before the first glofitamab dose (single dose or split over 2 days if required). Glofitamab step-up dosing was administered once a day on days 8 (2.5 mg) and 15 (10 mg) of cycle 1, with a target dose of 16 or 30 mg once every 3 weeks from cycle 2 day 1 onward, for 12 cycles. Efficacy end points included investigator-assessed complete response (CR) rate, overall response rate (ORR), and duration of CR.RESULTSOf 61 enrolled patients, 60 were evaluable for safety and efficacy. Patients had received a median of two previous therapies (range, 1-5). CR rate and ORR were 78.3% (95% CI, 65.8 to 87.9) and 85.0% (95% CI, 73.4 to 92.9), respectively. In patients who had received previous treatment with a Bruton tyrosine kinase inhibitor (n = 31), CR rate was 71.0% (95% CI, 52.0 to 85.8) and ORR was 74.2% (95% CI, 55.4 to 88.1). CRS after glofitamab administration occurred in 70.0% of patients, with a lower incidence in the 2,000 mg (63.6% [grade >= 2, 22.7%]) versus 1,000 mg (87.5%; grade >= 2, 62.5%) Gpt cohort. Four adverse events led to glofitamab withdrawal (all infections).CONCLUSIONFixed-duration glofitamab induced high CR rates in heavily pretreated patients with R/R MCL; the safety profile was manageable with appropriate support.A
Cell and transcriptomic diversity of infrapatellar fat pad during knee osteoarthritis
No full textObjectives In this study, we employ a multiomic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex and obesity status.Methods Single-nucleus RNA sequencing of 82 924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analyses were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status.Results We identified multiple subclusters of fibroblasts, macrophages, adipocytes and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of na & iuml;ve, profibrotic stimuli-treated and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFPs.Conclusions Overall, by employing a multiomic approach, this study provides the first comprehensive map of the cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as key cells contributing to transcriptomic and metabolic differences related to KOA disease, sex or obesity.Objectives In this study, we employ a multiomic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex and obesity status.Methods Single-nucleus RNA sequencing of 82 924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analyses were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status.Results We identified multiple subclusters of fibroblasts, macrophages, adipocytes and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of na & iuml;ve, profibrotic stimuli-treated and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFPs.Conclusions Overall, by employing a multiomic approach, this study provides the first comprehensive map of the cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as key cells contributing to transcriptomic and metabolic differences related to KOA disease, sex or obesity.A
Integrative assessment of total and intact HIV-1 reservoir by a 5-region multiplexed rainbow DNA digital PCR assay
No full textBackground Persistent latent reservoirs of intact HIV-1 proviruses, capable of rebounding despite suppressive antiretroviral therapy (ART), hinder efforts towards an HIV-1 cure. Hence, assays specifically quantifying intact proviruses are crucial to assess the impact of curative interventions. Two recent assays have been utilized in clinical trials: intact proviral DNA assay (IPDA) and quadruplex quantitative PCR (Q4PCR). While IPDA is more sensitive due to amplifying short fragments, it may overestimate intact fractions by relying only on quantification of 2 proviral regions. Q4PCR samples 4 proviral regions, yet is sequencing-based, favoring amplification of shorter, hence non-intact, proviral sequences.Methods Leveraging digital PCR (dPCR) advancements, we developed the "Rainbow" 5-plex proviral HIV-1 DNA assay. This first-in-its-kind assay was evaluated using standard materials and samples from 83 people living with HIV-1, enabling simultaneous quantification of both total and intact HIV-1 DNA levels. HIV proviral unique molecular identifier (UMI)-mediated long-read sequencing (HIV-PULSE) was used to validate the specificity of the Rainbow HIV-1 DNA assay.Results The Rainbow assay proved equally sensitive but more specific than IPDA and is not subjected to bias against full-length proviruses, enabling high-throughput quantification of total and intact reservoir size. The near full-length sequences allowed validation of the Rainbow specificity and the design of personalized Rainbow primer/probe sets, which enabled the detection of intact HIV-1 DNA.Conclusions This innovation offers potential for targeted evaluation and monitoring of potential rebound-competent reservoirs, contributing to HIV-1 management and cure strategies. ClinicalTrials.gov Registration Numbers: NCT04553081, NCT04305665.Background Persistent latent reservoirs of intact HIV-1 proviruses, capable of rebounding despite suppressive antiretroviral therapy (ART), hinder efforts towards an HIV-1 cure. Hence, assays specifically quantifying intact proviruses are crucial to assess the impact of curative interventions. Two recent assays have been utilized in clinical trials: intact proviral DNA assay (IPDA) and quadruplex quantitative PCR (Q4PCR). While IPDA is more sensitive due to amplifying short fragments, it may overestimate intact fractions by relying only on quantification of 2 proviral regions. Q4PCR samples 4 proviral regions, yet is sequencing-based, favoring amplification of shorter, hence non-intact, proviral sequences.Methods Leveraging digital PCR (dPCR) advancements, we developed the "Rainbow" 5-plex proviral HIV-1 DNA assay. This first-in-its-kind assay was evaluated using standard materials and samples from 83 people living with HIV-1, enabling simultaneous quantification of both total and intact HIV-1 DNA levels. HIV proviral unique molecular identifier (UMI)-mediated long-read sequencing (HIV-PULSE) was used to validate the specificity of the Rainbow HIV-1 DNA assay.Results The Rainbow assay proved equally sensitive but more specific than IPDA and is not subjected to bias against full-length proviruses, enabling high-throughput quantification of total and intact reservoir size. The near full-length sequences allowed validation of the Rainbow specificity and the design of personalized Rainbow primer/probe sets, which enabled the detection of intact HIV-1 DNA.Conclusions This innovation offers potential for targeted evaluation and monitoring of potential rebound-competent reservoirs, contributing to HIV-1 management and cure strategies. ClinicalTrials.gov Registration Numbers: NCT04553081, NCT04305665.A
Damage thresholds and population dynamics of the root-knot nematode, Meloidogyne javanica, on selected chickpea cultivars from Ethiopia
No full textThe root-knot nematode, Meloidogyne javanica, is one of the most damaging plant-parasitic nematodes, affecting chickpea and causing substantial yield losses worldwide. The damage potential and population dynamics of this nematode in chickpea in Ethiopia have yet to be investigated. In this study, six chickpea cultivars were tested using 12 ranges of initial population densities (Pi) of M. javanica second-stage juveniles (J2): 0, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 J2 (g dry soil)-1 in a controlled glasshouse pot experiment. The Seinhorst yield loss and population dynamics models were fitted to describe population development and the effect on different measured growth variables. The tolerance limit (TTFW) for total fresh weight ranged from 0.05 to 1.22 J2 (g dry soil)-1, with corresponding yield losses ranging from 31 to 64%. The minimum yield for seed weight (mSW) ranged from 0.29 to 0.61, with estimated yield losses of 71 and 39%. The 'Haberu' and 'Geletu' cultivars were considered good hosts, with maximum population densities (M) of 16.27 and 5.64 J2 (g dry soil)-1 and maximum multiplication rate (a) values of 6.25 and 9.23, respectively. All other cultivars are moderate hosts for M. javanica; therefore, it is crucial to initiate chickpea-breeding strategies to manage the tropical root-knot nematode M. javanica in Ethiopia.The root-knot nematode, Meloidogyne javanica, is one of the most damaging plant-parasitic nematodes, affecting chickpea and causing substantial yield losses worldwide. The damage potential and population dynamics of this nematode in chickpea in Ethiopia have yet to be investigated. In this study, six chickpea cultivars were tested using 12 ranges of initial population densities (Pi) of M. javanica second-stage juveniles (J2): 0, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 J2 (g dry soil)-1 in a controlled glasshouse pot experiment. The Seinhorst yield loss and population dynamics models were fitted to describe population development and the effect on different measured growth variables. The tolerance limit (TTFW) for total fresh weight ranged from 0.05 to 1.22 J2 (g dry soil)-1, with corresponding yield losses ranging from 31 to 64%. The minimum yield for seed weight (mSW) ranged from 0.29 to 0.61, with estimated yield losses of 71 and 39%. The 'Haberu' and 'Geletu' cultivars were considered good hosts, with maximum population densities (M) of 16.27 and 5.64 J2 (g dry soil)-1 and maximum multiplication rate (a) values of 6.25 and 9.23, respectively. All other cultivars are moderate hosts for M. javanica; therefore, it is crucial to initiate chickpea-breeding strategies to manage the tropical root-knot nematode M. javanica in Ethiopia.A
