The deep latent space particle filter for real-time data assimilation with uncertainty quantification.

In data assimilation, observations are fused with simulations to obtain an accurate estimate of the state and parameters for a given physical system. Combining data with a model, however, while accurately estimating uncertainty, is computationally expensive and infeasible to run in real-time for complex systems. Here, we present a novel particle filter methodology, the Deep Latent Space Particle filter or D-LSPF, that uses neural network-based surrogate models to overcome this computational challenge. The D-LSPF enables filtering in the low-dimensional latent space obtained using Wasserstein AEs with modified vision transformer layers for dimensionality reduction and transformers for parameterized latent space time stepping. As we demonstrate on three test cases, including leak localization in multi-phase pipe flow and seabed identification for fully nonlinear water waves, the D-LSPF runs orders of magnitude faster than a high-fidelity particle filter and 3-5 times faster than alternative methods while being up to an order of magnitude more accurate. The D-LSPF thus enables real-time data assimilation with uncertainty quantification for the test cases demonstrated in this paper.

Coherent control of rare earth 4f shell wavefunctions in the quantum spin liquid Tb2Ti2O7.

The resonant excitation of electronic transitions with coherent laser sources creates quantum coherent superpositions of the involved electronic states. Most time-resolved studies have focused on gases or isolated subsystems embedded in insulating solids, aiming for applications in quantum information. Here, we focus on the coherent control of orbital wavefunctions in the correlated quantum material Tb2Ti2O7, which forms an interacting spin liquid ground state. We show that resonant excitation with a strong THz pulse creates a coherent superposition of the lowest energy Tb 4f states. The coherence manifests itself as a macroscopic oscillating magnetic dipole, which is detected by ultrafast resonant x-ray diffraction. We envision the coherent control of orbital wavefunctions demonstrated here to become a new tool for the ultrafast manipulation and investigation of quantum materials.

Development and internal validation of a multivariable prognostic model to predict chronic pain after a new episode of non-specific idiopathic, non-traumatic neck pain in physiotherapy primary care practice.

OBJECTIVE: To develop and internally validate a prognostic model to predict chronic pain after a new episode of acute or subacute non-specific idiopathic, non-traumatic neck pain in patients presenting to physiotherapy primary care, emphasising modifiable biomedical, psychological and social factors. DESIGN: A prospective cohort study with a 6-month follow-up between January 2020 and March 2023. SETTING: 30 physiotherapy primary care practices. PARTICIPANTS: Patients with a new presentation of non-specific idiopathic, non-traumatic neck pain, with a duration lasting no longer than 12 weeks from onset. BASELINE MEASURES: Candidate prognostic variables collected from participants included age and sex, neck pain symptoms, work-related factors, general factors, psychological and behavioural factors and the remaining factors: therapeutic relation and healthcare provider attitude. OUTCOME MEASURES: Pain intensity at 6 weeks, 3 months and 6 months on a Numeric Pain Rating Scale (NPRS) after inclusion. An NPRS score of ≥3 at each time point was used to define chronic neck pain. RESULTS: 62 (10%) of the 603 participants developed chronic neck pain. The prognostic factors in the final model were sex, pain intensity, reported pain in different body regions, headache since and before the neck pain, posture during work, employment status, illness beliefs about pain identity and recovery, treatment beliefs, distress and self-efficacy. The model demonstrated an optimism-corrected area under the curve of 0.83 and a corrected R2 of 0.24. Calibration was deemed acceptable to good, as indicated by the calibration curve. The Hosmer-Lemeshow test yielded a p-value of 0.7167, indicating a good model fit. CONCLUSION: This model has the potential to obtain a valid prognosis for developing chronic pain after a new episode of acute and subacute non-specific idiopathic, non-traumatic neck pain. It includes mostly potentially modifiable factors for physiotherapy practice. External validation of this model is recommended.

Explorative Identification of Anatomical Parameters Associated with Successful Pessary Fitting in Pelvic Organ Prolapse Using Dynamic Magnetic Resonance Imaging.

Background: Pelvic organ prolapse (POP) affects many women and is often managed with pessary treatment, yet predicting the success of fitting remains challenging. This study aims to identify anatomical parameters associated with successful and unsuccessful pessary treatment using dynamic magnetic resonance imaging (dMRI). Methods: A cross-sectional study in Maastricht University Medical Centre (MUMC+), the Netherlands. Sixteen women with a cystocele and/or descensus uteri minimal POP-Q stage 2, using pessary treatment, were included. All women underwent a dynamic MRI of the pelvic floor at rest, during contraction and on Valsalva. The anatomical parameters evaluated included various lengths and angles. The association between the anatomical parameters and pessary fitted is assessed using partial least squares regression. The predictive accuracy was tested using cross-validation based on the partial least squares model with the most important variables. Results: Seven of the sixteen women (43.8%) were in the non-fitting group (due to movement, rotation or expulsion of the pessary), and nine women (56.3%) were in the fitting group. Participants in the non-fitting group had a significantly lower body mass index (BMI). Variables such as total vaginal length (TVL) and certain angles were highly predictive of pessary fitting success, with variable importance of projection (VIP) scores indicating their importance. The prediction models showed accuracies ranging from 53.3% to 80.0%. Conclusions: In this explorative study, TVL, cervical length (CL), sacrococcygeal angle and pubococcygeal angle were key variables associated with pessary fitting success. These findings offer valuable insights for optimizing pessary fitting procedures and the development of new pessaries.

The Role of Cognition, Affective Symptoms, and Apathy in Treatment Adherence with Noninvasive Home Mechanical Ventilation in Myotonic Dystrophy.

Background: Chronic respiratory failure often occurs in myotonic dystrophy type 1 (DM1) and can be treated with noninvasive home mechanical ventilation (HMV). Treatment adherence with HMV is often suboptimal in patients with DM1, but the reasons for that are not well understood. Objective: The aim of this exploratory study was to gain insight in the prevalence of mild cognitive impairment, affective symptoms, and apathy and to investigate their role in HMV treatment adherence in DM1. Methods: The Montreal Cognitive Assessment (MoCA), the Hospital Anxiety and Depression Scale (HADS), and the Apathy Evaluation Scale (AES) were used to assess cognition, affective symptoms, and apathy in DM1 patients that use HMV. Patients with low treatment adherence (average daily use HMV <5 h or <80% of the days) were compared with patients with high treatment adherence (average daily use of HMV≥5 h and ≥80% of the days). Results: Sixty patients were included. Abnormal scores were found in 40% of the total group for the MoCA, in 72-77% for the AES, and in 18% for HADS depression. There was no difference between the high treatment adherence group (n = 39) and the low treatment adherence group (n = 21) for the MoCA, AES, and HADS depression. The HADS anxiety was abnormal in 30% of the total group, and was significantly higher in the low treatment adherence group (p = 0.012). Logistic regression analysis revealed that a higher age and a higher BMI were associated with a greater chance of high treatment adherence. Conclusions: This exploratory study showed that cognitive impairment and apathy are frequently present in DM1 patients that use HMV, but they are not associated with treatment adherence. Feelings of anxiety were associated with low treatment adherence. Higher age and higher BMI were associated with high treatment adherence with HMV.

Quality of Reporting on Anastomotic Leaks in Colorectal Cancer Trials: A Systematic Review.

BACKGROUND: Although attempts have been made in the past to establish consensus regarding the definitions and grading of the severity of colorectal anastomotic leakage, widespread adoption has remained limited. OBJECTIVE: A systematic review of the literature was conducted with the objective of examining the various elements used to report and define anastomotic leakage in colorectal cancer resections. DATA SOURCES AND STUDY SELECTION: A systematic review, using the PubMed, Embase, and Cochrane Library Database, of all published randomized controlled trials, systematic reviews, and meta-analyses containing data related to adult patients undergoing colorectal cancer surgery and reporting anastomotic leakage as a primary or secondary outcome, with a definition of anastomotic leakage included. OUTCOMES: Definitions of anatomotic leakage, clinical symptoms, radiological modalities and findings, findings at reoperation, as well as grading terminology or classifications for anastomotic leakage. RESULTS: Of the 471 articles reporting anastomotic leakage as a primary or secondary outcome, a definition was reported in 95 studies (45 randomized controlled trials, 13 systematic reviews, and 37 meta-analyses), involving a total of 346,140 patients. Of these 95 articles, 68% reported clinical signs and symptoms of anastomotic leakage, 26% biochemical criteria, 63% radiological modalities, 62% radiological findings, and 13% findings at reintervention. Only 45% (n = 43) of included studies reported grading of anastomotic leakage severity or leak classification, and 41% (n = 39) included a timeframe for reporting. LIMITATIONS: There was a high heterogeneity between the included studies. CONCLUSION: This evidence synthesis confirmed incomplete and inconsistent reporting of anastomotic leakage across the published colorectal cancer literature. There is a great need for the development and implementation of a consensus framework for defining, grading, and reporting anastomotic leakage. REGISTRATION: Prospectively registered at PROSPERO ID 454660.

Effect of high versus standard protein provision on functional recovery in people with critical illness (PRECISe): an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in Belgium and the Netherlands.

BACKGROUND: Increased protein provision might ameliorate muscle wasting and improve long-term outcomes in critically ill patients. The aim of the PRECISe trial was to assess whether higher enteral protein provision (ie, 2·0 g/kg per day) would improve health-related quality of life and functional outcomes in critically ill patients who were mechanically ventilated compared with standard enteral protein provision (ie, 1·3 g/kg per day). METHODS: The PRECISe trial was an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in five Dutch hospitals and five Belgian hospitals. Inclusion criteria were initiation of invasive mechanical ventilation within 24 h of intensive care unit (ICU) admission and an expected duration of invasive ventilation of 3 days or longer. Exclusion criteria were contraindications for enteral nutrition, moribund condition, BMI less than 18 kg/m2, kidney failure with a no dialysis code, or hepatic encephalopathy. Patients were randomly assigned to one of four randomisation labels, corresponding with two study groups (ie, standard or high protein; two labels per group) in a 1:1:1:1 ratio through an interactive web-response system. Randomisation was done via random permuted-block randomisation in varying block sizes of eight and 12, stratified by centre. Participants, care providers, investigators, outcome assessors, data analysts, and the independent data safety monitoring board were all blinded to group allocation. Patients received isocaloric enteral feeds that contained 1·3 kcal/mL and 0·06 g of protein/mL (ie, standard protein) or 1·3 kcal/mL and 0·10 g of protein/mL (ie, high protein). The study-nutrition intervention was limited to the time period during the patient's ICU stay in which they required enteral feeding, with a maximum of 90 days. The primary outcome was EuroQoL 5-Dimension 5-level (EQ-5D-5L) health utility score at 30 days, 90 days, and 180 days after randomisation, adjusted for baseline EQ-5D-5L health utility score. This trial was registered with ClinicalTrials.gov (NCT04633421) and is closed to new participants. FINDINGS: Between Nov 19, 2020, and April 14, 2023, 935 patients were randomly assigned. 335 (35·8%) of 935 patients were female and 600 (64·2%) were male. 465 (49·7%) of 935 were assigned to the standard protein group and 470 (50·3%) were assigned to the high protein group. 430 (92·5%) of 465 patients in the standard protein group and 419 (89·1%) of 470 patients in the high protein group were assessed for the primary outcome. The primary outcome, EQ-5D-5L health utility score during 180 days after randomisation (assessed at 30 days, 90 days, and 180 days), was lower in patients allocated to the high protein group than in those allocated to the standard protein group, with a mean difference of -0·05 (95% CI -0·10 to -0·01; p=0·031). Regarding safety outcomes, the probability of mortality during the entire follow-up was 0·38 (SE 0·02) in the standard protein group and 0·42 (0·02) in the high protein group (hazard ratio 1·14, 95% CI 0·92 to 1·40; p=0·22). There was a higher incidence of symptoms of gastrointestinal intolerance in patients in the high protein group (odds ratio 1·76, 95% CI 1·06 to 2·92; p=0·030). Incidence of other adverse events did not differ between groups. INTERPRETATION: High enteral protein provision compared with standard enteral protein provision resulted in worse health-related quality of life in critically ill patients and did not improve functional outcomes during 180 days after ICU admission. FUNDING: Netherlands Organisation for Healthcare Research and Development and Belgian Health Care Knowledge Centre.

Therapy effect on hand function after home use of a wearable assistive soft-robotic glove supporting grip strength.

BACKGROUND: Soft-robotic gloves with an assist-as-needed control have the ability to assist daily activities where needed, while stimulating active and highly functional movements within the user's possibilities. Employment of hand activities with glove support might act as training for unsupported hand function. OBJECTIVE: To evaluate the therapeutic effect of a grip-supporting soft-robotic glove as an assistive device at home during daily activities. METHODS: This multicentre intervention trial consisted of 3 pre-assessments (averaged if steady state = PRE), one post-assessment (POST), and one follow-up assessment (FU). Participants with chronic hand function limitations were included. Participants used the Carbonhand glove during six weeks in their home environment on their most affected hand. They were free to choose which activities to use the glove with and for how long. The primary outcome measure was grip strength, secondary outcome measures were pinch strength, hand function and glove use time. RESULTS: 63 patients with limitations in hand function resulting from various disorders were included. Significant improvements (difference PRE-POST) were found for grip strength (+1.9 kg, CI 0.8 to 3.1; p = 0.002) and hand function, as measured by Jebson-Taylor Hand Function Test (-7.7 s, CI -13.4 to -1.9; p = 0.002) and Action Research Arm Test (+1.0 point, IQR 2.0; p≤0.001). Improvements persisted at FU. Pinch strength improved slightly in all fingers over six-week glove use, however these differences didn't achieve significance. Participants used the soft-robotic glove for a total average of 33.0 hours (SD 35.3), equivalent to 330 min/week (SD 354) or 47 min/day (SD 51). No serious adverse events occurred. CONCLUSION: The present findings showed that six weeks use of a grip-supporting soft-robotic glove as an assistive device at home resulted in a therapeutic effect on unsupported grip strength and hand function. The glove use time also showed that this wearable, lightweight glove was able to assist participants with the performance of daily tasks for prolonged periods.

Same-day discharge after laparoscopic hysterectomy for benign/premalignant disease: A multicentre randomised controlled trial.

OBJECTIVE: To evaluate whether physical function and quality of life was influenced by discharge on the same-day after a total laparoscopic hysterectomy. DESIGN: Multicentre non-inferiority randomised controlled trial. SETTING: Five teaching hospitals and two university hospitals in the Netherlands. POPULATION: Patients undergoing laparoscopic hysterectomy for benign or premalignant disease. METHODS: Following informed consent, participants were allocated 1:1 either to same-day discharge (SDD) or next-day discharge (NDD). MAIN OUTCOME MEASURES: The primary outcome was physical function at 7 days after surgery measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function short Form 10A. Secondary outcomes were physical function and quality of life at 1 and 3 days and 6 weeks after surgery measured with PROMIS short Form 10A and the EuroQol questionnaire (EQ-5D-5L). RESULTS: Two hundred and five patients were included of whom 105 were allocated to SDD and 100 to NDD. Physical function 7 days after surgery was 35.95 in the SDD group and 35.63 in the control group (mean difference 0.32; 95% CI [0.07-0.57]). As the upper limit of the 95% CI does not exceed the non-inferiority margin of 4 points, non-inferiority of SDD could be demonstrated. No difference in physical function nor quality of life on Days 1 and 3 and 6 weeks could be found. CONCLUSION: This research demonstrates same-day discharge after laparoscopic hysterectomy is non-inferior to next day discharge in physical function 7 days after surgery.

Two-Year Results of a Five-Year Personalized Integrative Obesity Coaching Program (IBO) Based upon a Systems Health Perspective and an Evolutionary Longitudinal Study Approach.

This study presents the outcomes of a 5-year personalized integrative coaching program for adults with obesity (body mass index BMI ≥ 30 kg/m2), based upon a systems health perspective, during the first 2 years. This longitudinal study, which had an evolutionary design, included all adults who enrolled in the program. Health-related quality of life (HRQoL) was measured with the Short Form-36 (SF-36), and physical outcomes included weight, waist circumference, aerobic capacity, lipid profile, and HbA1c. Subsequently, participants completed questionnaires (e.g., the Symptom Checlist-90 (SCL-90) and the Checklist Individual Strength (CIS)). Seventy-nine adults with a mean BMI of 39.5 kg/m2 (SD 5.3) were included. Forty-four participants completed 2 years in the program. Compared to baseline, there were significant improvements in the SF-36 subscales 'physical functioning' (MD 9.9 points, 95% CI: 2.1-17.5, p = 0.013) and 'general health perceptions' (MD 9.3 points, 95% CI 2.9-15.7, p = 0.006). Furthermore, significant improvements in physical outcomes and psychosocial questionnaires (e.g., weight loss (MD 3.5 kg, 95% CI: 1.2-5.7, p = 0.003), waist circumference (MD 5.1 cm, 95% CI: 2.4-7.8, p < 0.001), and CIS fatigue (MD 6.8, 95% CI: 3.1-10.5, p = 0.001) were observed. This study highlights the importance of a systems health perspective supporting the development of a personalized integrative coaching program for adults with obesity in a 'real-world' setting.

The neurovascular unit and its correlation with cognitive performance in patients with cerebral small vessel disease: a canonical correlation analysis approach.

Growing evidence indicates an important role of neurovascular unit (NVU) dysfunction in the pathophysiology of cerebral small vessel disease (cSVD). Individually measurable functions of the NVU have been correlated with cognitive function, but a combined analysis is lacking. We aimed to perform a unified analysis of NVU function and its relation with cognitive performance. The relationship between NVU function in the white matter and cognitive performance (both latent variables composed of multiple measurable variables) was investigated in 73 patients with cSVD (mean age 70 ± 10 years, 41% women) using canonical correlation analysis. MRI-based NVU function measures included (1) the intravoxel incoherent motion derived perfusion volume fraction (f) and microvascular diffusivity (D*), reflecting cerebral microvascular flow; (2) the IVIM derived intermediate volume fraction (fint), indicative of the perivascular clearance system; and (3) the dynamic contrast-enhanced MRI derived blood-brain barrier (BBB) leakage rate (Ki) and leakage volume fraction (VL), reflecting BBB integrity. Cognitive performance was composed of 13 cognitive test scores. Canonical correlation analysis revealed a strong correlation between the latent variables NVU function and cognitive performance (r 0.73; p = 0.02). For the NVU, the dominating variables were D*, fint, and Ki. Cognitive performance was driven by multiple cognitive tests comprising different cognitive domains. The functionality of the NVU is correlated with cognitive performance in cSVD. Instead of focusing on individual pathophysiological mechanisms, future studies should target NVU dysfunction as a whole to acquire a coherent understanding of the complex disease mechanisms that occur in the NVU in cSVD.Trial registration: NTR3786 (Dutch Trial Register).

Collateral-based selection for endovascular treatment of acute ischaemic stroke in the late window (MR CLEAN-LATE): 2-year follow-up of a phase 3, multicentre, open-label, randomised controlled trial in the Netherlands.

BACKGROUND: The MR CLEAN-LATE trial provided evidence for the safety and efficacy of endovascular treatment for acute ischaemic stroke within the late window (after 6-24 h) in patients who were preselected based on the presence of collateral flow on CT angiography. We aimed to evaluate clinical outcomes 2 years after randomisation. METHODS: MR CLEAN-LATE was a phase 3, multicentre, open-label, blinded-endpoint, randomised controlled trial conducted at 18 stroke intervention centres in the Netherlands. If endovascular treatment could be initiated within 6-24 h of symptom onset or last seen well, patients (aged 18 years or older) with an acute ischaemic stroke due to a large vessel occlusion in the anterior circulation and at least some collateral flow in the affected middle cerebral artery territory on CT angiography were randomly assigned (1:1) to either endovascular treatment with best medical treatment (endovascular treatment group) or best medical treatment alone (control group). Web-based randomisation, stratified by centre, was performed with the use of permuted blocks (block size eight to 20). The researchers who collected clinical outcomes and analysed the results were masked to treatment allocation; treating physicians, local investigators, and patients were aware of the received treatment. The primary outcome of MR CLEAN-LATE was the modified Rankin Scale (mRS) score at 90 days after randomisation. For this 2-year prespecified analysis, the primary outcome was mRS score at 2 years (minus 3 months to plus 6 months). Primary and safety analyses were performed based on the modified intention-to-treat principle, and included patients who provided (deferred) consent or died before consent could be obtained. Missing data were handled with multiple imputation by chained equations. The trial is completed and is registered at ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned in the MR CLEAN-LATE trial, of whom 502 (94%) gave deferred consent and comprised the modified intention-to-treat population (255 in the endovascular treatment group and 247 in the control group). 261 (52%) patients were female and 241 (48%) were male. Data for mRS score at 2 years were available for 226 (89%) patients in the endovascular treatment group and for 202 (82%) patients in the control group. The median mRS score at 2 years was 4 (IQR 2-6) in the endovascular treatment group and 6 (2-6) in the control group. The endovascular treatment group demonstrated a shift towards better functional outcomes on the mRS (adjusted common odds ratio 1·41 [95% CI 1·00-1·99]; p=0·049). All-cause mortality at 2 years was 34% (87 of 255) in the endovascular treatment group and 41% (101 of 247) in the control group (adjusted hazard ratio 0·81 [95% CI 0·60-1·08]; p=0·15). Major vascular events (ie, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, and cardiac events) were reported between 90 days and 2 years in 23 patients in the endovascular treatment group and 13 patients in the control group. INTERPRETATION: Our results show that the effectiveness of late-window (after 6-24 h) endovascular treatment in improving clinical outcomes is sustained for up to 2 years in a population preselected based on the presence of collateral flow on CT angiography. This finding might be important for prompting further evaluations of cost-effectiveness, health-care policy development, and clinical decision making. FUNDING: The Dutch Organization for Health Research and Health Innovation (ZonMW), Collaboration for New Treatments of Acute Stroke Consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Health Holland Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Shifting Views on Cancer Pain Management: A Systematic Review and Network Meta-Analysis.

CONTEXT: Strong opioids are the cornerstone in the treatment of cancer-related pain. OBJECTIVES: This study aims to compare analgesic effectiveness of different strong opioids for the treatment of cancer-related pain. METHODS: PubMed and Embase were searched for RCTs that compared strong opioids for treatment of cancer-related pain against one another. A network meta-analysis was conducted and the related Surface Under the Cumulative RAnking (SUCRA)-based treatment ranks were calculated. Primary outcome was pain intensity (numerical rating scale (NRS)) and/or the percentage of patients with ≥50% pain reduction, after 1 and 2-4 weeks. RESULTS: Sixteen RCTs (1813 patients) were included. Methadone showed, with a high certainty of evidence, increased ORs for treatment success at 1 week, compared with morphine, buprenorphine, fentanyl, and oxycodone, range 3.230-36.833. Methadone had the highest likelihood to be the treatment of preference (ToP) (SUCRA 0.9720). For fentanyl, ORs were lower, however significant and with high certainty. After 2-4 weeks, methadone again showed the highest likelihood for ToP, however, with moderate certainty and nonsignificant ORs. The combination of morphine/methadone, compared with morphine, buprenorphine, fentanyl, hydromorphone, methadone, and oxycodone achieved a treatment effect of mean NRS difference after 2-4 weeks between -1.100 and -1.528 and had the highest likelihood for ToP. CONCLUSION: The results suggest that methadone possibly deserves further promotion as first-line treatment for the treatment of cancer-related pain.

Surgical outcomes and prognosis of HER2+ invasive breast cancer patients with a DCIS component treated with breast-conserving surgery after neoadjuvant systemic therapy.

INTRODUCTION: In up to 72 % of HER2+ invasive breast cancer (IBC), a ductal carcinoma in situ (DCIS) component is present. The presence of DCIS is associated with increased positive surgical margins after breast-conserving surgery (BCS). The aim of this study was to assess surgical margins, recurrence and survival in a nationwide cohort of HER2+ IBC with versus without a DCIS component, treated with neoadjuvant systemic therapy (NST) and BCS. MATERIALS AND METHODS: Women diagnosed with HER2+ IBC treated with NST and BCS, between 2010 and 2019, were selected from the Netherlands Cancer Registry and linked to the Dutch Nationwide Pathology Databank. Kaplan-Meier and Cox regression analyses were performed to determine locoregional recurrence rate (LRR) and overall survival (OS) and associated clinicopathological variables. Surgical outcomes and prognosis were compared between IBC only and IBC+DCIS. RESULTS: A total of 3056 patients were included: 1832 with IBC and 1224 with IBC+DCIS. Patients with IBC+DCIS had significantly more often positive surgical margins compared to IBC (12.8 % versus 4.9 %, p < 0.001). Five-year LRR was significantly higher in patients with IBC+DCIS compared to IBC (6.8 % versus 3.6 %, p < 0.001), but the presence of DCIS itself was not significantly associated with LRR after adjusting for confounders in multivariable analysis. Five-year OS did not differ between IBC+DCIS and IBC (94.9 % versus 95.7 %, p = 0.293). CONCLUSION: The presence of DCIS is associated with higher rates of positive surgical margins, but not with LRR and lower OS when adjusted for confounders. Further research is necessary to adequately select IBC+DCIS patients for BCS after NST.

Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.

Glutaric Aciduria Type 1 (GA1) is a serious inborn error of metabolism with no pharmacological treatments. A novel strategy to treat this disease is to divert the toxic biochemical intermediates to less toxic or nontoxic metabolites. Here, we report a putative novel target, succinyl-CoA:glutarate-CoA transferase (SUGCT), which we hypothesize suppresses the GA1 metabolic phenotype through decreasing glutaryl-CoA and the derived 3-hydroxyglutaric acid. SUGCT is a type III CoA transferase that uses succinyl-CoA and glutaric acid as substrates. We report the structure of SUGCT, develop enzyme- and cell-based assays, and identify valsartan and losartan carboxylic acid as inhibitors of the enzyme in a high-throughput screen of FDA-approved compounds. The cocrystal structure of SUGCT with losartan carboxylic acid revealed a novel pocket in the active site and further validated the high-throughput screening approach. These results may form the basis for the future development of new pharmacological intervention to treat GA1.

Patient reported and functional outcome measures after surgical salvage procedures for posttraumatic radiocarpal osteoarthritis - a systematic review.

BACKGROUND: Posttraumatic wrist osteoarthritis is an irreversible and often progressive condition. Many surgical treatments, used in (daily) practice, aim to relieve symptoms like pain and restore function. The aim of this systematic review is to assess the patient reported and functional outcomes of the most common surgical interventions in patients with posttraumatic wrist osteoarthritis. This overview can help clinicians select the best treatment and manage patient's expectations. METHODS: A literature search was performed in Pubmed, Embase and Cochrane for articles published between 1990 and November 2022 according to the PRISMA guidelines. The study protocol has been registered in the PROSPERO database (CRD42017080427). Studies that describe patient reported outcomes (pain and Disability of Arm, Shoulder and Hand (DASH) -score) and functional outcomes (range of motion (ROM) and grip strength) after surgical intervention with a minimal follow-up of 1 year were included. The identified surgical procedures included denervation, proximal row carpectomy, interpositional- and total arthroplasty, and midcarpal-, radiocarpal- and total arthrodesis. The pre-and postoperative outcomes were pooled and presented per salvage procedure. RESULTS: Data from 50 studies was included. Pain score improved after all surgeries except denervation. Flexion/extension decreased after radiocarpal arthrodesis, did not show significant changes after proximal row carpectomy, and improved for all other surgeries. DASH score improved after arthroplasty, proximal row carpectomy and midcarpal arthrodesis. Grip strength improved after interposition arthroplasty and partial arthrodesis. CONCLUSION: Evidence from this review did not support the indication for denervation in this particular patient population. In patients with SLAC/SNAC II, proximal row carpectomy might be favourable to a midcarpal arthrodesis solely based on better FE ROM of the radiocarpal joint after proximal row carpectomy. In terms of radiocarpal mobility, total wrist arthroplasty might be preferred to radiocarpal arthrodesis in patients with osteoarthritis after a distal radius fracture. More uniform measurements of outcomes would improve the understanding of the effect of surgical treatments of the posttraumatic osteoarthritic wrist.

Reduced preoperative serum choline esterase levels and fecal peritoneal contamination as potential predictors for the leakage of intestinal sutures after source control in secondary peritonitis.

BACKGROUND: The high rate of stoma placement during emergency laparotomy for secondary peritonitis is a paradigm in need of change in the current fast-track surgical setting. Despite growing evidence for the feasibility of primary bowel reconstruction in a peritonitic environment, little data substantiate a surgeons' choice between a stoma and an anastomosis. The aim of this retrospective analysis is to identify pre- and intraoperative parameters that predict the leakage risk for enteric sutures placed during source control surgery (SCS) for secondary peritonitis. METHODS: Between January 2014 and December 2020, 497 patients underwent SCS for secondary peritonitis, of whom 187 received a primary reconstruction of the lower gastro-intestinal tract without a diverting stoma. In 47 (25.1%) patients postoperative leakage of the enteric sutures was directly confirmed during revision surgery or by computed tomography. Quantifiable predictors of intestinal suture outcome were detected by multivariate analysis. RESULTS: Length of intensive care, in-hospital mortality and failure of release to the initial home environment were significantly higher in patients with enteric suture leakage following SCS compared to patients with intact anastomoses (p < 0.0001, p = 0.0026 and p =0.0009, respectively). Reduced serum choline esterase (sCHE) levels and a high extent of peritonitis were identified as independent risk factors for insufficiency of enteric sutures placed during emergency laparotomy. CONCLUSIONS: A preoperative sCHE < 4.5 kU/L and generalized fecal peritonitis associate with a significantly higher incidence of enteric suture insufficiency after primary reconstruction of the lower gastro-intestinal tract in a peritonitic abdomen. These parameters may guide surgeons when choosing the optimal surgical procedure in the emergency setting.