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BACKGROUND: Immunotherapy is used routinely for treating deficient mismatch repair (dMMR) colon cancer (CC). This case series highlights an emerging safety issue, where patients develop bowel obstruction associated with immunotherapy response. PATIENTS AND METHODS: Patients with dMMR CC who developed bowel obstruction while responding to immunotherapy were retrospectively identified. Data on patient, disease, treatment, and response-specific factors were explored for potential risk factors. Overall treatment numbers were used to estimate incidence. RESULTS: Nine patients from eight European centres were included. Common features were hepatic flexure location (5/9), T4 radiological staging (6/9), annular shape (8/9), radiological stricturing (5/9), and endoscopic obstruction (6/9). All received pembrolizumab and obstructed between 45 and 652 days after starting treatment. Seven patients underwent surgical resection; one was managed with a defunctioning stoma; and one was managed conservatively. One patient died from obstruction. Radiological response was seen in eight patients, including two complete responses. Pathological response was seen in all seven who underwent resection, including four complete responses. The overall incidence of immunotherapy response-related obstruction in these centres was 1.51%. CONCLUSIONS: Bowel obstruction associated with immunotherapy response may represent a rare treatment-related complication in dMMR CC. Clinicians must recognise this safety signal and share experience to maintain patient safety.

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BACKGROUND: Women in leadership in obstetrics and gynaecology in Australia and Aotearoa New Zealand have historically been underrepresented, despite forming a significant portion of the workforce. This study extends prior research from 2017, examining shifts in gender representation, attitudes, and perceived leadership barriers within the specialty. AIMS: The study aims to evaluate changes in gender diversity among leadership positions in the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) and accredited training hospitals since 2017. Additionally, it seeks to understand current attitudes toward leadership and identify perceived barriers among RANZCOG consultants and trainees. MATERIALS AND METHODS: A cross-sectional approach was employed, utilising publicly available information, a survey distributed to RANZCOG members, and data from accredited training hospitals. Gender representation in leadership positions was analysed, and survey responses were collected from consultants and trainees to evaluate attitudes and perceived barriers. RESULTS: The study reveals an increase in women's representation in RANZCOG leadership, particularly on the council and in clinical leadership positions. While the proportion of women trainees remained stable, there was a noteworthy increase in women specialists. Survey responses revealed shared perceptions on leadership qualities but diverged on barriers, with more women expressing concerns about skillsets, caring responsibilities, and mentorship support. CONCLUSIONS: The findings underscore substantial progress in achieving gender equity in obstetrics and gynaecology leadership roles, attributed to RANZCOG initiatives, societal changes, and improved policies. Ongoing efforts, including structured mentorship and flexible arrangements, are recommended to sustain and further enhance gender representation and address specific barriers identified by women in the specialty.

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In 30 patients (average age 38 ± 8 years, 77% male, 23% female) with intra-oral scans made at intake and after 3 years, tooth wear progression was measured. With the aid of GeoMagic to superimpose the scans, the maximum difference in height of 64 surfaces was measured per surface. A large variation was found in progression rates between patients, between various teeth in a single mouth, and between surfaces on a single tooth. Tooth wear progression rates are therefore highly individual and can even be very localized. Treatment must therefore be individualized, with an essential role for measuring tooth wear when deciding on the need for restorative treatment.

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BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19. METHODS: Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442. FINDINGS: Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group. INTERPRETATION: Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19. FUNDING: None.

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AIMS: To evaluate the ability of logistic regression and machine learning methods to predict active arterial extravasation on computed tomographic angiography (CTA) in patients with acute gastrointestinal hemorrhage using clinical variables obtained prior to image acquisition. MATERIALS AND METHODS: CT angiograms performed for the indication of gastrointestinal bleeding at a single institution were labeled retrospectively for the presence of arterial extravasation. Positive and negative cases were matched for age, gender, time period, and site using Propensity Score Matching. Clinical variables were collected including recent history of gastrointestinal bleeding, comorbidities, laboratory values, and vitals. Data were partitioned into training and testing datasets based on the hospital site. Logistic regression, XGBoost, Random Forest, and Support Vector Machine classifiers were trained and five-fold internal cross-validation was performed. The models were validated and evaluated with the area under the receiver operating characteristic curve. RESULTS: Two-hundred and thirty-one CTA studies with arterial gastrointestinal extravasation were 1:1 matched with 231 negative studies (N=462). After data preprocessing, 389 patients and 36 features were included in model development and analysis. Two hundred and fifty-five patients (65.6%) were selected for the training dataset. Validation was performed on the remaining 134 patients (34.4%); the area under the receiver operating characteristic curve for the logistic regression, XGBoost, Random Forest, and Support Vector Machine classifiers was 0.82, 0.68, 0.54, and 0.78, respectively. CONCLUSION: Logistic regression and machine learning models can accurately predict presence of active arterial extravasation on CTA in patients with acute gastrointestinal bleeding using clinical variables.

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Background: Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13 gene, also called the Dutch founder variant. Objective: To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13 gene. Results: We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivo functional tests was observed. This was confirmed by in vitro functional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier. Conclusions: The c.1222C > A p.(Arg408Ser) variant in the KBTBD13 gene is a likely pathogenic variant causing NEM6.

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OBJECTIVES: To assess the relative frequency and associated factors of disorders of gut-brain interaction (DGBIs) in outpatient gastrointestinal (GI) clinics in young children of Latin America. METHODS: Cross-sectional study in 10 pediatric GI outpatient clinics (private and public) in five countries of Latin America (El Salvador, México, Colombia, Panamá, and Nicaragua). Parents of patients 1 month 4 years of age from outpatient clinics complete/d a diagnostic questionnaire for DGBIs per Rome IV criteria (QPGS-IV, Spanish version). We conducted descriptive analysis, two-sample t-tests and chi-square tests, univariate analyses, and logistic regression to evaluate risk factors. RESULTS: We collected data from 783 children. In total, 34.5% had a DGBI. Overall, functional constipation (FC) was the most common diagnosis (23.4%) in children of all ages (infants, 16.1%, 1-4-years-old, 32.7%). In infants, the second most common DGBI was regurgitation (6.6%) and in 1-4-years-old and cyclic vomiting syndrome (4.1%). The diagnosis of a DGBI was significantly associated with a family history of DGBIs (odds ratio [OR] 2.97, 95% confidence interval [CI] 1.61-5.57, p = 0.0001). Patients who identified as black (OR 2.25, 95% CI 1.28-3.92, p = 0.0021) or mixed race (OR 1.76, 95% CI 1.25-2.48, p = 0.0006) were also significantly associated with a higher likelihood of DGBIs. CONCLUSIONS: DGBIs are a common diagnosis in pediatric GI clinics of Latin America. Overall, FC was the most common DGBI.

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GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF-ß signaling. In this study, we investigated the role of TGF-ß-signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of GorabPrx1 conditional knockouts with the TGF-ß neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF-ß overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF-ß dysregulation was not a cell-intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF-ß signaling caused elevated Nox4 expression in GorabPrx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN-mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating GorabPrx1 mutants with the antioxidant N-acetylcysteine ameliorated the osteoporosis phenotype. TGF-ß induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the GorabPrx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF-ß-Nox4-senescence axis and therapeutic strategies for GO.

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BACKGROUND: People with incomplete spinal cord injury (iSCI) often have gait impairments that negatively affect daily life gait performance (i.e., ambulation in the home and community setting) and quality of life. They may benefit from light-weight lower extremity exosuits that assist in walking, such as the Myosuit (MyoSwiss AG, Zurich, Switzerland). A previous pilot study showed that participants with various gait disorders increased their gait speed with the Myosuit in a standardized environment. However, the effect of a soft exosuit on daily life gait performance in people with iSCI has not yet been evaluated. OBJECTIVE: The primary study objective is to test the effect of a soft exosuit (Myosuit) on daily life gait performance in people with iSCI. Second, the effect of Myosuit use on gait capacity and the usability of the Myosuit in the home and community setting will be investigated. Finally, short-term impact on both costs and effects will be evaluated. METHODS: This is a two-armed, open label, randomized controlled trial (RCT). Participants will be randomized (1:1) to the intervention group (receiving the Myosuit program) or control group (initially receiving the conventional program). Thirty-four people with chronic iSCI will be included. The Myosuit program consists of five gait training sessions with the Myosuit at the Sint Maartenskliniek. Thereafter, participants will have access to the Myosuit for home use during 6 weeks. The conventional program consists of four gait training sessions, followed by a 6-week home period. After completing the conventional program, participants in the control group will subsequently receive the Myosuit program. The primary outcome is walking time per day as assessed with an activity monitor at baseline and during the first, third, and sixth week of the home periods. Secondary outcomes are gait capacity (10MWT, 6MWT, and SCI-FAP), usability (D-SUS and D-QUEST questionnaires), and costs and effects (EQ-5D-5L). DISCUSSION: This is the first RCT to investigate the effect of the Myosuit on daily life gait performance in people with iSCI. TRIAL REGISTRATION: Clinicaltrials.gov NCT05605912. Registered on November 2, 2022.

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Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is the leading cause of childhood chronic kidney failure and a significant cause of chronic kidney disease in adults. Genetic and environmental factors are known to influence CAKUT development, but the currently known disease mechanism remains incomplete. Our goal is to identify affected pathways and networks in CAKUT, and thereby aid in getting a better understanding of its pathophysiology. With this goal, the miRNome, peptidome, and proteome of over 30 amniotic fluid samples of patients with non-severe CAKUT was compared to patients with severe CAKUT. These omics data sets were made findable, accessible, interoperable, and reusable (FAIR) to facilitate their integration with external data resources. Furthermore, we analysed and integrated the omics data sets using three different bioinformatics strategies: integrative analysis with mixOmics, joint dimensionality reduction and pathway analysis. The three bioinformatics analyses provided complementary features, but all pointed towards an important role for collagen in CAKUT development and the PI3K-AKT signalling pathway. Additionally, several key genes (CSF1, IGF2, ITGB1, and RAC1) and microRNAs were identified. We published the three analysis strategies as containerized workflows. These workflows can be applied to other FAIR data sets and help gaining knowledge on other rare diseases.

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A 22-year-old male patient reported swelling in relation to the right eye and developed recurrent purulent discharge and epiphora following a reconstructive traumatic orbital floor fracture repair two years ago. Radiographic investigation and surgical exploration reveal obstruction of the lacrimal apparatus at the lacrimal sac level due to over-extension/migration of the orbital floor mesh. The migration of the mesh was probably due to the extension of the mesh medially into the paranasal region.

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This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

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This second paper in a series of two describes the chirped-pulse ice apparatus that permits the detection of buffer gas cooled molecules desorbed from an energetically processed ice using broadband mm-wave rotational spectroscopy. Here, we detail the lower ice stage developed to generate ices at 4 K, which can then undergo energetic processing via UV/VUV photons or high-energy electrons and which ultimately enter the gas phase via temperature-programmed desorption (TPD). Over the course of TPD, the lower ice stage is interfaced with a buffer gas cooling cell that allows for sensitive detection via chirped-pulse rotational spectroscopy in the 60-90 GHz regime. In addition to a detailed description of the ice component of this apparatus, we show proof-of-principle experiments demonstrating the detection of H2CO products formed through irradiation of neat methanol ices or 1:1 CO + CH4 mixed ices.

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Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau ( VHL ) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL , and uncover that loss of Core Binding Factor ß (CBF-ß) causes cell death in VHL -null ccRCC cell lines and impairs tumour establishment and growth in vivo . This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL -null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-ß. Mechanistically, CBF-ß loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-ß at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-ß in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.

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CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naïve MS patients and control participants. A small subset of highly expanded and activated CSF-enriched CD8+ T cells were abundant in people with MS and displayed high cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, several MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and novel mimotopes were identified. These findings shed insight into the functions of CD8+ T cells in MS and may serve as potential disease biomarkers and therapeutic targets.

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Thin-film nanocomposite (TFN) membranes with a polyamide (PA) active layer modified with carbon nanotubes (CNTs) hold promise for water desalination and wastewater reuse via forward osmosis (FO). We hypothesise that modifying the PA active layer with hydroxyl-functionalised multi-wall carbon nanotubes (f-MWCNTs) will enhance the water flux of the FO membrane while maximising salt rejection. TFN membranes were modified using in situ interfacial polymerisation, with varying f-MWCNT mass content to minimise agglomeration. These modified FO membranes are designated as CTFN-x, where x represents the mass content of f-MWCNTs, ranging from 0.001%, CTFN-1 to 0.008%, CTFN-8 (w/v). The surface properties of CTFN-x were characterised using electron microscopy, atomic force microscopy, and molecular spectroscopy. IR spectroscopic data confirm the successful adherence of f-MWCNTs as a bridging agent between the 1,3-phenylenediamine (MPD) and trimesoyl chloride (TMC) polymers, preserving FO membrane integrity. The CTFN-4 FO membrane shows the highest water flux (29 LMH) and the lowest reverse salt flux (2.90 gHM), attributed to preferential water flow channels in the f-MWCNTs. The integration of f-MWCNTs into the active layer improved water flux, reduced reverse salt flux, and enhanced the antifouling properties of FO membranes.