The enteric nervous system (ENS) controls many aspects of intestinal homeostasis, including parameters that shape the habitat of microbial residents. Previously we showed that zebrafish lacking an ...ENS, due to deficiency of the sox10 gene, develop intestinal inflammation and bacterial dysbiosis, with an expansion of proinflammatory Vibrio strains. To understand the primary defects resulting in dysbiosis in sox10 mutants, we investigated how the ENS shapes the intestinal environment in the absence of microbiota and associated inflammatory responses. We found that intestinal transit, intestinal permeability, and luminal pH regulation are all aberrant in sox10 mutants, independent of microbially induced inflammation. Treatment with the proton pump inhibitor, omeprazole, corrected the more acidic luminal pH of sox10 mutants to wild type levels. Omeprazole treatment also prevented overabundance of Vibrio and ameliorated inflammation in sox10 mutant intestines. Treatment with the carbonic anhydrase inhibitor, acetazolamide, caused wild type luminal pH to become more acidic, and increased both Vibrio abundance and intestinal inflammation. We conclude that a primary function of the ENS is to regulate luminal pH, which plays a critical role in shaping the resident microbial community and regulating intestinal inflammation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Some of the densest microbial ecosystems in nature thrive within the intestines of humans and other animals. To protect mucosal tissues and maintain immune tolerance, animal hosts actively sequester ...bacteria within the intestinal lumen. In response, numerous bacterial pathogens and pathobionts have evolved strategies to subvert spatial restrictions, thereby undermining immune homeostasis. However, in many cases, it is unclear how escaping host spatial control benefits gut bacteria and how changes in intestinal biogeography are connected to inflammation. A better understanding of these processes could uncover new targets for treating microbiome-mediated inflammatory diseases. To this end, we investigated the spatial organization and dynamics of bacterial populations within the intestine using larval zebrafish and live imaging. We discovered that a proinflammatory Vibrio symbiont native to zebrafish governs its own spatial organization using swimming motility and chemotaxis. Surprisingly, we found that Vibrio's motile behavior does not enhance its growth rate but rather promotes its persistence by enabling it to counter intestinal flow. In contrast, Vibrio mutants lacking motility traits surrender to host spatial control, becoming aggregated and entrapped within the lumen. Consequently, nonmotile and nonchemotactic mutants are susceptible to intestinal expulsion and experience large fluctuations in absolute abundance. Further, we found that motile Vibrio cells induce expression of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) in gut-associated macrophages and the liver. Using inducible genetic switches, we demonstrate that swimming motility can be manipulated in situ to modulate the spatial organization, persistence, and inflammatory activity of gut bacterial populations. Together, our findings suggest that host spatial control over resident microbiota plays a broader role in regulating the abundance and persistence of gut bacteria than simply protecting mucosal tissues. Moreover, we show that intestinal flow and bacterial motility are potential targets for therapeutically managing bacterial spatial organization and inflammatory activity within the gut.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Essentials
Low‐molecular‐weight heparin (LMWH) injections for venous thromboembolism (VTE) may be burdensome.
Patients with active cancer and confirmed VTE were included to evaluate LMWH ...continuation.
The cumulative incidence of discontinuation was 21% after a median period of 90 days.
One out of five patients discontinued LMWH injections because of side effects.
Summary
Background
Current guidelines recommend low‐molecular‐weight heparin (LMWH) monotherapy for 3–6 months as the first‐line treatment for cancer‐associated venous thromboembolism (VTE). However, although daily administration of LMWH injections over a course of several months may be burdensome, the number of patients who stop treatment because of LMWH side‐effects is unknown.
Objectives
To evaluate the continuation rate and complications of daily LMWH injections in patients with cancer‐associated VTE.
Methods
Consecutive patients with active cancer and objectively confirmed symptomatic proximal deep vein thrombosis and/or pulmonary embolism, treated at three Dutch hospitals and one Spanish hospital, were included to evaluate continuation LMWH therapy during LMWH treatment. Patients were excluded when they received other anticoagulants, were lost to follow‐up, or experienced a venous catheter‐associated thrombosis.
Results
A total of 372 patients were analyzed during LMWH treatment for a maximum of 180 days. The cumulative incidence of discontinuation was 21% (95% confidence interval CI 17–25) after a median period of 90 days (interquartile range 60–120 days). Only female sex was found to be significantly associated with premature LMWH discontinuation (odds ratio 1.6; 95% CI 1.03–2.5). Thirty patients (8.1%) developed recurrent VTE, 30 patients (8.3%) suffered a major bleed, and 106 patients (28%) died.
Conclusion
Our study reveals that one of five patients with cancer‐associated VTE stopped LMWH injections because of side‐effects. This finding provides relevant background information for current clinical trials investigating the efficacy and safety of direct oral anticoagulants as compared with LMWH.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Fluid resuscitation is challenging in low resource settings.•Pilot study to evaluate safety of a new protocol.•Practical protocol appears safe and reasonable.
Appropriate fluid resuscitation of ...acute burn injury is critical and there are recognized challenges with fluid resuscitation, including those with relevance to low resource settings. We developed a practical protocol that guides burn resuscitation and sought to evaluate the safety of our modified resuscitation formula through a small pilot study that particularly addresses the problems we have experienced in a low resource setting.
Children with burns more than 15% total body surface area admitted within 24 h of injury to Edendale Hospital between 1 June 2021 and 31 August 2021 were included. The resuscitation formula used was 2 mls of Ringers Lactate per bodyweight in kilograms per% total body surface area (TBSA) given over 24 h and adjusted according to urine output. Data analysed included age, weight, mechanism, TBSA, hours post burn at presentation to hospital, total fluid given in the first 24 h of admission, total urine output in the first 24 h of admission, number of fluid adjustments made during the first 24 h and complications related to fluid resuscitation.
Ten children were included. The median age was 3 (IQR 2–5) years old, with a mean weight of 14.9 (SD 5.07) kilograms, a median TBSA of 17.4 (IQR 16–26)%, presenting at a median of 12 (6.5–18) hours post burn injury. Mechanism of burn was scald in all cases, with 9 being hot water and hot food in one. In the first 24 h a mean of 2.05 (SD 0.58) mls/kg of fluid was received with a mean urine output of 1.66 (SD 0.57) mls/kg/hr.
The results of this pilot study to evaluate the safety of our protocol seem reasonable. It is limited by the lack of larger injuries as well as adult patients and a larger prospective study is pertinent.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Are there general biophysical relationships governing the spatial organization of the gut microbiome? Despite growing realization that spatial structure is important for population stability, ...interbacterial competition, and host functions, it is unclear in any animal gut whether such structure is subject to predictive, unifying rules or if it results from contextual, species-specific behaviors. To explore this, we used light sheet fluorescence microscopy to conduct a high-resolution comparative study of bacterial distribution patterns throughout the entire intestinal volume of live, larval zebrafish. Fluorescently tagged strains of seven bacterial symbionts, representing six different species native to zebrafish, were each separately monoassociated with animals that had been raised initially germ-free. The strains showed large differences in both cohesion—the degree to which they auto-aggregate—and spatial distribution. We uncovered a striking correlation between each strain’s mean position and its cohesion, whether quantified as the fraction of cells existing as planktonic individuals, the average aggregate size, or the total number of aggregates. Moreover, these correlations held within species as well; aggregates of different sizes localized as predicted from the pan-species observations. Together, our findings indicate that bacteria within the zebrafish intestine are subject to generic processes that organize populations by their cohesive properties. The likely drivers of this relationship—peristaltic fluid flow, tubular anatomy, and bacterial growth and aggregation kinetics—are common throughout animals. We therefore suggest that the framework introduced here of biophysical links between bacterial cohesion and spatial organization should be useful for directing explorations in other host-microbe systems, formulating detailed models that can quantitatively map onto experimental data, and developing new tools that manipulate cohesion to engineer microbiome function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gender Identity Disparities in Cancer Screening Behaviors Tabaac, Ariella R.; Sutter, Megan E.; Wall, Catherine S.J. ...
American journal of preventive medicine,
March 2018, 2018-03-00, 20180301, Volume:
54, Issue:
3
Journal Article
Peer reviewed
Transgender (trans) and gender-nonconforming adults have reported reduced access to health care because of discrimination and lack of knowledgeable care. This study aimed to contribute to the nascent ...cancer prevention literature among trans and gender-nonconforming individuals by ascertaining rates of breast, cervical, prostate, and colorectal cancer screening behaviors by gender identity.
Publicly available de-identified data from the 2014–2016 Behavioral Risk Factor Surveillance System surveys were utilized to evaluate rates of cancer screenings by gender identity, while controlling for healthcare access, sociodemographics, and survey year. Analyses were conducted in 2018.
Weighted chi-square tests identified significant differences in the proportion of cancer screening behaviors by gender identity among lifetime colorectal cancer screenings, mammography tests, Pap tests, prostate-specific antigen tests, discussing prostate-specific antigen test advantages/disadvantages with their healthcare provider, and up-to-date colorectal cancer screenings and Pap tests (all p<0.048). Weighted logistic regressions found that although some differences based on gender identity were fully explained by covariates, gender-nonconforming individuals had reduced odds of ever having a sigmoidoscopy/colonoscopy compared to cisgender (cis) men (AOR=0.46) and cis women (AOR=0.43), whereas trans men were more likely to have an up-to-date colorectal cancer screening as compared to cis men (AOR=2.29) and cis women (AOR=1.97). Trans women were less likely than cis women to have ever had a mammography screening (AOR=0.33) and trans men were more likely than cis women to have an up-to-date mammography test (AOR=2.03). Finally, trans men and gender-nonconforming individuals had reduced odds of lifetime Pap tests versus cis women (AOR=0.50 and 0.20, respectively), and gender-nonconforming individuals had lower odds of being up-to-date for Pap tests (AOR=0.33; all p<0.05).
The findings indicate that gender identity disparities in cancer screenings persist beyond known sociodemographic and healthcare factors. It is critical that gender identity questions are included in cancer and other health-related surveillance systems to create knowledge to better inform healthcare practitioners and policymakers of appropriate screenings for trans and gender-nonconforming individuals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Many remarkable properties of quantum materials emerge from states with intricate coupling between the charge, spin and orbital degrees of freedom. Ultrafast photo-excitation of these materials holds ...great promise for understanding and controlling the properties of these states. Here, we introduce time-resolved resonant inelastic X-ray scattering (tr-RIXS) as a means of measuring the charge, spin and orbital excitations out of equilibrium. These excitations encode the correlations and interactions that determine the detailed properties of the states generated. After outlining the basic principles and instrumentations of tr-RIXS, we review our first observations of transient antiferromagnetic correlations in quasi two dimensions in a photo-excited Mott insulator and present possible future routes of this fast-developing technique. The increasing number of X-ray free electron laser facilities not only enables tackling long-standing fundamental scientific problems, but also promises to unleash novel inelastic X-ray scattering spectroscopies. This article is part of the theme issue 'Measurement of ultrafast electronic and structural dynamics with X-rays'.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Targeted radiotherapies maximize cytotoxicty to cancer cells. In vivo α-generator targeted radiotherapies can deliver multiple α particles to a receptor site dramatically amplifying the radiation ...dose delivered to the target. The major challenge with α-generator radiotherapies is that traditional chelating moieties are unable to sequester the radioactive daughters in the bioconjugate which is critical to minimize toxicity to healthy, non-target tissue. The recoil energy of the (225)Ac daughters following α decay will sever any metal-ligand bond used to form the bioconjugate. This work demonstrates that an engineered multilayered nanoparticle-antibody conjugate can deliver multiple α radiations and contain the decay daughters of (225)Ac while targeting biologically relevant receptors in a female BALB/c mouse model. These multi-shell nanoparticles combine the radiation resistance of lanthanide phosphate to contain (225)Ac and its radioactive decay daughters, the magnetic properties of gadolinium phosphate for easy separation, and established gold chemistry for attachment of targeting moieties.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Molecular basis for insulin fibril assembly Ivanova, Magdalena I; Sievers, Stuart A; Sawaya, Michael R ...
Proceedings of the National Academy of Sciences - PNAS,
11/2009, Volume:
106, Issue:
45
Journal Article
Peer reviewed
Open access
In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest ...segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-β spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 Å resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated β-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
•Amputations are a devastating consequence of severe burn injuries.•The impact of an amputation in terms cultural beliefs, re-integration back into the community and return to work or loss of future ...income is immense.•Epileptics are a vulnerable group and more likely to sustain severe burn injuries requiring amputation.•Low-voltage electrical injuries most commonly result in amputations following burn injuries in the paediatric population.
Amputations are a devastating consequence of severe burns. Amputations in a resource-limited setting are challenging as rehabilitation services available to these patients are inconsistent and often fragmented. Epileptic patients are a particularly vulnerable group when it comes to burn-injuries and often sustain deeper burns. The aim of this study is to analyse amputations secondary to burn injuries. We seek to identify vulnerable groups as a means for advocacy efforts to reduce the devastation of an amputation secondary to a burn injury. This paper highlights the burden of these injuries on the healthcare system and emphasizes the need for additional trained therapists for the rehabilitation of these patients.
A retrospective database review was conducted. All burns admissions who underwent an amputation between 1 February 2016 and 31 January 2019 were considered.
A total of 1575 patients were admitted during the study period. Fifty-four percent of the admissions were paediatric patients. The amputation rate in the paediatric population was 1.5% (13/850) while in the adult population it was 4.8% (35/724) . Most paediatric amputations were as a result of electrical injuries. Flame burns were most likely to result in amputations in the adult group and convulsions were the leading circumstance leading to the injury. There was no significant difference in sepsis or length of stay between the groups. There were no mortalities in the paediatric group but there was an 11% mortality rate in the adult group.
The incidence of amputations in burns is low, however, it remains a devastating morbidity. Epileptics are a vulnerable group and these patients account for the most amputations among adult burns patients. Education interventions are needed regarding their diagnosis, administration of their medication and the importance of compliance. Advocacy efforts to ensure constant supply of anti-epileptic drugs at the clinics and other district level health facilities is also essential. Electrical injuries in children are not as common as hot water scalds, however, they are more likely to result in amputation. Communities need to be informed of the risk associated with illegal electrical connections and initiatives need to drive the safe provision of affordable electricity to these under-privileged, vulnerable communities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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