Pregnancy in Patients with the Fontan Operation.

Improved survival rates for patients with a Fontan circulation has allowed more women with this complex cardiac physiology to contemplate pregnancy. However, pregnancy in women with a Fontan circulation is associated with a high risk of adverse maternal and fetal outcomes, high rates of miscarriage and preterm delivery. Factors associated with a successful pregnancy outcome are: younger age, normal body weight, absence of significant functional limitation, no Fontan-related complications, and well-functioning single ventricle physiology. Appropriate care with timely preconception counselling and regular, frequent clinical reviews by a multidisciplinary team based at a tertiary centre, improves the chance of a successful pregnancy. Empowerment of patients with education on their specific congenital cardiac condition and its projected trajectory, helps them make informed choices regarding their health, reproductive choices and assists them to achieve their life goals.

Connectivity of stormwater ponds impacts Odonata abundance and species richness.

Context: The successful dispersal of an animal depends, partly, on landscape connectivity. Urbanization poses risks to dispersal activities by increasing hostile land cover types. Objectives: We investigated how connectivity of urban ponds impacted Odonata communities (dragonflies and damselflies), an order of semi-aquatic insects that actively disperse. Methods: We sampled 41 constructed stormwater ponds and 8 natural ponds in a metropolitan area. The effect of connectivity and the quantity of available adjacent habitats was tested at different scales for dragonflies (900 m) and damselflies (300 m), determined by a literature analysis, to account for differences in suborder dispersal capabilities. Results: Lower levels of connectivity and fewer nearest neighbours negatively impacted abundance, species richness, and composition of dragonflies (p values < 0.01, R2 = 0.18-0.70). Adult dragonfly abundance had a stronger positive relationship with connectivity than species richness. In particular, the abundance of adult dragonfly Leucorrhinia frigida, found almost exclusively at natural ponds, had a positive relationship with connectivity. Connectivity and the number of nearest neighbours had no significant impact on damselflies apart from a slight negative relationship between connectivity and species richness (p value = 0.02, R2 = 0.11). Natural ponds had significantly higher levels of connectivity when compared to stormwater ponds. Conclusions: Our results suggest that dragonflies are positively affected by increased connectivity in an urban landscape, with no benefit of connectivity to damselflies at the scale measured. We recommend intentional planning of urban stormwater pond networks, where individual ponds can act as stepping stones, incorporated with strategic inclusion of beneficial land cover types. Supplementary Information: The online version contains supplementary material available at 10.1007/s10980-024-01817-z.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

Self-reported gastrointestinal disorders among veterans with gulf war illness with and without posttraumatic stress disorder.

BACKGROUND: Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting 25%-32% of Gulf War veterans. Veterans with GWI disproportionately suffer from gastrointestinal (GI) disorders. Given the increasing evidence supporting a gut-brain axis, we explore the relationship between post-traumatic stress disorder (PTSD), GWI, and self-reported GI disorders among GW veterans. METHODS: Veterans from the Gulf War Era Cohort and Biorepository responded to a mail-based survey (N = 1058). They were stratified by GWI (Centers for Disease Control definition) and PTSD status. This yielded three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression adjusting for demographic and military characteristics examined associations between GWI/PTSD groups and GI disorders. Results were expressed as adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). KEY RESULTS: The most frequently reported GI disorders were irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and colon polyps (CP). The GWI+/PTSD+ group had a higher odds of these disorders than the GWI+/PTSD- group (aORIBS  = 3.12, 95% CI: 1.93-5.05; aORGERD  = 2.04, 95% CI: 1.44-2.90; aORCP  = 1.85, 95% CI: 1.23-2.80), which had a higher odds of these disorders than the GWI- group (aORIBS  = 4.38, 95% CI: 1.55-12.36; aORGERD  = 2.51 95% CI: 1.63-3.87; aORCP  = 2.57, 95% CI: 1.53-4.32). CONCLUSIONS & INFERENCES: GW veterans with GWI and PTSD have significantly higher odds of specific self-reported GI disorders than the other groups. Given the known bidirectional influences of the gut and brain, these veterans may benefit from a holistic healthcare approach that considers biopsychosocial contributors to the assessment and management of disease.

Unexpected intraoperative hypotension in a chronic cocaine user.

It is not uncommon for patients to present for procedures under anaesthesia with a history of recent cocaine use. The acute effects of cocaine toxicity are well documented, but the pathophysiological changes caused by chronic use are complex and can result in unexpected cardiovascular responses and interactions with anaesthetic agents. In this case report, we describe an episode of hypotension under general anaesthesia, likely due to catecholamine depletion, an unusual but significant consequence of chronic cocaine use. It should be treated with intravenous fluids and direct-acting vasopressors such as phenylephrine or noradrenaline, as they are likely to be more effective than indirect acting agents. As the prevalence of cocaine use continues to increase, anaesthesia providers need to not only be familiar with the treatment of acute cocaine toxicity, but also to anticipate and manage the cardiovascular changes associated with chronic use of this drug.

Oro-Naso-Sino-Orbital-Cutaneous Fistula From Prolonged Cocaine Use.

Presentation We present the case of a 48-year-old man with nasal cellulitis and subsequent oro-naso-sino-orbital-cutaneous fistula from prolonged cocaine use. Diagnosis Initial laboratory investigations reported a raised white cell count (WBC) and C-Reactive Protein (CRP) and subsequently a positive atypical anti-neutrophil cytoplasm antibodies (ANCA) and positive anti-proteinase (PR3). Perihilar lung nodularity on chest imaging raised the possibility of a systemic autoimmune response. His urinalysis was positive for cocaine. Treatment He was commenced on Augmentin, Amphotericin B and Prednisolone. An obturator was created to manage the oro-nasal fistula. A subsequent naso-cutaneous defect was re-approximated. Daily nasal saline douche and abstinence of cocaine were recommended. Discussion Cocaine use in the community is rising and poses a challenge to multiple facets of our health care system.

An awareness and prevalence study of Irish cold-water athletes and external auditory canal exostoses.

OBJECTIVE: This study aimed to determine the awareness, otological symptoms and prevalence of external auditory canal exostoses in Irish cold-water athletes. METHOD: An online and in person cross-sectional survey was undertaken with Irish cold-water athletes to explore athletes' awareness, known prevalence of external auditory canal exostoses and attitudes towards preventive measures. RESULTS: Of the 926 participants surveyed, 67.5 per cent were aware of external auditory canal exostoses. Triathletes reported the lowest awareness (39.9 per cent) among water athletes. A total of 9.7 per cent (n = 90) had previously been diagnosed with external auditory canal exostoses and 46.7 per cent (n = 42) were non-surfers. Ear symptoms were reported in 76 per cent of athletes. Otoscopic examinations showed that 23.7 per cent had external auditory canal exostoses, 3.6 per cent of whom were aware of their diagnosis. CONCLUSION: The majority of Irish surfing athletes are aware of external auditory canal exostoses. There is less awareness with regard to Ireland's newly emerging sports such as open water swimming and triathlons. Over 90 per cent of athletes surveyed had no idea they had external auditory canal exostoses, which highlights the need to increase public awareness.

Predictors of antidepressant use in the English population: analysis of the Adult Psychiatric Morbidity Survey.

OBJECTIVES: The rate of antidepressant use in the United Kingdom has outpaced diagnostic increases in the prevalence of depression. Research has suggested that personal and socioeconomic risk factors may be contributing to antidepressant use. To date, few studies have addressed these possible contributions. Thus, this study aimed to assess the relative strength of personal, socioeconomic and trauma-related risk factors in predicting antidepressant use. METHODS: Data were derived from the Adult Psychiatric Morbidity Survey (n=7403), a nationally representative household sample of adults residing in England in 2007. A multivariate binary logistic regression model was developed to assess the associations between personal, socioeconomic and trauma-related risk factors and current antidepressant use. RESULTS: The strongest predictor of current antidepressant use was meeting the criteria for an ICD-10 depressive episode [odds ratio (OR)=9.04]. Other significant predictors of antidepressant use in this analysis included English as first language (OR=3.45), female gender (OR=1.98), unemployment (OR=1.82) and childhood sexual abuse (OR=1.53). CONCLUSIONS: Several personal, socioeconomic and trauma-related factors significantly contributed to antidepressant use in the multivariate model specified. These findings aid our understanding of the broader context of antidepressant use in the United Kingdom.

Development of an auxotrophic, live-attenuated Brucella suis vaccine strain capable of expressing multimeric GnRH.

Feral swine cost around $1.5 billion each year in agricultural, environmental, and personal property damages. They are also the most widespread carriers of the zoonotic disease brucellosis, which threatens both livestock bio-security and public health. Currently, there is no approved vaccine against brucellosis in pigs. This is a preliminary report on the development of a live-attenuated B. suis vaccine that could be employed to deliver heterologous antigens to control swine populations. An attenuated vaccine strain provided significant protection against B. suis challenge in mice. Leucine auxotrophy in the vaccine strain allowed the over-expression of heterologous antigens without the use of antibiotic resistant markers. Vaccinated mice showed the development of antibodies against expressed antigen. Further evaluation is required to assess its ability to cause infertility using the mouse model prior to further testing for use as a tool for feral swine population and disease control.

Process evaluation of a cluster-randomised controlled trial of multi-component weight management programme in adults with intellectual disabilities and obesity.

BACKGROUND: Providing effective weight management to adults with intellectual disabilities is necessary to challenge the high rates of obesity. The aim of this process evaluation was to explore the feasibility of conducting a full-scale clinical trial of the TAKE 5 multi-component weight management programme. METHODS: The study was a 12-month pilot cluster-randomised controlled trial. Adults with intellectual disabilities and obesity were randomised to either TAKE 5, which included an energy deficit diet (EDD) or Waist Winners Too, based on health education principles. A mixed-methods process evaluation was conducted focussing on the reach, recruitment, fidelity, implementation, dose (delivered/received) and context. RESULTS: The study successfully recruited adults with intellectual disabilities. Both weight management programmes were delivered with high fidelity and implemented as intended. Only one weight management programme, TAKE 5, demonstrated potential efficacy in reducing body weight and body composition. The effectiveness was largely attributed to the EDD and social support from carers. CONCLUSIONS: The extensive process evaluation illustrated that a full-scale trial of a multi-component programme including an EDD is feasible and an acceptable approach to weight management for adults with intellectual disabilities and obesity.

Donor-Derived Metastatic Melanoma and Checkpoint Inhibition.

Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.

A pilot study using preoperative cerebral tissue oxygen saturation to stratify cardiovascular risk in major non-cardiac surgery.

This prospective pilot study evaluated whether low preoperative cerebral tissue oxygen saturation is associated with unfavourable outcomes after major elective non-cardiac surgery. Eighty-one patients over 60 years of age, American Society of Anesthesiologists physical status 3 or 4, were recruited. Resting cerebral tissue oxygen saturation was recorded on room air, and after oxygen supplementation, using cerebral oximetry. The primary outcome was 30-day major adverse event of combined mortality or severe morbidity, and the secondary outcome was 30-day new disability. Eleven patients (13.6%) suffered a major adverse event, and 28 patients (34.6%) experienced new disability. Room air cerebral tissue oxygen saturation was significantly different between patients who had a major adverse event, 67% (95% confidence interval [CI] 65-70) versus unaffected, 71% (95% CI 70-72; P=0.04). No statistical difference was found between patients for new disability (range 70%-74%; P=0.73). Room air cerebral tissue oxygen saturation was significantly associated with major adverse events (odds ratio 1.36 (95% CI 1.03-1.79), P=0.03). Saturation levels ≤68% carried a positive likelihood ratio of 2.2 for death or severe morbidity, P=0.04. A definitive trial is required to confirm if cerebral oximetry can be used to stratify the cardiovascular risk of patients presenting for non-cardiac surgery.

Attrition and weight loss outcomes for patients with complex obesity, anxiety and depression attending a weight management programme with targeted psychological treatment.

The objective of the study is to investigate the effect of baseline anxiety and depression, using different definitions for caseness, on attrition and weight outcomes following a multidisciplinary weight management programme. The study design is a prospective observational study. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression with 'caseness' scoring ≥11 and severity ≥14. The participants were all patients who began a weight management programme between 1 October 2008 and 30 September 2009 (n = 1838). The setting was the Glasgow and Clyde Weight Management Service (GCWMS), a specialist multidisciplinary service, which aims to achieve a minimum of ≥5 kg weight loss. The results were as follows: patients with HADS score ≥14 were referred to the integrated psychology service for psychological assessment or intervention. Patients with caseness (HADS ≥11) for anxiety (33%) and depression (27%) were significantly younger, heavier, more socio-economically deprived and a higher proportion was female. There was a significant positive correlation between HADS anxiety and depression scores and increasing body mass index (r(2) = 0.094, P < 0.001 and r(2) = 0.175, P < 0.001, respectively). Attendance and completion was lower throughout follow-up amongst patients with anxiety or depression. More patients with HADS score ≥11 achieved ≥5 kg or ≥5% weight loss and by 12 months those with anxiety had a significantly higher mean weight loss (P = 0.032). Participants who scored for severe anxiety (HADS ≥14) achieved similar weight loss to those without, whilst participants who scored for severe depression achieved significantly greater weight loss than non-cases at 3, 6 and 12 months of follow-up (P < 0.01). Despite a less favourable case-mix of risk-factors for poor weight loss, patients who scored caseness for severe anxiety or depression and were offered additional psychological input achieved similar or better weight loss outcomes.

The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells.

The chemokine receptor CCR7 is widely implicated in breast cancer pathobiology. Although recent reports correlated high CCR7 levels with more advanced tumor grade and poor prognosis, limited in vivo data are available regarding its specific function in mammary gland neoplasia and the underlying mechanisms involved. To address these questions we generated a bigenic mouse model of breast cancer combined with CCR7 deletion, which revealed that CCR7 ablation results in a considerable delay in tumor onset as well as significantly reduced tumor burden. Importantly, CCR7 was found to exert its function by regulating mammary cancer stem-like cells in both murine and human tumors. In vivo experiments showed that loss of CCR7 activity either through deletion or pharmacological antagonism significantly decreased functional pools of stem-like cells in mouse primary mammary tumors, providing a mechanistic explanation for the tumor-promoting role of this chemokine receptor. These data characterize the oncogenic properties of CCR7 in mammary epithelial neoplasia and point to a new route for therapeutic intervention to target evasive cancer stem cells.

Low rates of vaccination in listed kidney transplant candidates.

Despite clear consensus and strong recommendations, vaccination rates of kidney transplant (KT) recipients have remained below targets. As vaccination is most effective if it is given prior to transplantation and the initiation of immunosuppression, patients should ideally have their vaccination status assessed and optimized in the pre-transplant period. We performed a retrospective chart review to characterize vaccination rates and factors associated with gaps in vaccination in a single-center population of waitlisted patients being evaluated for kidney transplantation. We evaluated 362 KT patients. Three-quarters were receiving dialysis at the time of evaluation. Immunization rates were low with 35.9% of patients having completed vaccination for Pneumococcus, 55% for influenza, 6.9% for zoster, and 2.5% for tetanus. On multivariable analysis, patients who received other vaccines, including influenza, tetanus, or zoster vaccine (odds ratio [OR] 10.55, 95% confidence interval [CI] 5.65-19.71) were more likely to receive pneumococcal vaccine. Blacks (OR 0.24, 95% CI 0.12-0.47) were less likely to receive pneumococcal vaccine compared to whites. Patients on dialysis, and those active on the waiting list were more likely to receive pneumococcal vaccine than other groups (OR 2.81, 95% CI 1.44-5.51, and OR 1.84, 95% CI 1.08-3.14, respectively). We found that the overall immunization rate against common vaccine-preventable infections was low among patients evaluated for kidney transplantation. A significant gap remains between recommendations and vaccine uptake in clinical practice among this high-risk population.

A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results.

The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range [IQR], 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.

PRC2-independent chromatin compaction and transcriptional repression in cancer.

The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high-H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations.

Immunotherapeutics to prevent the replication of Brucella in a treatment failure mouse model.

Outer membrane vesicles (OMVs) from Brucella melitensis and irradiated Brucella neotomae have been shown to be effective vaccines against a B. melitensis challenge in a mouse model. The present study evaluates the efficacy of these two vaccines as immuno-therapeutics in combination with conventional antibiotics against a B. melitensis infection. BALB/c mice chronically infected with B. melitensis were treated for 4 weeks with doxycycline and gentamicin and vaccinated twice during the course of therapy. Antibiotics in sub-therapeutic concentrations were chosen in such a way that the treatment would result in a therapeutic failure in mice. Although no additive effect of vaccines and antibiotics was seen on the clearance of B. melitensis, mice receiving vaccines along with antibiotics exhibited no Brucella replication post-treatment compared to mice treated only with antibiotics. Administration of irradiated B. neotomae along with antibiotics led to higher production of IFN-γ ex vivo by splenocytes upon stimulation with heat inactivated B. melitensis while no such effect was seen by splenocytes from mice vaccinated with OMVs. OMV vaccinated mice developed significantly higher anti-Brucella IgG antibody titers at the end of the treatment compared to the mice that received only antibiotics. The mice that received only vaccines did not show any significant clearance of Brucella from spleens and livers compared to non-treated control mice. This study suggests that incorporating OMVs or irradiated B. neotomae along with conventional antibiotics might be able to improve therapeutic efficacy and control the progression of disease in treatment failure cases.