Outcomes of Pregnancy in Recipients of Liver Transplants.

BACKGROUND & AIMS: Despite increasing reports of pregnancy in women who received liver transplants, it is not clear how transplantation and immunosuppression affect pregnancy. We collected data from liver transplant recipients who became pregnant on immunosuppression regimens, pregnancy management, graft morbidity, and outcomes of mothers and neonates. METHODS: We searched the liver transplant database in Birmingham, United Kingdom, for women who reported pregnancy after liver transplantation from August 1986 through May 2016. We collected information on morbidities and outcomes of 139 pregnancies in 83 women (median age at conception, 27 y; range, 15-46 y). Fisher exact tests were used to compare categoric variables and Mann-Whitney U and Kruskal-Wallis tests were used to compare continuous variables. The primary outcome was the live birth rate in the entire cohort. Additional outcomes analyzed included differences in immunotherapy regimens, and outcomes associated with exposure to cyclosporine and tacrolimus, time to transplantation (<12 vs >12 mo), and time period of pregnancy (1986-2000 vs 2001-2016). RESULTS: Of the pregnancies, 69% resulted in live births, 19% resulted in miscarriages or still births, and 9% were terminated. A higher proportion of patients who conceived more than 1 year after liver transplantation had live births than of women who conceived before this time (98% vs 80%; P = .006). Tacrolimus exposure was associated with higher risks of premature delivery (P = .045) and caesarian section (P = .031) than cyclosporine exposure. Compared with the period from 1986 to 2000, women who conceived from 2001 to 2016 had a significantly shorter time between transplantation and conception (median, 3 vs 7 y; P = .027), frequent use of tacrolimus vs cyclosporine (84% vs 26%; P = .001), and a higher incidence of cesarean section (44% vs 32%; P = .025). CONCLUSIONS: Almost 70% of women who conceive after liver transplantation have live births, although this rate is lower than that of women in the overall population. These cases require involvement of hepatologists and obstetricians.

Comparison of modeling methods to determine liver-to-blood inocula and parasite multiplication rates during controlled human malaria infection.

Controlled human malaria infection is used to measure efficacy of candidate malaria vaccines before field studies are undertaken. Mathematical modeling using data from quantitative polymerase chain reaction (qPCR) parasitemia monitoring can discriminate between vaccine effects on the parasite's liver and blood stages. Uncertainty regarding the most appropriate modeling method hinders interpretation of such trials. We used qPCR data from 267 Plasmodium falciparum infections to compare linear, sine-wave, and normal-cumulative-density-function models. We find that the parameters estimated by these models are closely correlated, and their predictive accuracy for omitted data points was similar. We propose that future studies include the linear model.

Clinical effectiveness and cost-effectiveness of Structured Psychological Support for people with probable personality disorder in mental health services in England: study protocol for a randomised controlled trial.

INTRODUCTION: Evidence-based psychological treatments for people with personality disorder usually involve attending group-based sessions over many months. Low-intensity psychological interventions of less than 6 months duration have been developed, but their clinical effectiveness and cost-effectiveness are unclear. METHODS AND ANALYSIS: This is a multicentre, randomised, parallel-group, researcher-masked, superiority trial. Study participants will be aged 18 and over, have probable personality disorder and be treated by mental health staff in seven centres in England. We will exclude people who are: unwilling or unable to provide written informed consent, have a coexisting organic or psychotic mental disorder, or are already receiving psychological treatment for personality disorder or on a waiting list for such treatment. In the intervention group, participants will be offered up to 10 individual sessions of Structured Psychological Support. In the control group, participants will be offered treatment as usual plus a single session of personalised crisis planning. The primary outcome is social functioning measured over 12 months using total score on the Work and Social Adjustment Scale (WSAS). Secondary outcomes include mental health, suicidal behaviour, health-related quality of life, patient-rated global improvement and satisfaction, and resource use and costs. The primary analysis will compare WSAS scores across the 12-month period using a general linear mixed model adjusting for baseline scores, allocation group and study centre on an intention-to-treat basis. In a parallel process evaluation, we will analyse qualitative data from interviews with study participants, clinical staff and researchers to examine mechanisms of impact and contextual factors. ETHICS AND DISSEMINATION: The study complies with the Helsinki Declaration II and is approved by the London-Bromley Research Ethics Committee (IRAS ID 315951). Study findings will be published in an open access peer-reviewed journal; and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13918289.

Morphometric evaluation of duodenal biopsies in celiac disease.

OBJECTIVES: The Marsh classification is a semiquantitative method for the diagnosis and monitoring of changes in duodenal biopsies in celiac disease. We have explored the possibility that quantitative changes in villous area and crypt length (morphometry) may provide better information on changes in duodenal morphology, particularly after the introduction of a gluten-free diet. METHODS: We measured villous height, apical and basal villous widths, and crypt length in 57 adults with celiac disease and 83 control subjects. Villous area was calculated as a trapezoid approximation. Serial changes in villous area and crypt length were determined at regular intervals for up to 4 years after the introduction of a gluten-free diet. Morphometric changes were also correlated with Marsh grade, self-reported adherence to a gluten-free diet, and changes in celiac serology. RESULTS: The gluten-free diet resulted in a progressive increase in villous area and a progressive decrease in crypt length. Morphometric improvement reached a plateau after 6-12 months with mean villous area attaining a value approximately half that of control subjects. Morphometric data were more sensitive than Marsh grade. Improvement in morphometric indices was significantly associated with the disappearance of anti-endomysial IgA antibody but not with dietary compliance. CONCLUSIONS: Morphometry is a sensitive way to document changes in duodenal biopsies in celiac disease. In adults treated with a gluten-free diet, it is uncommon for villous area to return to values observed in control subjects, but morphometric improvement is associated with the disappearance of anti-endomysial IgA antibody.

Type 2 Autoimmune Hepatitis and Nonadherence to Medication Correlate With Premature Birth and Risk of Postpartum Flare.

Autoimmune hepatitis (AIH) is an immune-mediated chronic liver disease that affects all ages, including women of childbearing age. Optimal management during pregnancy is poorly defined. We aimed to explore the clinical and biochemical course of AIH in the antenatal and postpartum periods, and assess factors associated with premature birth and postpartum flares. Pregnant women with AIH reviewed in the autoimmune liver disease clinic at the Queen Elizabeth Hospital Birmingham between 2009 and 2020 were identified retrospectively, and clinical, biochemical, and immunological data 1 year before conception to 1 year postpartum were collected. Analysis was performed to identify trends in blood markers over the antenatal period, with an interrupted time series approach used to assess postpartum trends. Data were available for n = 27 pregnancies (n = 20 women), with median gestation of 38 weeks (30% premature) and most having type 1 AIH (78%) and delivering via caesarean section (63%). Levels of alanine transaminase, aspartate transaminase, and immunoglobulin G all declined significantly during gestation, followed by significant step-change increases after delivery. Postpartum flare developed in 58% of pregnancies. AIH type 2 was associated with a higher rate of premature births (67% vs. 19%, P = 0.044), and a trend toward a higher rate of postpartum flare (100% vs. 48%, P = 0.053). Although not significant, medication nonadherence was associated with almost double the risk of prematurity (40% vs. 24%, P = 0.415) and postpartum flare (80% vs. 44%, P = 0.109). Conclusion: Biochemical and immunological remission of AIH occurs during pregnancy, although subsequent postpartum flare is common. Type 2 AIH is associated with a higher risk of premature birth and postpartum flare, although further research is required to validate and explain this finding.

Tunnelled peritoneal drainage catheter placement for the palliative management of refractory ascites in patients with liver cirrhosis.

OBJECTIVE: Refractory ascites is an established indication for liver transplantation. While transplantation is regarded as the definitive therapy for this condition, many patients are unsuitable due to comorbidity or frailty. Alternatives such as transjugular intrahepatic portosystemic shunt (TIPSS) and large-volume paracentesis can lead to complications, including encephalopathy, circulatory and renal dysfunction, and protein-calorie deficiency that may accelerate sarcopenia. Cost and complication rates limit therapies such as alfapump. While there are data to support the use of indwelling catheters in the management of patients with malignant ascites, there is limited evidence to support their routine use in the context of end-stage liver cirrhosis. Here we describe our centres' experience using indwelling tunnelled ascitic drains over a 6-year period. METHODS: A retrospective review of data (January 2012-May 2018) was undertaken for all patients with refractory ascites who underwent a tunnelled ascitic drain. Demographics, disease aetiology, procedure data and follow-up data were obtained through interrogation of electronic records and reports. RESULTS: Twenty-five drains were placed. All procedures were technically successful with no immediate complications. Six patients were readmitted following their index admission with abdominal pain and suspected infected ascites (although only two had a positive ascitic fluid culture). There were three cases of abdominal wall cellulitis and three of leakage around the tunnel site; all managed conservatively. CONCLUSION: Indwelling drains appear an effective strategy for palliative management of select patients with liver cirrhosis complicated by refractory ascites who are not amenable to undergo TIPSS or transplantation. While complications can occur, these are most usually minor and can be managed on an outpatient basis.

Factors in Psychiatric Admissions: Before and During the Covid-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic has impacted community mental health, but the effect on psychiatric admissions is unknown. We investigated factors contributing to acute psychiatric admissions, and whether this changed during the first UK lockdown. METHOD: A retrospective case-note review study with an exploratory mixed-methods design to examine factors for psychiatric admissions following the first UK 2020 lockdown compared to the same time periods in 2019 and 2018. RESULTS: Themes of psychopathology, risk, social stressors, community treatment issues, and physical health concerns were generated. The mean number of codes per case was 6.19 (s . d. = 2.43), with a mean number of categories per case of 3.73, (s. d. = 0.98). Changes in routines and isolation were common factors in the study year; accommodation and substance abuse were more prominent in the control year. Relationship stressors featured strongly in both groups. There were significantly more women (χ2(1, N = 98) = 20.80, p < 0.00001) and older adults (χ2(1, N = 98) = 8.61, p = 0.0033) in the study group than the control. Single people, compared to those in a relationship (χ2(1, N = 45) = 4.46, p = 0.035), and people with affective disorders compared to psychotic disorders ((χ2(1, N = 28) = 5.19, p = 0.023), were more likely to have a COVID-19 related admission factor. CONCLUSIONS: Early stages of the COVID-19 pandemic amplified pre-existing psychosocial vulnerabilities with a disproportionate psychiatric admissions impact on the mental health of women, older adults and those with affective disorders.

Multiple functions of human T cells generated by experimental malaria challenge.

Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-gamma, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum-infected RBC (iRBC) Ag, 28 and 90 days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-gamma cultured ELISPOT, were low and unstable over time, despite CD4(+) T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-beta, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-gamma measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed.

Synthetic GPI array to study antitoxic malaria response.

Parasite glycosylphosphatidylinositol (GPI) is an important toxin in malaria disease, and people living in malaria-endemic regions often produce high levels of anti-GPI antibodies. The natural anti-GPI antibody response needs to be understood to aid the design of an efficient carbohydrate-based antitoxin vaccine. We present a versatile approach based on a synthetic GPI glycan array to correlate anti-GPI antibody levels and protection from severe malaria.

Migration-related changes in gene expression in leg muscle of the Christmas Island red crab Gecarcoidea natalis: seasonal preparation for long-distance walking.

During their annual breeding migration the Christmas Island land crab Gecarcoidea natalis sustains locomotion aerobically for up to 12 h per day compared with just 10 min during the dry season when their muscles quickly become anaerobic. A seasonal transition to an endurance-muscle phenotype would thus seem essential for migrating crabs. The current study employed a gene discovery approach comparing two expressed sequence tag (EST) libraries, one each for leg muscle from dry (non-migrating) and wet season (migrating) crabs. The 14 most abundant transcripts differed in their representation between the two libraries. The abundances of transcripts of genes predicted to code for different proteins forming contractile muscle components, including actin, troponin and tropomyosin, were significantly different between seasons and thus between physiological states. The shift in the isoform composition of the contractile elements provided evidence for a switch from slow phasic (S1) to slow tonic (S2) fatigue-resistant muscle fibres. A tropomyosin (tm) transcript aligned with a tm isoform of lobster (tmS2), and semi-quantitative RT-PCR confirmed this isoform to be more abundant in the migrating crab muscle. Two LIM protein coding genes, a paxillin-like transcript (pax) and a muscle LIM protein (mlp), were relatively up-regulated in muscle of wet season crabs. These proteins have a fundamental role in muscle development and reconstruction, and their comparative up-regulation is consistent with a remodelling of leg muscle for migration in the wet season. Such a transition would result in an increased representation of aerobic endurance-type fibres concomitant with the greater aerobic exercise capacity of the migrating red crabs.

Review article: chronic liver disease and pregnancy.

BACKGROUND: The prevalence of chronic liver disease in women of child bearing age is increasing, leading to a higher incidence of pregnancy in this cohort. Chronic medical conditions have a significant adverse effect on maternal morbidity and mortality. To date, reviews on this topic have been written either from a hepatology or obstetrics viewpoint, and no specific guidelines are available solely for the management of chronic liver disease in pregnancy. AIMS: To produce a comprehensive review on the clinical management of women with chronic liver disease during pregnancy, addressing the risks of pregnancy to mother and child, how these risks can be ameliorated, and what additional considerations are required for management of chronic liver disease in pregnancy. METHODS: Data were collected up to May 2020 from the biomedical database PubMed, national and international guidelines in gastroenterology and hepatology. RESULTS: During pregnancy, women with cirrhosis are more likely to develop decompensated disease, worsening of portal hypertension, and to deliver premature infants. CONCLUSIONS: The risks associated with pregnancy can be ameliorated by advanced planning, assessing risk using the model for end stage liver disease score and risk reduction through varices screening. A multidisciplinary approach is paramount in order to minimise complications and maximise the chance of a safe pregnancy and birth for mother and baby.

The early impact of COVID-19 on mental health and community physical health services and their patients' mortality in Cambridgeshire and Peterborough, UK.

BACKGROUND: COVID-19 has affected social interaction and healthcare worldwide. METHODS: We examined changes in presentations and referrals to the primary provider of mental health and community health services in Cambridgeshire and Peterborough, UK (population ~0·86 million), plus service activity and deaths. We conducted interrupted time series analyses with respect to the time of UK "lockdown", which was shortly before the peak of COVID-19 infections in this area. We examined changes in standardized mortality ratio for those with and without severe mental illness (SMI). RESULTS: Referrals and presentations to nearly all mental and physical health services dropped at lockdown, with evidence for changes in both supply (service provision) and demand (help-seeking). This was followed by an increase in demand for some services. This pattern was seen for all major forms of presentation to liaison psychiatry services, except for eating disorders, for which there was no evidence of change. Inpatient numbers fell, but new detentions under the Mental Health Act were unchanged. Many services shifted from face-to-face to remote contacts. Excess mortality was primarily in the over-70s. There was a much greater increase in mortality for patients with SMI, which was not explained by ethnicity. CONCLUSIONS: COVID-19 has been associated with a system-wide drop in the use of mental health services, with some subsequent return in activity. "Supply" changes may have reduced access to mental health services for some. "Demand" changes may reflect a genuine reduction of need or a lack of help-seeking with pent-up demand. There has been a disproportionate increase in death among those with SMI during the pandemic.

The relationship between human effector and memory T cells measured by ex vivo and cultured ELISPOT following recent and distal priming.

Maintenance of T-cell responses is an essential feature in protection from many infectious diseases that must be harnessed in vaccination. The relationship between effector T-cell responses and more durable and highly proliferative T-cell memory, particularly in humans, is not well understood. In this study, effector T-cell responses were measured by overnight ex vivo interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell assay (ELISPOT), whereas memory T cells were measured by 10-day culture followed by IFN-gamma ELISPOT (cultured ELISPOT). We observed a significant correlation between IFN-gamma responses to CD4-stimulatory, but not to CD8-stimulatory, recall antigens measured by these assays, suggesting a divergence in regulation. In vaccine trial participants who received a prime-boost vaccination regimen comprising malaria antigens delivered by poxviruses, there was a correlation between ex vivo and cultured responses on day 7, but not 3 months post-vaccination, with the ratio of cultured : ex vivo response increasing over time. To compare responses revealed by cultured ELISPOT in more detail, tetramers comprising viral recall antigens were used to ascribe effector-memory and central-memory T-cell phenotypes through CCR7 and CD62L costaining. For CD8(+) responses the effector phenotype decreased during the initial culture period and memory populations remained high within the resulting 20-fold to 50-fold increased IFN-gamma-secreting or tetramer(+) population. This was less marked for CD4(+) responses, which had higher starting memory phenotype. Depletion of these central-memory T-cell populations generally ablated responses in cultured ELISPOT and reduced ex vivo responses. This study highlights differences between CD4(+) and CD8(+) effector and memory T cells, and the more complex phenotype of CD4(+) T cells.

Transcript profiles of long- and short-lived adults implicate protein synthesis in evolved differences in ageing in the nematode Strongyloides ratti.

The nematode Strongyloides ratti shows remarkable phenotypic plasticity in ageing, with parasitic adults living at least 80-times longer than free-living adults. Given that long- and short-lived adults are genetically identical, this plasticity is likely to be due to differences in gene expression. To try and understand how this inter-morph difference in longevity evolved, we compared gene expression in long- and short-lived adults. DNA microarray analysis of long- and short-lived adults identified 32 genes that were up-regulated in long-lived adults, and 96 genes up-regulated in short-lived adults. Strikingly, 38.5% of the genes expressed more in the short-lived morph are predicted to encode ribosomal proteins, compared with only 9% in the long-lived morph. Among the 32 longevity-associated genes there was very little enrichment of genes linked to cellular maintenance. Overall, we have therefore observed a negative correlation between expression of ribosomal protein genes and longevity in S. ratti. Interestingly, engineered reduction of expression of ribosomal protein genes increases lifespan in the free-living nematode Caenorhabditis elegans. Our study therefore suggests that differences in levels of protein synthesis could contribute to evolved differences in animal longevity.

Liver disease in the young adult: the challenges and rewards.

Increasing numbers of children are surviving into adulthood with a diagnosis of liver disease or having undergone liver transplantation. This population presents some challenges for the adult hepatologist, and a formal transition service clearly improves outcomes for patients in this group. Evidence of ongoing neurological development in young people up to the age of 25 years exists, and understanding these physiological processes is important in overcoming some of the challenges that caring for this population presents. A well designed transition service is key to maximising potential for these patients, and should enable young people to take control of their illness and achieve their life goals.

Genes important in the parasitic life of the nematode Strongyloides ratti.

Parasitic nematodes are important pathogens of humans and other animals. The genus Strongyloides has both a parasitic and a free-living adult generation. S. ratti infections of its rat host are negatively affected by the host immune response, such that a month after infection, worms are lost from the hosts. Here we have investigated the changes in parasite gene expression that occur as the anti-S. ratti immune pressure increases. Existing S. ratti expressed sequence tags were used to construct a microarray consisting of 2227 putative genes. This was probed with cDNA prepared from parasites subject to low or high immune pressures. There are significant changes in the gene expression of S. ratti when subject to different immune pressures. Most of the genes whose expression changes have no significant alignment to known genes. These data together with previous S. ratti EST data were then used to identify genes that we hypothesise are central to the parasitic life of S. ratti and, perhaps, other parasitic nematodes. These analyses have identified genes likely to play a key role in the parasitic life of S. ratti; these genes should be the priority for further investigation.

Microarray analysis of gender- and parasite-specific gene transcription in Strongyloides ratti.

The molecular mechanisms by which parasitic nematodes reproduce and have adapted to life within a host are unclear. In the present study, microarray analysis was used to explore differential transcription among the different stages and sexes of Strongyloides ratti, a parasitic nematode of brown rats. Specifically, gender-biased transcription between free-living females and free-living males, and parasitic-biased transcription between parasitic females and free-living females was determined. Of the estimated 3,688 distinct transcripts represented on the microarray, 743 (20%) exhibited male-biased transcription of >1.4-fold (2(0.5)), 689 (19%) female-biased transcription, 418 (11%) parasitic-biased transcription and 305 (8%) free-living-biased transcription. Among those transcripts that exhibited the highest levels of differential transcription, an orthologue of major sperm protein was identified in males, distinct aspartic protease orthologues in either parasitic or in free-living females, and orthologues of hsp-17 chaperone in parasitic females. These 3,688 transcripts were separated into 12 clusters, such that the pattern of transcription between life-stages and biological replicates was similar among transcripts within a cluster and dissimilar between clusters. Using annotation inferred from Caenorhabditis elegans, gene ontology terms over-represented in one or more clusters were identified and showed that female-biased transcription was associated with genes involved in reproductive processes and larval development, male-biased transcription was linked to genes involved in metabolism, and free-living-biased transcription related to genes involved in the regulation of body fluids and response to external stimulus. The association of gene ontology with parasite-biased transcription was less clear. The present findings for S. ratti provide a basis for a detailed exploration of differentially regulated molecules and might assist in the search for novel drug or vaccine targets in parasitic nematodes.

Crypt fission peaks early during infancy and crypt hyperplasia broadly peaks during infancy and childhood in the small intestine of humans.

BACKGROUND: Postnatal growth of the small intestine occurs by crypt hyperplasia and by the less recognised mechanism of crypt fission. How the small intestine grows is largely extrapolated from animals and is poorly described in humans. AIM: To investigate crypt fission and crypt hyperplasia as mechanisms of intestinal growth in humans. PATIENTS AND METHODS: Proximal intestinal samples were taken from 3 neonates at surgical anastomosis, and duodenal biopsies were taken at endoscopy from 16 infants (mean age 0.7, range 0.3-1.7 years), 14 children (mean age 7.9, range 2.4-16.2 years), and 39 adults. Morphometric measures of villous area, crypt length (measure of crypt hyperplasia), and percentage of bifid crypts (measure of crypt fission) were assessed by a microdissection technique. RESULTS: Mean crypt fission rates in neonates, infants, children, and adults were 7.8%, 15%, 4.9%, and 1.7%, respectively. In particular, crypt fission peaked at 18% in 5 infants from 6 to 12 months of age. Mean crypt length was 123 microm in neonates, 287 microm in infants, 277 microm in children, and 209 microm in adults. Thus, crypt hyperplasia had a broad peak during infancy and childhood. CONCLUSIONS: We conclude that crypt fission was present predominantly during infancy, and crypt hyperplasia occurred during both infancy and childhood.