Elevated cord levels of ustekinumab following its use in the treatment of Crohn's disease in pregnancy.

Ustekinumab (USK) was used in the treatment of two pregnant patients with Crohn's disease. It was given in the third trimester and restarted postnatally for both women. One woman remained on USK and in remission throughout pregnancy. The second woman, took a treatment break, flared, and then had remission induced with reintroduction of USK. Both women delivered healthy term infants. The interval from last dose to birth was 11 and 8 weeks respectively. Interestingly, USK levels in cord blood was observed in higher concentrations than in the maternal serum taken in third trimester. While no adverse effect in infants has been observed, clinicians should remain aware of fetal transfer when using USK in pregnancy. An evaluation of risk and benefit may favour continuing USK in pregnancy in patients with refractory disease.

Corticosteroid injection versus immobilisation for the treatment of De Quervain's tenosynovitis: A systematic review and meta-analysis.

OBJECTIVE: De Quervain's tenosynovitis causes pain and impairment of thumb function. Conservative treatments comprise corticosteroid injection and immobilization, and it is unclear which offers greater efficacy. Previous reviews were limited by the small number of included studies; thus an updated review and meta-analysis is warranted. METHODS: A systematic review of the PubMed, Embase, and Web of Science databases was conducted. Randomized control trials comparing corticosteroid injection to immobilization were included. Two authors screened articles, extracted data, and assessed the risk of bias of included studies. Meta-analyses using the random-effects model were conducted, calculating pooled relative risks and mean differences with 95% confidence intervals. RESULTS: 16 studies comprising 1206 patients were included. Corticosteroid injection showed greater treatment success than immobilization (relative risk: 1.61; 95% confidence interval: 1.21-2.15). Combining treatments demonstrated greater efficacy than immobilization (relative risk: 2.15; 95% confidence interval: 1.77-2.62) or injection alone (relative risk: 1.23; 95% confidence interval: 1.12-1.34). Pain and disability scores were lower with injection than immobilization and with combined treatment than with either alone. CONCLUSION: Corticosteroid injection is more effective than immobilization for De Quervain's tenosynovitis, and combining the two treatments provides additional benefit. We recommend corticosteroid injection in first line treatment and immobilization as adjuvant therapy. Further research is required regarding optimal corticosteroid and local anesthetic formulations.

Malignant upgrade rate and associated clinicopathologic predictors for concordant intraductal papilloma without atypia: A systematic review and meta-analysis.

Previously reported upgrade rates for benign breast intraductal papilloma (IDP) are widely variable. However, many previous studies have failed to consider radiologic-pathologic discordance of lesions. This review aims to synthesize malignant upgrade data for benign, concordant IDP at surgical excision. Thirteen studies were included in our meta-analysis. The pooled estimate for percentage underestimation of carcinoma was 1.4% (95% CI: 0.8%-2.0%). We conclude that these lesions can be safely managed by active surveillance.

Comparison of risk scoring systems for critical care patients with upper gastrointestinal bleeding: predicting mortality and length of stay.

INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is a common reason for intensive care admission. While there exist a number of UGIB scoring systems which are used to predict mortality, there are limited studies assessing the discriminative value of these scores in intensive care unit (ICU) patients. The purpose of this study was to analyse five different UGIB scoring systems in predicting ICU mortality and length of stay and compare them to two commonly used ICU mortality scoring systems. MATERIAL AND METHODS: We retrospectively identified all patients requiring ICU admission for UGIB to St James's Hospital over an 18-month period. We calculated their AIM65, Glasgow- Blatchford score, pre- and post-Rockall score, ABC, APACHE II and SOFA scores. We used area under the receiver operating characteristic curve (AUROC) to compare the predictive values of these six scoring systems for ICU and hospital mortality as well as ICU length of stay greater than seven days. RESULTS: APACHE II showed excellent discriminative value in predicting mortality in ICU patients (AUROC: 0.87; CI: 0.75-0.99) while the SOFA score showed good discriminative value (AUROC: 0.71; CI: 0.50-0.93). None of the UGIB scoring systems predicted mortality in these patients. All scoring systems showed poor discriminative value in predicting ICU length of stay. CONCLUSIONS: We were not able to validate any of these UGIB scoring systems for mortality or length of stay prediction in ICU patients. This study supports the validity of APACHE II as a clinical tool for predicting mortality in ICU patients with UGIB.

Aerobic or Resistance Exercise for Improved Glycaemic Control and Pregnancy Outcomes in Women with Gestational Diabetes Mellitus: A Systematic Review.

Exercise is often recommended in addition to diet and medication in the management of gestational diabetes mellitus (GDM). Our aim was to determine if strength training compared with aerobic exercise had an impact on glycaemic control, maternal and neonatal outcomes. The Cochrane library, Embase, PubMed, CINAHL, Medline, Google Scholar, and OpenGrey were searched. Over 758 pregnant women (mother-baby pairs) from 14 studies are included in this systematic review. Interventions ranged from cycling, aerobic exercises, walking, yoga, or combined aerobic and resistance exercises. Of the studies identified, none directly compared aerobic exercise with strength training. Half of the studies showed benefit in glycaemic control with additional exercise compared with usual physical activity. There was largely no impact on obstetric or neonatal outcomes. Studies on exercise in GDM have reiterated the safety of exercise in pregnancy and shown mixed effects on maternal glycaemic control, with no apparent impact on pregnancy outcomes. The heterogenicity of reported studies make it difficult to make specific recommendations on the optimum exercise modality for the management of GDM. The use of a core outcome set for GDM may improve reporting of studies on the role of exercise in its management.

Clinical Outcomes Following a Change in Gestational Diabetes Mellitus Diagnostic Criteria Due to the COVID-19 Pandemic: A Case-Control Study.

BACKGROUND: Due to COVID-19, many centres adopted a change to the diagnosis of GDM. METHODS: A case-control study of antenatal patients between 1 April and 30 June in 2019 and 2020 looking at detection rates of GDM, use of medication, obstetric, and fetal outcomes. RESULTS: During COVID-19, the rate of positive GDM tests approximately halved (20% (42/210) in 2020 vs. 42.2% (92/218) in 2019, (p < 0.01)) with higher rates of requirement for insulin at diagnosis (21.4% (2020) vs. 2.2% (2019); p < 0.01), and at term (31% (2020) vs. 5.4% (2019); p < 0.01). and metformin at diagnosis (4.8% (2020) vs. 1.1% (2019); p < 0.01), and at term (14.3% (2020) vs. 7.6% (2019) p < 0.01), with no differences in birth outcomes. CONCLUSIONS: There was likely an underdiagnosis of GDM while women at a higher risk of hyperglycaemia were correctly identified. The GTT should be maintained as the gold-standard test where possible, with provisions made for social distancing during testing if required.

Women's experience of pregnancy and birth during the COVID-19 pandemic: a qualitative study.

BACKGROUND: The COVID-19 pandemic has changed how maternity care services are provided worldwide. To contain the virus, many providers reduced the number of face-to-face visits for women. In addition, partner attendance was prohibited in many circumstances to protect staff, and other service users, from potential infection. AIMS: To explore women's experience of pregnancy and birth in the Republic of Ireland during the COVID-19 pandemic. METHODS: A qualitative study with 14 women was conducted using a grounded theory approach. Data were collected between April and July 2020, and in-depth interviews were conducted either in pregnancy or in the first 12 weeks after the birth. RESULTS: Six categories emerged: loss of normality, navigating "new" maternity care systems, partners as bystanders, balancing information, uncertainty, and unexpected benefits of pregnancy during the pandemic. While benefits were reported (working from home and additional time spent with partners during the "fourth trimester"), in general, the themes were of increased anxiety and uncertainty. CONCLUSION: The pandemic caused additional anxiety for pregnant women. This was exacerbated by uncertainty about the effects of COVID-19 on pregnancy and unclear messaging about restrictions. More interactive and personalized communication is required to support women to cope with uncertainty during a pandemic. The birth partner plays an important role as an advocate for women and excluding them from pregnancy care caused additional anxiety for pregnant women. Containment strategies for a pandemic should be developed with this in mind, to view the family as a unit rather than the woman in isolation.

"Does the use of gestation-specific centiles for cervical length change the management of pregnancies at risk of recurrent spontaneous preterm birth?"

INTRODUCTION: Preterm birth is the leading cause of neonatal morbidity and mortality. Spontaneous Preterm Birth (sPTB) has many and varied causes but is known to be strongly associated with a short or shortening cervix in the midtrimester of pregnancy. The strongest risk factor for sPTB is a previous sPTB. In women with a history of sPTB, we can offer surveillance and treatments which have been proven to reduce the risk of sPTB, such as cervical cerclage and vaginal progesterone supplementation. Alongside other indications, we currently use 25 mm or shorter as a "trigger threshold" for offering cervical cerclage treatment in the Preterm Birth Prevention Clinic at The National Maternity Hospital. AIM: To determine if using gestation-specific centiles instead of a 25 mm cut-off for cervical length changes the antenatal management of women at high risk of sPTB. METHOD: This was a retrospective chart review of all women attending the preterm birth clinic over the 2-year period 2018-2020 in a large tertiary referral unit in Dublin, Ireland. Demographic details, obstetric history, preterm birth risk factors and preventative treatments offered were collected and analysed. Cervical lengths were measured with ultrasound using a standardised protocol and all performed or supervised by 2 experienced sonographers. RESULTS: A total of 200 patients with known risk factors for sPTB attended the Preterm Birth Surveillance Clinic at the National Maternity Hospital during the study period. Of these, 36/200 (18%) went on to deliver again prior to 37 weeks despite attending the clinic +/- receiving interventions & this group are the focus of this paper. The indications for surveillance in this group that had a recurrent sPTB included recurrent second-trimester pregnancy losses/preterm delivery < 34 weeks (26/36 (72%)), cervical trauma (including treatment of CIN) (12/36 (33%)), congenital abnormalities (1/36 (2.8%)), uterine anomaly (1/36 (2.8%)) and placental bleeding (1/36 (2.8%)). There was one smoker in this series. Funnelling was observed in 3/36 cases (8.3%). Of the 36 patients, an additional 15 would have received a cerclage had gestation-specific centiles, i.e., <5th centile, been used and an additional 10/36 (28%) would have been offered progesterone therapy. CONCLUSION: In those at high risk of preterm birth, the use of gestation-specific centiles for cervical length increases the proportion of patients that would be eligible for cervical cerclage. It is unclear whether this would change clinical outcome.

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.

Postural prioritization is differentially altered in healthy older compared to younger adults during visual and auditory coded spatial multitasking.

Many daily activities require appropriate allocation of attention between postural and cognitive tasks (i.e. dual-tasking) to be carried out effectively. Processing multiple streams of spatial information is important for everyday tasks such as road crossing. Fifteen community-dwelling healthy older (mean age=78.3, male=1) and twenty younger adults (mean age=25.3, male=6) completed a novel bimodal spatial multi-task test providing contextually similar spatial information via separate sensory modalities to investigate effects on postural prioritization. Two tasks, a temporally random visually coded spatial step navigation task (VS) and a regular auditory-coded spatial congruency task (AS) were performed independently (single task) and in combination (multi-task). Response time, accuracy and dual-task costs (% change in multi-task condition) were determined. Results showed a significant 3-way interaction between task type (VS vs. AS), complexity (single vs. multi) and age group for both response time (p ≤ 0.01) and response accuracy (p ≤ 0.05) with older adults performing significantly worse than younger adults. Dual-task costs were significantly greater for older compared to younger adults in the VS step task for both response time (p ≤ 0.01) and accuracy (p ≤ 0.05) indicating prioritization of the AS over the VS stepping task in older adults. Younger adults display greater AS task response time dual task costs compared to older adults (p ≤ 0.05) indicating VS task prioritization in agreement with the posture first strategy. Findings suggest that novel dual modality spatial testing may lead to adoption of postural strategies that deviate from posture first, particularly in older people. Adoption of previously unreported postural prioritization strategies may influence balance control in older people.

Farnesoid X receptor agonists attenuate colonic epithelial secretory function and prevent experimental diarrhoea in vivo.

OBJECTIVE: Bile acids are important regulators of intestinal physiology, and the nuclear bile acid receptor, farnesoid X receptor (FXR), is emerging as a promising therapeutic target for several intestinal disorders. Here, we investigated a role for FXR in regulating intestinal fluid and electrolyte transport and the potential for FXR agonists in treating diarrhoeal diseases. DESIGN: Electrogenic ion transport was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers or mouse tissues in Ussing chambers. NHE3 activity was measured as BCECF fluorescence in Caco-2 cells. Protein expression was measured by immunoblotting and cell surface biotinylation. Antidiarrhoeal efficacy of GW4064 was assessed using two in vivo mouse models: the ovalbumin-induced diarrhoea model and cholera toxin (CTX)-induced intestinal fluid accumulation. RESULTS: GW4064 (5 µmol/L; 24 h), a specific FXR agonist, induced nuclear translocation of the receptor in T84 cells and attenuated Cl(-) secretory responses to both Ca(2+) and cAMP-dependent agonists. GW4064 also prevented agonist-induced inhibition of NHE3 in Caco-2 cells. In mice, intraperitoneal administration of GW4064 (50 mg/mL) also inhibited Ca(2+) and cAMP-dependent secretory responses across ex vivo colonic tissues and prevented ovalbumin-induced diarrhoea and CTX-induced intestinal fluid accumulation in vivo. At the molecular level, FXR activation attenuated apical Cl(-) currents by inhibiting expression of cystic fibrosis transmembrane conductance regulator channels and inhibited basolateral Na(+)/K(+)-ATPase activity without altering expression of the protein. CONCLUSIONS: These data reveal a novel antisecretory role for the FXR in colonic epithelial cells and suggest that FXR agonists have excellent potential for development as a new class of antidiarrheal drugs.

Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line.

Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na(+) channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCalpha at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCalpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCbeta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I(TE)). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.

JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.

Bile acids in regulation of intestinal physiology.

In addition to their roles in facilitating lipid digestion and absorption, bile acids are recognized as important regulators of intestinal function. Exposure to bile acids can dramatically influence intestinal transport and barrier properties; in recent years, they have also become appreciated as important factors in regulating cell growth and survival. Indeed, few cells reside within the intestinal mucosa that are not altered to some degree by exposure to bile acids. The past decade saw great advances in the knowledge of how bile acids exert their actions at the cellular and molecular levels. In this review, we summarize the current understanding of the role of bile acids in regulation of intestinal physiology.

Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells.

In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl(-) and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl(-) secretion was measured as changes in short-circuit current across voltage-clamped T(84) cell monolayers. At high concentrations (0.5-1 mM), DCA acutely stimulated Cl(-) secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10-200 microM) inhibited responses to Ca(2+) and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids - taurodeoxycholic acid, chenodeoxycholic acid and cholic acid - had similar antisecretory effects. DCA (50 microM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity.