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Hypogammaglobulinemia (HGG) is well-characterized as a common phenomenon after kidney transplantation. However, no reports of pre-existing HGG from kidney transplantation seem to be available. We have reviewed three patients who developed HGG prior to kidney transplantation, and all three were treated successfully with immunoglobulin replacement therapy before and after kidney transplantation. The kidney grafts were functioning at follow-up 1.5-8 years (mean: 3.6 years) after transplantation, and there were no diagnosed episodes of clinical rejections and no severe infection complications post-transplantation. [ABSTRACT FROM AUTHOR]

Alpacas have evolved digestive and metabolic adaptations that enable them to survive in environments where the available feed varies in nutritional quality. Alpacas are thought to derive glucose from the deamination of amino acids in the liver, rather than via the conversion of propionate like true ruminants. Because fibre growth is dependent on the availability of absorbed amino acids, alpacas using amino acids as a source of energy should leave less amino acids available for fibre growth. If alpacas were to obtain glucose from a source of propionate, such as calcium propionate, the dependence on amino acids would be reduced leaving more available for fibre growth. Calcium propionate was added to the ration fed to 32 alpaca wethers, and fibre production was measured to monitor important fibre attributes in response to calcium propionate. Although the diets supplemented with calcium propionate should have provided more energy than the diets without calcium propionate, the metabolisable energy intake of all animals was similar (p = 0.278). It seems that rather than sparing amino acids, the alpacas regulated their energy intake and refused to consume the additional energy offered as calcium propionate. Consequently, they produced less fibre, and the diameter of their fibre was smaller than those alpacas that were not fed calcium propionate. It seems that alpacas rely on their digestive and metabolic adaptations to efficiently obtain and conserve energy for their survival. [ABSTRACT FROM AUTHOR]

Background Subcutaneous specific immunotherapy ( SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide ( AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. Objective To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. Methods Mice were immunized with various concentrations of Phleum pratense ( Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. Results Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. Conclusion The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. Clinical Relevance This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing. [ABSTRACT FROM AUTHOR]

Background The governing factor of both effector-cell activation and facilitated antigen presentation is IgE-repertoire complexity (IgE-clonality, -affinity and -concentration). Yet, the compositions of individual IgE repertoires and correlation between IgE-repertoire complexity and establishment of allergic sensitization remain to be determined. Objective In complex formation assays with recombinant IgE, allergen and CD23+ B cells, we assess the composition of serum IgE repertoires and examine the correlation between IgE-titre and IgE-repertoire complexity. Methods The capacity of sera, from house dust mite-sensitized individuals, to mediate IgE-Der p 2- CD23 complex formation on CD23+ B cells was measured. In parallel experiments, the effect of supplementing each serum with one or more Der p 2-specific monoclonal recombinant IgE antibodies on complex formation was determined. Results Only sera with the highest concentration of Der p 2-specific IgE resulted in complex formation without supplementary recombinant IgE. Intermediately titred sera supported complex formation to various degrees when supplemented with individual recombinant IgE. The degree of complex formation depended on the affinity and epitope specificity of the recombinant IgE. Complex formation by combining serum and recombinant IgEs could not be obtained with sera of relatively low titres of specific IgE. However, these sera had the capacity to dramatically enhance the low complex formation achieved with pairs of affinity-engineered recombinant IgEs. Conclusion and Clinical Relevance Serum IgE complexity can be indirectly assessed by combining sera with defined monoclonal IgEs in IgE-allergen- CD23 complex assays. The observed differences in epitope-coverage of Der p 2-specific serum-IgE in sera of different specific IgE titres indicate that increased IgE titres correlate with increased complexity of the IgE-repertoire. A detailed knowledge of the composition and complexity of allergen-specific IgE repertoires (and the relation to IgE titre), particularly in the early phase of sensitization, may be used to improve the prediction of the persistence and severity of allergic symptoms, as well as the progression of the Allergic March. [ABSTRACT FROM AUTHOR]

To cite this article: Shamji MH, Ljørring C, Francis JN, Calderon MA, Larché M, Kimber I, Frew AJ, Ipsen H, Lund K, Würtzen PA, Durham SR. Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy. Allergy 2012; 67: 217-226. Abstract Background: Induction of allergen-specific IgG4 antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG4 antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG4 titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. Methods: In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100 000 SQ-U, 10 000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG4 titres and IgG-associated inhibitory activity were evaluated. Results: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG4 antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = −0.25, P = 0.0002; IgE-blocking factor: r = −0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG4 levels ( r = −0.11, P = 0.12). Conclusions: Functional assays of inhibitory IgG4 and IgE-blocking factor may be more useful surrogates of clinical response than IgG4. Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation. [ABSTRACT FROM AUTHOR]

BERLAND A., RICHARDS J. & LUND K.D. (2010). A Canada-Bangladesh partnership for nurse education: case study. International Nursing Review 57, 352–358 Aim: To describe the lessons learned from a partnership in nurse education between a Bangladesh university and a group of Canadian volunteers. Background: In the host country, nursing enjoys low status and pay, which adversely affect professional standards. Method: The paper describes implementation details of training a core of nurses to international standards, using limited resources. The first cohort received their Bachelor of Nursing degrees in 2009. Outcomes: The Bangladeshi partners benefit from access to up-to-date curriculum materials, current clinical expertise, and interaction with visiting faculty and students. The Canadian nursing instructors enjoy professional development opportunities; visiting Canadian students gain exposure to a practice setting in a low-income country. Lessons learned: These include the importance of (1) integrating nurse training with a general university able to provide core courses (e.g. English as second language, computer training), (2) countering the low status of nursing and inculcating a caring attitude among students, and (3) instilling critical thinking as opposed to rote learning. Next, the following were identified: mechanisms to support networking in the local health system, sharing of resources (e.g. electronic course material adapted to host country context), and assuring programme quality. Implications for practice: The paper will be of interest to those concerned with nurse education and human resource development in less developed countries. [ABSTRACT FROM AUTHOR]

Current day practice of sublingual immunotherapy (SLIT) includes varying modalities of treatment that differ with regard to formulation, dosing and administration regimens. The aim of this study was to explore the importance of the dosing intervals in SLIT. The immunological effect of increased SLIT dosing frequency was tested in a mouse model of allergic inflammation. Mice sensitized to Phleum pratense ( Phl p) were SLIT-treated with the same weekly cumulative dose administered with different administration frequencies. A SLIT sham-treated group was also included. All mice were challenged intra-nasally with Phl p extract following SLIT. Local and systemic cytokine production, eosinophil infiltration into airways and the development of Phl p-specific antibody responses were determined. Higher frequency of sublingual administration of allergen extract has a profound positive impact on the effect of SLIT, measured as induction of IgG and IgA antibodies. The once daily SLIT was the only treatment regimen being able to reduce all systemic Th2 cytokines and systemic IgE antibody responses when compared to sham-treated mice after the intra-nasal challenge period. The group receiving SLIT with the highest frequency of administration had the most pronounced effect of the treatment. In the same group, there was also a higher degree of protection against increase in IgE antibody levels after intra-nasal challenge with the allergen, our data demonstrate that a once daily regimen is more efficacious than regimens where SLIT, with the same weekly cumulative allergen dose, is administered with longer intervals but higher doses. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of IgE-mediated allergic disease is closely related to the production of T-helper type 2 (Th2) cytokines, which lead to IgE production pivotal for activation of mast cells and basophils. Proliferating T cells along with eosinophils expanded and attracted by Th2 cytokines are major contributors to the late-phase reaction. The activation of these Th2 cells is strongly enhanced by CD23-mediated IgE facilitated allergen presentation (FAP). Objective The present study aims to investigate the effect of specific immunotherapy (SIT)-induced allergen-specific non-IgE antibodies (blocking antibodies) on IgE binding to allergen, histamine release (HR) and CD23-mediated allergen uptake in antigen-presenting cells. Methods Competition between IgE and non-IgE for allergen binding was studied by Advia Centaur antibody measurements, passively sensitized basophils were used to study HR and IgE-facilitated binding of allergen to B cells (FAP) was studied by flow cytometry. FAP measurements were performed both with and without the addition of a reference IgE serum, which was included to obtain optimal complex formation. The serum samples were obtained from birch pollen immunotherapy ( n=21) or placebo control patients ( n=21) before and after 1 and 2 years of treatment. Results Statistically significant reduction of all parameters investigated was observed after 1 year of treatment and the effect was maintained during the second year of treatment. There was a clear correlation between the two FAP measurements and between each of them and the level of T cell activation reported upon previously. Moreover, strong correlations were found between changes in FAP, IgE binding and HR. Conclusion The present study clearly demonstrates that SIT induces changes in the composition of serum antibodies that inhibit IgE binding, HR and FAP to a similar extent. This suggests that these measurements, individually or in combination, may be used to monitor the immunological effect of SIT, even though direct correlations to changes in clinical parameters could not be demonstrated. [ABSTRACT FROM AUTHOR]

Background Sublingual immunotherapy (SLIT) is a clinically effective treatment in both pollen and house dust mite-induced rhinitis and asthma. However, the mechanisms by which this is accomplished are not clear. Objective The objective of the current study was to establish a mouse model of rhinitis in order to study the effect and mechanisms of SLIT. Methods Mice were sensitized by intraperitoneal injections of alum-adsorbed Phleum pratense extract. Sensitized mice were SLIT-treated and subsequently challenged intranasally and analysed for clinical symptoms, antibody levels, eosinophilia and T cell response. Results Intranasal challenge of sensitized mice led to the development of rhinitis characterized by significantly increased sneezing and influx of eosinophils into the nose. Levels of specific IgE were fivefold increased in nasopharyngeal lavage (NAL) fluid and more than doubled in serum. Furthermore, a T-helper type 2 (Th2) like T cell response was observed in local draining lymph nodes. SLIT treatment of sensitized mice reduced sneezing, eosinophilia and IgE levels in the NAL by more than 50%. Moreover, serum levels of IgE and IgG1 as well as T cell response in the draining lymph nodes were also significantly reduced. Treatment for a shorter time or with a lower dose only led to minor reductions of the clinical and immunological parameters, indicating that the effect of SLIT is time and dose dependent. Conclusion In the present study, we have established a mouse model displaying the hallmarks of allergic rhinitis using a clinically relevant allergen. Using this model, we have demonstrated that SLIT treatment is able to reduce allergic symptoms in a time- and dose-dependent manner. [ABSTRACT FROM AUTHOR]

Design of educational multimedia rarely starts from scratch, but rather by attempting to reuse existing software. Although redesign has been an issue in research on evaluation and on learning objects, how it should be carried out in a principled way has remained relatively unexplored. Furthermore, understanding how empirical research on information and communication technologies (ICT) should feed back into redesign remains difficult. The present paper addresses these problems from the viewpoint of carrying out pedagogical expert evaluations, in the absence of empirical studies of target learners, in order to generate recommendations for redesign. Firstly, redesign proposals should be based on a coherent reconstruction of pedagogical foundations of educational ICT (software, documentation). Secondly, redesign proposals should result from dialogue between stakeholders, such as future users, pedagogical experts, software designers, and deciders. To these ends, we propose a framework, called GESTALT ( Goals, ( E) Si Tuations, Actions, Learners, Tools), as a ‘boundary object’ for dialogical redesign. Within an activity theory approach, GESTALT is based on analysis of available tools, the actions they support, the characteristics of learners who perform actions, and pedagogical goals that could be achieved in specific situations. An illustrative GESTALT analysis of educational software is provided, principally from the viewpoint of pedagogical experts. Finally, the strengths and limits of GESTALT are discussed. [ABSTRACT FROM AUTHOR]

Background: The low reproducibility of the QT dispersion (QTD) method is a major reason why it is not used in clinics. The purpose of this study was to develop QT dispersion parameters with better reproducibility and identification of patients with a high risk of ventricular arrhythmia or death.Methods and Results: Three institutions using different methods for measuring QT intervals provided QT databases, which included more than 3500 twelve-lead surface ECGs. The data represented low and high risk subjects from the following groups: the normal population EpiSet (survivors vs dead from cardiovascular causes), acute myocardial infarction patients AmiSet (survivors vs dead) and remote myocardial infarction patients ArrSet (with vs without a history of ventricular arrhythmia). The EpiSet, AmiSet, and the ArrSet contributed with N = 122, 0, and 110 ECGs for reproducibility analysis, and 3244, 446, and 100 ECGs for the analysis of prognostic accuracy. The prognostic accuracy was measured as the area under the Receiver Operator Curve. The QT intervals were divided into six QT pairs; the longest pair consisted of the longest and the shortest QT intervals etc. The QT dispersion trend (QTDT) was defined as the slope of the linear regression of the N longest QT pairs after estimation of missing QT intervals by interpolation of measured QT intervals. The QTMAD and the QTSTD methods were defined as twice the mean absolute deviation and the standard deviation of the N longest QT pairs. The reproducibility was improved by 27% and 19% in the EpiSet and the ArrSet relative to the reproducibility of QTD. The accuracy improved for the EpiSet and the ArrSet and was maintained for the AmiSet.Conclusions: By using the three longest and the three shortest QT intervals in QTDT, QTMAD, or QTSTD, the reproducibility improved significantly while maintaining or improving the prognostic accuracy compared to QTD. [ABSTRACT FROM AUTHOR]

Background: Prolonged QT dispersion (QTD) is associated with an increased risk of arrhythmic death but its accuracy varies substantially between otherwise similar studies. This study describes a new type of bias that can explain some of these differences.Material: One dataset (DiaSet) consisted of 356 subjects: 169 with diabetes, 187 nondiabetic control persons. Another dataset (ArrSet) consisted of 110 subjects with remote myocardial infarction: 55 with no history of arrhythmia and 55 with a recent history of ventricular tachycardia or fibrillation.Methods: 12-lead surface ECGs were recorded with an amplification of 10 mm/mV at a paper speed of 50 mm/s. The QT interval was measured manually by the tangent-method. The bias depends on the magnitude of the measurement errors and the measurable part of the bias increases with the number of the repeated measurements of QT.Results: The measurable bias was significant for both datasets and decreased for increasing QTD in the DiaSet (P < 0.001) and in the ArrSet (P = 0.11). The bias was 2.5 ms and 1.9 ms at QTD = 38 ms and 68 ms, respectively, in the ArrSet, and 7.5 ms and 2.8 ms at QTD = 19 ms and 55 ms, respectively, in the DiaSet.Conclusions: This study shows that random measurement errors of QT introduces a type of bias in QTD that decreases as the dispersion increases, thus reducing the separation between patients with low versus high dispersion. The bias can also explain some of the differences in the mean QTD between studies of healthy populations. Averaging QT over three successive beats reduces the bias efficiently. [ABSTRACT FROM AUTHOR]

- Urinary excretion of glycosaminoglycans (GAGs) was studied in 9 anaesthetised dogs and 10 patients with single kidneys. The animals were studied for 4 to 5 hours after administration of shock waves to 1 kidney, the contralateral organ serving as control. Urinary excretion of GAGs was measured on both sides. The patients were studied 0 to 24 and 32 to 56 h after extracorporeal shock wave lithotripsy (ESWL). In the animals an increased mean urinary excretion of GAGs was observed on both sides; this was more marked in the treated kidney. The increase reflects tissue injury in the exposed kidney induced by the extracorporeal shock waves. No increase in mean urinary excretion of GAGs was observed in the patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to a study about the potential perioperative use of dexmedetomidine, a sedative medication.

The article presents a case study of a 69-year-old woman with vomiting and intermittent right upper quadrant pain. The patient underwent ultrasound scan, which revealed multiple gallstones in a thick walled gallbladder. She also underwernt other tests such as an X-ray, computed tomography (CT) scan of the abdomen, and magnetic resonance cholangiopancreatography (MRCP). A diagnosis of Bouveret's syndrome was made, which usually needs surgical or endoscopic treatment.

Background & Aims: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) is a non-invasive diagnostic biomarker of liver fibrosis. It is uncertain if LSM can predict risk for future liver-related outcomes in large, heterogenous populations., Methods: This Swedish multi-centre cohort study included patients (n = 14 414) from 16 sites who underwent LSM by VCTE between 2008 and 2020. Outcomes were ascertained from national registers. We investigated progression to cirrhosis with portal hypertension or hepatocellular carcinoma (HCC), separately. Cox regression was used to obtain hazard ratios (HRs). Harrel's C-index was used to measure discrimination of VCTE., Results: Included patients had a median age of 46 (interquartile range 34-57), median LSM of 5.9 kPa (4.6-8.0), 59% were male, and the majority had hepatitis C (50.1%). During a median follow-up of 5.9 (4.3-8.0) years, 402 patients (2.7%) developed cirrhosis with portal hypertension. In patients with an LSM ≥25 kPa, 28.7% developed cirrhosis with portal hypertension within 5 years of follow-up, while only .6% of patients with an LSM <10 kPa did. This translated to a HR of 48.3 (95% confidence interval = 37.6-62.0). VCTE had a high discriminative ability, with C-indices above .80 for most liver diseases, including .82 for MASLD. Similar findings were seen for incident HCC., Conclusions: Increased LSM by VCTE was associated with an increased risk of progression to both cirrhosis with portal hypertension, and to HCC, and had a high discriminative ability across different aetiologies of chronic liver diseases. These results support the use of VCTE to guide follow-up and treatment decisions., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: The risk of chronic opioid use after surgery for Crohn's disease (CD) is not known., Aim: The aim of this study is to examine the chronic opioid use after surgery according to age at time of surgery and to opioid use prior to surgery., Methods: This nationwide cohort study included patients with a first surgery for CD (January 1, 1996 through 2021). We examined prescribed opioids 9 months after surgery and estimated adjusted odds ratios (OR) for chronic opioid use in elderly (≥60 years), adults (≥40 and <60 years), and young adults (≥18 and <40 years) according to opioid use prior to surgery. Chronic opioid use was defined as prescriptions in at least two of three consecutive quarters., Results: A total of 797 patients had surgery as elderly, 1603 as adults, and 2786 as young adults. Across all age groups, 18%-38% received opioid prescriptions throughout 9 months after surgery, if opioids were prescribed prior to surgery. If opioids were not prescribed prior to surgery, the corresponding proportions were 2%-5%. If patients were prescribed opioids (≥1) prior to surgery, the adjusted ORs (95% CIs) for their chronic use after surgery in elderly, adults, and young adults were 10.37 (6.77-15.88), 10.48 (7.74-14.19), and 6.55 (4.93-8.72), respectively., Conclusion: Clinicians should be aware that in patients with a need for opioids before surgery, the surgery may not change the need for opioids. Future research should examine effective analgesic strategies that help minimise opioid use in this population., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children., Objectives: This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception., Materials and Methods: All live-born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups., Results: There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06-1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02-1.11) and 1.02 (CI: 0.97-1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram., Discussion and Conclusion: Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period., (© 2024 American Society of Andrology and European Academy of Andrology.)

Background and Aim: Paternal use of analgesics during the time of conception and adverse birth outcomes are poorly studied. We investigated the association between paternal exposure to non-steroid anti-inflammatory drugs and opioids within 3 months before the date of conception and the risk of adverse birth outcomes (preterm birth, small for gestational age, low Apgar score, and major congenital malformations)., Methods: We used nationwide data from the Danish health registers. We included information on all singleton live births, and their fathers and mothers from 1997 to 2018. We created two exposed cohorts, children with preconception paternal exposure to (1) non-steroid anti-inflammatory drugs and (2) opioids. The unexposed cohort was children without preconception paternal exposure to non-steroid anti-inflammatory drugs or opioids, and we performed a sub-analysis against paternal use of acetaminophen (paracetamol). We used logistic regression models to estimate the odds ratios of adverse birth outcomes including 95% confidence intervals., Results: We identified 1,260,934 children, 45,667 children with paternal exposure to non-steroid anti-inflammatory drugs, 10,086 children with paternal exposure to opioids, and 1,205,181 unexposed children. The adjusted odds ratio for preterm birth was 1.08 (95% confidence interval, 1.03-1.13) after paternal exposure to non-steroid anti-inflammatory drugs and 1.21 (95% confidence interval, 1.08-1.35) after paternal exposure to opioids. The adjusted odds ratio for small for gestational age was 1.09 (95% confidence interval, 1.03-1.17) after paternal exposure to non-steroid anti-inflammatory drugs, and 1.03 (95% confidence interval, 0.88-1.21) after paternal exposure to opioids. We found null-associations for a low Apgar score and major congenital malformations. Estimates were attenuated when compared against paternal paracetamol exposure., Conclusions: Overall, we found null-associations across the comparisons made. Weak associations were found for paternal exposure to non-steroid anti-inflammatory drugs or opioids and preterm birth and small for gestational age, but not with low Apgar score or major congenital malformation. All associations were attenuated when compared against an active comparator of paternal paracetamol exposure. The effect sizes were small and less likely to be of clinical relevance., (© 2023 American Society of Andrology and European Academy of Andrology.)

Objective: In patients with elderly (≥60 years) onset inflammatory bowel disease (IBD), we studied initiation of medications, drug persistency and surgeries., Design: A nationwide cohort study based on Danish registries, comprising incident IBD patients ≥18 years from 1995 to 2020 (N = 69,039). Patients were divided into elderly (N = 19,187) and adult onset (N = 49,852). Outcomes were initiation of thiopurines, 5-ASA, biologics and corticosteroids within 1 and 5 years after diagnosis, and for those who initiated medications, we estimated drug persistency. Surgeries were examined within 1 and 5 years. We used regression models controlling for covariates., Results: In elderly patients, the adjusted hazard ratios (aHR) for initiating thiopurines, 5-ASA and biologics within 1 year were 0.44 (95% CI 0.42-0.47), 0.77 (95% CI 0.75-0.79) and 0.29 (95% CI 0.26-0.31) respectively. The results were similar within 5 years. In elderly patients, drug persistency for thiopurines, 5-ASA and biologics was not impaired within 5 years. The aHR of stopping steroids within 1 and 5 years were 0.80 (95% CI 0.76-0.84) and 0.77 (95% CI 0.74-0.80) respectively. The risk of surgeries was increased in the elderly patients (in ulcerative colitis, within 5 years, aHR 1.39 [95% CI 1.27-1.52], and in Crohn's disease 1.13 [95% CI 1.04-1.23])., Conclusion: We found significantly low chance of initiation of IBD medications in elderly patients, the reason may not be due to mild disease course. In elderly patients, drug persistency was comparable to adults. Clinicians should carefully consider whether they underuse IBD-specific medications in elderly patients, and special attention should be applied to timely discontinuation of corticosteroids., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The long-term effects of anti-TNFα therapy in ulcerative colitis are debatable., Aim: To examine whether anti-TNFα therapy changed the colectomy proportion and reduced the use of corticosteroids., Methods: A nationwide cohort study among patients (age 0-20) diagnosed with ulcerative colitis through 1995-2015 from Danish health registries. We calculated the cumulative 5-year risk of colectomy after diagnosis and used a Cox regression model for comparison between a historical pre-anti-TNFα cohort 1 (1995-2003) and a cohort 2 for the era of anti-TNFα (2004-2015). Based on anti-TNFα users, defined as patients who had at least four anti-TNFα treatments within 4 months, we examined the subsequent need for corticosteroids., Results: We identified 3001 patients from 1995 to 2015. The 5-year cumulative proportion of colectomy in cohort 2 was 9.7% (95% confidence interval [CI] 8.4-11.1) and 12.3% (95% CI 10.4-14.6) in cohort 1. The adjusted 5-year hazard ratio (HR) was 0.76 (95% CI 0.60-0.96) for colectomy in cohort 2 compared to cohort 1. A total of 334 patients received anti-TNFα treatments, and 16.8% (56/334) were prescribed corticosteroids in the subsequent 3-month period. Corticosteroid treatment declined with follow-up after 6 and 12 months, 5.4% and 1.2%, respectively., Conclusion: In patient's ≤20 years, the HR for colectomy within a period of 5 years from the time of diagnosis was reduced in the era of anti-TNFα compared to a historical cohort. In patients treated with anti-TNFα, prescriptions of corticosteroids were virtually ceased after 12 months., (© 2019 John Wiley & Sons Ltd.)

Background: This randomized, double-blind trial was conducted to determine the optimal dose for clinical efficacy of the SQ tree SLIT-tablet. An environmental exposure chamber (EEC) was used to reduce variability of allergen exposure and allow investigation of symptom reduction towards different species from the birch homologous group in separate EEC sessions., Methods: Eligible subjects (N = 219) were randomized to receive treatment with placebo or the SQ tree SLIT-tablet (2, 7, or 12 DU) for 24 weeks. EEC pollen challenges were conducted outside the birch pollen season and included four birch and two oak EEC sessions. The primary efficacy endpoint was the average allergic rhinoconjunctivitis (ARC) total symptom score (TSS) after 24 weeks of treatment., Results: There was a statistically significantly lower TSS during the 24-week birch EEC session for 7 DU and 12 DU compared to placebo with relative differences of 24% (P = 0.03) and 25% (P = 0.02). For the 24-week oak EEC session, there was a statistically significant difference for 12 DU (24%, P = 0.03). IgE and IgG4 measurements supported these findings and demonstrated cross-reactivity to all other species within the birch homologous group. Treatment was well-tolerated with the most frequently reported adverse reactions being the local reactions in the oral cavity of mild-to-moderate severity., Conclusion: This trial demonstrates that the SQ tree SLIT-tablet reduce ARC symptoms triggered by birch or oak pollen. The optimal dose for further development was 12 DU. Clinical and immunological findings suggest that the tablet may be used to treat allergies to all species within the birch homologous group., (© 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Poor warfarin control with resultant high International Normalized Ratios (INRs) and bleeding events is most common during the first months of treatment. The effects of genetic polymorphisms at the vitamin K epoxide reductase [VKORC1] and cytochrome P450 2C9 [CYP2C9] loci have been increasingly acknowledged as contributory factors of enhanced warfarin sensitivity. In our prospective, blinded study, 557 patients (49·1% male, mean age 65·4 years, range 18-91 years) commencing warfarin (target INR 2·5) were genotyped and monitored through the first 3 months of anticoagulation. Homozygosity for the -1639 G>A single nucleotide functional promoter polymorphism of the VKORC1 gene (genotype AA; 14·5% of cases) was associated with a significantly shortened time to therapeutic INR ≥ 2 (P < 0·01), reduced stable warfarin dose (P < 0·01), and an increased number of INRs > 5 (P < 0·001) and occurrence of bleeding events (P < 0·01) during the first month, as compared to the GG genotype. CYP2C9 genetic variations *2 and *3 were not associated with significant effect on these factors. Neither VKORC1 nor CYP2C9 polymorphisms influenced these parameters beyond the first month of treatment. These findings imply possible benefits of assessing VKORC1 polymorphisms prior to anticoagulation, particularly as a low dose induction regime in VKORC1 AA individuals appears to reduce the incidence of high INRs., (© 2012 Blackwell Publishing Ltd.)

Background: Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response., Methods: In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated., Results: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG(4) antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = -0.25, P = 0.0002; IgE-blocking factor: r = -0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG(4) levels (r = -0.11, P = 0.12)., Conclusions: Functional assays of inhibitory IgG(4) and IgE-blocking factor may be more useful surrogates of clinical response than IgG(4). Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation., (© 2011 John Wiley & Sons A/S.)