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Archives of Times Past: Conversations about South Africa's Deep History explores particular sources of evidence on southern Africa's time before the colonial era. It gathers recent ideas about archives and archiving from scholars in southern Africa and elsewhere, focusing on the question: 'How do we know, or think we know, what happened in the times before European colonialism?' Historians who specialise in researching early history have learnt to use a wide range of materials from the past as source materials. What are these materials? Where can we find them? Who made them? When? Why? What are the problems with using them? The essays by well-known historians, archaeologists and researchers engage these questions from a range of perspectives and in illuminating ways. Written from personal experience, they capture how these experts encountered their archives of knowledge beyond the textbook. The book aims to make us think critically about where ideas about the time before the colonial era originate. It encourages us to think about why people in South Africa often refer to this 'deep history' when arguing about public affairs in the present. The essays are written at a time when public discussion about the history of southern Africa before the colonial era is taking place more openly than at any other time in the last hundred years. They will appeal to students, academics, educationists, teachers, archivists, and heritage, museum practitioners and the general public. Archives of Times Past explores particular sources of evidence on southern Africa's time before the colonial era. It gathers recent ideas about archives and archiving from scholars in southern Africa and elsewhere, focusing on the question: 'How do we know, or think we know, what happened in the times before European colonialism?' The essays by well-known historians, archaeologists and researchers engage these questions from a range of perspectives and in illuminating ways. Written from personal experience, they capture how these experts encountered their archives of knowledge beyond the textbook. The essays are written at a time when public discussion about the history of southern Africa before the colonial era is taking place more openly than at any other time in the last hundred years They will appeal to students, academics, educationists, teachers, archivists, and heritage, museum practitioners and the general public.

Background: Many women of childbearing age with inflammatory bowel disease (IBD) require advanced therapies. While biologics are largely low risk during pregnancy, the novel small molecules tofacitinib, filgotinib, upadacitinib and ozanimod (TFUO) have shown concerning teratogenic effects, and decreased fertility in animal studies. Therefore, their use in women of childbearing age needs careful consideration. Design: RAND/University of California Los Angeles (UCLA) Appropriateness Method (RAM). Objective: To evaluate the appropriateness of TFUO in women of childbearing age. Methods: We convened a panel of six gastroenterologists, two IBD nurses, one IBD pharmacist and three expert patients. Following a literature review, 13 statements were drafted and voted upon in 2 rounds. Results: All 13 statements were deemed appropriate. The panel concluded that women with IBD of childbearing age who wish to commence therapy with TFUO, need to use effective contraception and be counselled regarding the risk in unplanned pregnancies. For women using contraception while on Janus kinase inhibitor (JAKi) therapy, we suggest the preferred use of progesterone-only or non-hormonal long-acting contraception. TFUO are contraindicated during pregnancy and breast feeding. We recommend that women receiving TFUO cease therapy in time to establish clinical remission for at least 3 months prior to conception. Therapies other than TFUO should be considered as first-line therapy in women with IBD of childbearing age, except in select individual circumstances. TFUO may be appropriate for women of childbearing age after failure of, intolerance or contraindications to one biological agent. Conclusion: TFUO should be avoided during pregnancy and breastfeeding, and alternative therapies should be considered as first-line treatments. Summary: We provide clinical practice recommendations regarding the use of TFUO for IBD in women of childbearing age. Plain language summary Small Molecules for Patients with IBD of Childbearing Age The maintenance of remission is vital for good fetal and maternal outcomes in IBD pregnancies and biological therapies used in IBD have been associated with favourable pregnancy outcomes. The safety profile of novel small molecules in human pregnancy is however largely unknown. We conducted a RAND appropriateness panel to agree recommendation son the use of Tofacitinib, Filgotinib, Upadacitinib and Ozanimod in women of childbearing age. Tofacitinib, Filgotinib, Upadacitinib and Ozanimod should be avoided during pregnancy due to serious concerns regarding birth defects. Small molecule therapies Tofacitinib, Filgotinib, Upadacitinib and Ozanimod should be given due consideration in the management of IBD in women of childbearing age, provided there are no immediate plans for conception. Counselling about potential risk of adverse effects during pregnancy, risk of venous thromboembolism and effective contraception are needed. Clinicians need to consider time to establish alternative therapies when switching away from Tofacitinib, Filgotinib, Upadacitinib and Ozanimod in the pre-conception period. Future research should examine pregnancy outcomes in cases where Tofacitinib, Filgotinib, Upadacitinib and Ozanimod exposure occurred but data may be difficult to compare to biologics due to differences in exposure duration. Guidelines should be updated as further maternal and fetal safety data become available

Experimental autoimmune epididymo-orchitis (EAEO) is a model of chronic inflammation, induced by immunisation with testicular antigens, which reproduces the pathology of some types of human infertility. Activins A and B regulate spermatogenesis and steroidogenesis, but are also pro-inflammatory, pro-fibrotic cytokines. Expression of the activins and their endogenous antagonists, inhibin and follistatin, was examined in murine EAEO. Adult untreated and adjuvant-treated control mice showed no pathology. All mice immunised with testis antigens developed EAEO by 50 days, characterised by loss of germ cells, immune cell infiltration and fibrosis in the testis, similar to biopsies from human inflamed testis. An increase of total CD45+ leukocytes, comprising CD3+ T cells, CD4 + CD8− and CD4 + CD25+ T cells, and a novel population of CD4 + CD8+ double positive T cells was also detected in EAEO testes. This was accompanied by increased expression of TNF, MCP-1 and IL-10. Activin A and B and follistatin protein levels were elevated in EAEO testes, with peak activin expression during the active phase of the disease, whereas mRNA expression of the inhibin B subunits ( Inha and Inhbb ) and activin receptor subunits ( Acvr1b and Acvr2b ) were downregulated. These data suggest that activin–follistatin regulation may play a role during the development of EAEO.

Recent data have indicated a relationship between placental oxygen and angiogenic protein levels in the first trimester of normal pregnancies. Our objective was to investigate if maternal serum levels of angiogenic factors Soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1), soluble Endoglin and placental growth factor (PlGF) are altered in women with symptoms of threatened miscarriage (TM) and if they are predictive of a subsequent miscarriage. Blood samples were collected at 6-10 weeks from women presenting with TM (n = 40), from asymptomatic controls (n = 32) and from non- pregnant women in their luteal phase (n = 14). All samples were assayed for serum level of sFLT-1, PlGF, sEndoglin and HSP70 using commercial ELISAs. Samples were analysed retrospectively on the basis of pregnancy outcome. TM group included 21 women with a normal pregnancy outcome and 19 with subsequent complete miscarriage. The latter subgroup had significantly lower mean maternal serum (MS) sFlt-1 (83%, P<0.001) and PlGF (44%, P<0.001) compared to those with a normal pregnancy outcome. Asymptomatic control pregnant women had similar MS levels of sFlt-1 and PlGF compared to the TM patients with a normal outcome. The mean MS sFlt-1 (>10 fold) and MS PlGF (∼2 fold) levels were significantly (P<0.001) higher in control pregnant women compared to the non-pregnant group in the luteal phase of the menstrual cycle. Soluble Endoglin was not altered in the normal pregnant women compared to non pregnant women, although lower in the TM subgroup with a subsequent miscarriage (∼25%, P<0.001) compared to TM with a live birth. There was no significant difference in the mean MS HSP 70 levels between the different groups. This study shows that sFlt1 and PlGF MS levels are increased by several folds in early pregnancy and that MS sFlt-1 and MS PlGF are markedly decreased in threatened miscarriage patients who subsequently have a miscarriage suggesting these proteins are sensitive predictive markers of subsequent pregnancy loss.

Background Investigations of activin family proteins as serum biomarkers for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). CFS/ME is a disease with complex, wide-ranging symptoms, featuring persistent fatigue of 6 months or longer, particularly post exertion. No definitive biomarkers are available. Methods A cross-sectional, observational study of CFS/ME patients fulfilling the 2003 Canadian Consensus Criteria, in parallel with healthy non-fatigued controls, was conducted. Comparisons with a previously defined activin reference population were also performed. For the total study cohort the age range was 18–65 years with a female: male participant ratio of greater than 3:1. All participants were assessed via a primary care community clinic. Blood samples were collected for pathology testing after physical examination and orthostatic intolerance assessment. Cytokines, activin A, activin B and follistatin were also measured in sera from these samples. All data were compared between the CFS/ME and control cohorts, with the activins and follistatin also compared with previously defined reference intervals. Results Serum activin B levels for CFS/ME participants were significantly elevated when compared to the study controls, as well as the established reference interval. Serum activin A and follistatin were within their normal ranges. All routine and special pathology markers were within the normal laboratory reference intervals for the total study cohort, with no significant differences detected between CFS/ME and control groups. Also, no significant differences were detected for IL-2, IL-4, IL-6, IL-10, IL-17A, TNF or IFN-gamma. Conclusion Elevated activin B levels together with normal activin A levels identified patients with the diagnostic symptoms of CFS/ME, thus providing a novel serum based test. The activins have multiple physiological roles and capture the diverse array of symptoms experienced by CFS/ME patients.

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment. Methods This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed. Results WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines. Conclusions The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

This article examines the colonial education project at the Cape of Good Hope during a time of transition, 1865-72. Whereas the first half of the 19th century had found the British colonial state prioritising a liberal programme of free, non-racial education, the discourses shifted in the second half of the century. The goal became gaining wider local support for state-aided schooling while reducing the costs of education through partnerships with 'inhabitants' or religious organisations. The project was the education, at varying levels, of the colonial youth. Identifying denominational competition as an impediment to progress in building effective partnerships, it was official policy to fund only 'secular' education. The focus of this article is on the transition to aided public schooling through Undenominational Public Schools (UPS) in four Cape villages. It follows the interventions of the head of Cape education in achieving 'one good public school' with colonists whom he categorised as 'able and willing to act for themselves'. It asks what the resulting messy processes and small struggles over schooling reveal about the meaning of public education in the Cape Colony in the 1860s and 1870s. It concludes that denominational identity was strong and 'secularity' problematic. For some, however, the prospects of social advancement gained through a UPS outweighed the costs of modifying a public Dutch and Dutch Reformed identity at school. For others, in a still fragile education system, local rejection of the UPS teacher could result in no schooling or temporary participation in the local mission school set up 'for education of the poor'.

BackgroundMany women of childbearing age with IBD require advanced therapies. While biologics are largely low risk during pregnancy, the novel small molecules Tofacitinib, Filgotinib, Upadacitinib and Ozanimod (TFUO) have shown concerning reproductive results in animal studies. Therefore, their use in women of childbearing age needs careful consideration.MethodsWe convened a RAND appropriateness panel of 6 gastroenterologists, 2 IBD nurses, 1 IBD pharmacist and 3 expert patients. Following a literature review, 13 statements were drafted and voted upon in 2 rounds.Results13 statements were voted on in two rounds. All statements were deemed appropriate after one round of revisions. Here we present a selection of key statements:Women with IBD of childbearing age who wish to commence therapy with TFUO, need to use effective contraception. Counselling regarding the risk of TFUO in unplanned pregnancies should be provided.For women using contraception while on JAK therapy, we suggest the preferred use of progesterone-only or non-hormonal long-acting contraception over combined oestrogen-progesterone formulations to reduce the risk of venous thromboembolism.TFUO are contraindicated during pregnancy due to serious teratogenicity concerns.Regardless of physical wash out periods, we recommend that women currently receiving TFUO cease therapy with enough time to establish clinical remission ideally for at least 3 months prior to conception. This window allows to safely establish whether the alternative (or no) therapy can maintain remission.Therapies other than TFUO should be considered as first line therapy in women with IBD of childbearing age, with the exception of select individual social or medical circumstances, or women who have completed family planning and agree to use effective contraception.TFUO may be appropriate choices for women of childbearing age after failure of, intolerance of or contraindications to one biological agent licensed for IBD.In women who wish to have children in the future, a minimum treatment period for TFUO should be considered. Where the wish to start a family is less than 1 year in the future it is recommended to consider agents other than TFUO.TFUO are contraindicated during breastfeeding.If a woman conceives while taking TFUO, the medication should be ceased, she should receive counselling about potential known and unknown maternofoetal complications, and alternative IBD therapy may be commenced if required.ConclusionWe developed 13 practice statements derived from a RAND appropriateness panel of clinicians and patients to guide decision making for women of childbearing age regarding TFUO small molecules therapies for IBD.

Pelvic radiotherapy can damage surrounding tissue and organs, causing chronic conditions including bowel symptoms. We systematically identified quantitative, population-based studies of patient-reported bowel symptoms following pelvic radiotherapy to synthesize evidence of symptom type, prevalence, and severity. Medline, CINAHL, EMBASE, and PsychINFO were searched from inception to September 2022. Following independent screening of titles, abstracts, and full-texts, population and study characteristics and symptom findings were extracted, and narrative synthesis was conducted. In total, 45 papers (prostate, n = 39; gynecological, n = 6) reporting 19 datasets were included. Studies were methodologically heterogeneous. Most frequently assessed was bowel function (‘score’, 26 papers, ‘bother’, 19 papers). Also assessed was urgency, diarrhea, bleeding, incontinence, abdominal pain, painful hemorrhoids, rectal wetness, constipation, mucous discharge, frequency, and gas. Prevalence ranged from 1% (bleeding) to 59% (anal bleeding for >12 months at any time since start of treatment). In total, 10 papers compared radiotherapy with non-cancer comparators and 24 with non-radiotherapy cancer patient groups. Symptom prevalence/severity was greater/worse in radiotherapy groups and symptoms more common/worse post-radiotherapy than pre-diagnosis/treatment. Symptom prevalence varied between studies and symptoms. This review confirms that many people experience chronic bowel symptoms following pelvic radiotherapy. Greater methodological consistency, and investigation of less-well-studied survivor populations, could better inform the provision of services and support.

BackgroundSteroid free remission is an important goal of IBD therapy. The aim of this study was to evaluate temporal changes in steroid prescribing in UK IBD outpatients in the context of major changes in UK prescribing guidelines and physician participation in audit and tailored service changes.MethodsSteroid use over the previous 12 months was recorded for unselected outpatient attenders against a definition of excess from ECCO guidelines. Data were collected from 7 centres that had completed a steroid assessment audit cycle in 2015, as well as from 12 new matched centres.ResultsData was collected for 2385 patients May-July 2017 and compared with 2015 data from 1176 patients. Overall disease distribution was 47.1% CD, 49.6% UC and 3.3% IBD-U, whilst 77.7% of patients were in clinical remission at the time of assessment. There was only a modest increase in patient exposure to anti-TNF from 2015 to 2017: 30.6% to 37.2% in CD (p=0.009) and 9.9% to 12.0% in UC (p=NS). Anti-integrin usage increased from 0.8% to 3.3% in CD (p=0.002) and from 1.6% to 2.4% in UC (p=NS). For centres taking part in the 2015 audit, steroid exposure rates fell from 30% to 23.8% (p=0.003) and steroid excess from 13.7% to 11.5% (p=NS). Steroid exposure and excess rates for sites that had not been part of the previous audit were significantly higher (31.0% excess, 17.1% exposure, p=0.0001 for both). There were no significant differences in important baseline characteristics of 2 groups of sites. Logistic regression analysis revealed independent predictors of reduced risk of steroid excess, after correction for disease severity. For CD these included treatment with anti-TNF therapy (p=0.04), treatment in a centre with regular IBD multidisciplinary team (MDT) meetings (p=0.01) and treatment in an original 2015 centre (p=0.02). For UC treatment in a 2015 centre was also significant predictor of protection (p=0.04) and treatment with thiopurine monotherapy a predictor of risk of excess (p=0.01); usage of anti-TNF therapy in UC did not reach significance for protection from excess.ConclusionsChanges in biologic access in the UK have resulted in only modest changes in prescribing behaviour and have not yet impacted significantly on excess steroid exposure in UC, unlike in CD. Participation in an audit cycle of steroid usage was associated with a meaningful reduction in steroid excess. These data support the concept that steroid excess could be used as a key performance indicator in IBD and physicians should be engaged in this process.