Flipped learning: Turning medical education upside down.

BACKGROUND: Flipped learning is an approach in which core teaching is delivered using online material viewed prior to face-to-face learning, applying knowledge gained from online material. Core teaching in a module for third-year undergraduate medical students was based around a 1-week course comprising 32 hours of lectures. Feedback suggested that students were poorly engaged and attendance was poor. OBJECTIVES: To develop and evaluate a programme of learning for medical students using flipped learning. METHODS: Core lectures were videoed and students were advised to watch online at home in the morning prior to a case-based interactive discussion session in the afternoon. Feedback was undertaken prior to and following change in delivery; changes in Likert scale feedback were assessed. Thematic assessment of free-text feedback was undertaken. Results of in-course assessment examinations were compared prior to and following change in delivery. RESULTS: Student feedback showed a significant improvement in satisfaction with flipped learning compared to standard lectures, both in scores and free-text feedback. Results of in-course assessments did not change between the two methods of delivery. CONCLUSIONS: Flipped learning can improve student satisfaction and engagement with teaching, but our study has not demonstrated an improvement in assessment scores.

Diagnostic Performance of a Saliva Urea Nitrogen Dipstick to Detect Kidney Disease in Malawi.

INTRODUCTION: Kidney disease (KD), including acute kidney injury, is common, severe and leads to significant mortality in the developing world. However, simple tools to facilitate diagnosis and guide treatment are lacking. We studied the diagnostic performance of saliva urea nitrogen (SUN) measured by dipstick to diagnose KD in a low-resource setting. METHODS: Medical admissions to a tertiary hospital in Malawi had serum creatinine tested at presentation; SUN was measured using a dipstick. Patients with serum creatinine above normal range underwent serial measurements of SUN and blood urea nitrogen for up to 7 days. Hospital outcome was recorded in all patients. RESULTS: A total of 742 patients were included (age 41 ± 17·3 years, 56.1% male); 146 (19.7%) had KD, including 114 (15.4%) with acute kidney injury. SUN >14 mg/dl had a sensitivity of 0.72 and a specificity of 0.87 to diagnose KD; specificity increased to 0.97 when SUN levels were combined with self-reported urine output. The diagnostic performance of SUN was comparable with the one of blood urea nitrogen (SUN area under curve, 0.82; 95% confidence interval, 0.78-0.87; blood urea nitrogen area under curve, 0.82; 95% confidence interval, 0.59-1.0). SUN >14 mg/dl on admission was an independent predictor of all-cause mortality (hazard ratio = 2.43 [95% confidence interval, 1.63-3.62]). DISCUSSION: SUN measured by dipstick can be used to identify patients with KD in a low-resource setting. SUN is an independent predictor of mortality in this population.

Incidence, aetiology and outcome of community-acquired acute kidney injury in medical admissions in Malawi.

BACKGROUND: Epidemiological data on Acute Kidney Injury (AKI) from low-income countries is sparse. The aim of this study was to establish the incidence, severity, aetiology, and outcomes of community-acquired AKI in Malawi. METHODS: We conducted a prospective observational study of general medical admissions to a tertiary hospital in Blantyre between 27th April and 17th July 2015. All patients were screened on admission with a serum creatinine; those with creatinine above laboratory reference range were managed by the nephrology team. Hospital outcome was recorded in all patients. RESULTS: Eight hundred ninety-two patients were included; 188 (21 · 1%) had kidney disease on admission, including 153 (17 · 2%) with AKI (median age 41 years; 58 · 8% HIV seropositive). 60 · 8% of AKI was stage 3. The primary causes of AKI were sepsis and hypovolaemia in 133 (86 · 9%) cases, most commonly gastroenteritis (n = 29; 19 · 0%) and tuberculosis (n = 18; 11 · 8%). AKI was multifactorial in 117 (76 · 5%) patients; nephrotoxins were implicated in 110 (71 · 9%). Inpatient mortality was 44 · 4% in patients with AKI and 13 · 9% if no kidney disease (p <0.0001). 63 · 2% of patients who recovered kidney function left hospital with persistent kidney injury. CONCLUSION: AKI incidence is 17 · 2% in medical admissions in Malawi, the majority is severe, and AKI leads to significantly increased in-hospital mortality. The predominant causes are infection and toxin related, both potentially avoidable and treatable relatively simply. Effective interventions are urgently required to reduce preventable young deaths from AKI in this part of the world.

A nurse-led intervention improves detection and management of AKI in Malawi.

BACKGROUND: Acute kidney injury is common and has significant impact on mortality and morbidity. There is a global drive to improve the lack of knowledge and understanding surrounding the recognition, diagnosis and management of patients with AKI in resource poor healthcare systems. OBJECTIVES: We propose a nurse-led education programme to medical and nursing staff of the Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi, will improve the overall care and understanding of patients with AKI that will still be effective 3 months later. METHODS: This was a three phase, prospective interventional pilot study which evaluated base line knowledge and clinical practice amongst healthcare workers, provided a comprehensive combination nurse-led class room and ward based teaching programme and evaluated the change in knowledge and clinical management of patients in the high dependency areas of the hospital immediately, and 3 months, after the teaching intervention. RESULTS: The nurse-led intervention significantly improved the healthcare workers attitudes towards detecting or managing patients with suspected AKI (p < 0.0001). There were also significant improvements in the completion of fluid charts and recording of urine output (p < 0.0001), corner stones of AKI management. Knowledge and clinical intervention was still present three months later. There was however little change in the understanding that AKI could be a significant clinical problem in QECH and that it may have a major impact on mortality and working practice and this needs to be addressed in future teaching programmes. CONCLUSIONS: A low cost, nurse-led AKI educational intervention improved the knowledge and management of AKI at QECH, which was still evident 3 months later.

Critically ill patients requiring acute renal replacement therapy are at an increased risk of long-term renal dysfunction, but rarely receive specialist nephrology follow-up.

BACKGROUND: Episodes of acute kidney injury (AKI) have been associated with the development of chronic kidney disease (CKD). However, follow-up pathways for patients who have survived AKI complicating critical illness are not well established. We hypothesised that patients who had AKI requiring renal replacement therapy (RRT) in intensive care are at risk of CKD, but are rarely referred for nephrology follow-up at hospital discharge. METHODS: We performed a retrospective analysis of all patients who survived AKI requiring renal replacement therapy in intensive care units (ICUs) in the East London region, examining renal function at baseline, hospital discharge and 3-6 months follow-up. We excluded patients who were known to renal services prior to index admission. RESULTS: From 5,544 critical care admissions, we identified 219 patients who survived to be discharged, having undergone RRT for AKI, that were not previously known to renal services. Of these, 124 (57%) had creatinine measured within 3-6 months after discharge, 104 having a pre-morbid baseline for comparison. Only 26 patients (12%) received specialist nephrology follow-up. At 3-6 months follow-up, the estimated glomerular filtration rate was significantly lower than baseline (48 vs. 60 ml/min/1.73 m(2); p < 0.001), with the prevalence of CKD stage III-V rising from 49 to 70% (p < 0.001). CONCLUSIONS: Follow-up of patients who required RRT for AKI in ICU is inconsistent despite evidence of a significant increase in the prevalence of CKD. There is strong justification for the development of robust pathways to identify survivors of AKI in order to detect and manage CKD and its complications.

The role of salt intake and salt sensitivity in the management of hypertension in South Asian people with chronic kidney disease: a randomised controlled trial.

BACKGROUND: The effectiveness of salt restriction to lower blood pressure (BP) in Bangladeshi patients with chronic kidney disease (CKD) is uncertain. OBJECTIVE: To test the hypothesis that a tailored intervention intended to reduce salt intake in addition to standard care will achieve a greater reduction in BP in UK Bangladeshi patients with CKD than standard care alone. DESIGN: A randomised parallel-group controlled trial conducted over a 6 month period. SETTING: A tertiary renal unit based in acute care hospital in East London. PARTICIPANTS: 56 adult participants of Bangladeshi origin with CKD and BP >130/80 mm Hg or on antihypertensive medication. INTERVENTION: Participants were randomly allocated to receive a tailored low-salt diet or the standard low-salt advice. BP medication, physical activity and weight were monitored. MAIN OUTCOME MEASURES: The primary outcome was change in ambulatory BP. Adherence to dietary advice was assessed by measurement of 24 h urinary salt excretion. RESULTS: Of 56 participants randomised, six withdrew at the start of the study. During the study, one intervention group participant died, one control group participant moved to Bangladesh. Data were available for the primary endpoint on 48 participants. Compared with control group the intervention urinary sodium excretion fell from 260 mmol/d to 103 mmol/d (-131 to -76, p<0.001) at 6 months and resulted in mean (95% CI) falls in 24 h systolic/diastolic BP of -8 mm Hg (-11 to -5)/2 (-4 to -2) both p<0.001. CONCLUSIONS: A tailored intervention can achieve moderate salt restriction in patients with CKD, resulting in clinically meaningful falls in BP independent of hypertensive medication. TRIAL REGISTRATION: ClinicalTrials.gov NCT00702312.

Presentation, diagnosis, and treatment outcome of tuberculous-mediated tubulointerstitial nephritis.

Insidious Mycobacterium tuberculosis infection causing tubulointerstitial nephritis is a rare disorder. Here we report on a single-center case series of patients with tubulointerstitial nephritis due to tuberculosis, addressing clinicopathologic features and treatment outcome. Twenty-five adult patients with clinical evidence of tuberculosis and significant renal disease were assessed, 17 of whom had a kidney biopsy and were subsequently diagnosed with chronic granulomatous tubulointerstitial nephritis as the primary lesion. All patients were given standard antitubercular treatment, with some receiving corticosteroids, and showed a good response in clinical symptoms and inflammatory markers. Nine of the 25 patients, however, started renal replacement therapy within 6 months of presentation. Of the remaining 16, renal function improved for up to a year after presentation but subsequently declined through a median follow-up of 36 months. This case series supports that chronic tubulointerstitial nephritis is the most frequent kidney biopsy finding in patients with renal involvement from tuberculosis. Thus, a kidney biopsy should be considered in the clinical evaluation of kidney dysfunction with tuberculosis since tubulointerstitial nephritis presents late with advanced disease. A low threshold of suspicion in high-risk populations might lead to earlier diagnosis and treatment, preserving renal function and delaying initiation of renal replacement therapy.

Direct micropuncture evidence that matrix extracellular phosphoglycoprotein inhibits proximal tubular phosphate reabsorption.

BACKGROUND: Matrix extracellular phosphoglycoprotein (MEPE) is a putative phosphatonin that we have shown in previous studies to be phosphaturic in rats. Its site of action in the nephron remains to be confirmed. METHODS: We made micropuncture collections from late proximal convoluted tubules in anaesthetized rats to assess directly the effect of MEPE on phosphate reabsorption in the proximal tubule. RESULTS: MEPE had no effect on glomerular filtration rate or single-nephron filtration rate, but it increased phosphate excretion significantly. In animals infused with vehicle alone (time controls), no significant change was seen in either the proximal tubular fluid:plasma phosphate concentration ratio (TF/P(Pi)) or the fraction of filtered phosphate reaching the late proximal convoluted tubule (FD(Pi)); whereas in rats infused with MEPE, TF/P(Pi) increased from 0.49 ± 0.07 to 0.68 ± 0.04 (n = 22; P = 0.01) and FD(Pi) increased from 0.20 ± 0.03 to 0.33 ± 0.03 (n = 22; P < 0.01). CONCLUSIONS: The results confirm the phosphaturic effect of MEPE and indicate that much, if not all, of this effect is a result of reduced reabsorption of phosphate in the proximal convoluted tubule. This is consistent with the recent finding of MEPE-induced reductions in apically located NaPT2a in the proximal tubule.

Matrix extracellular phosphoglycoprotein causes phosphaturia in rats by inhibiting tubular phosphate reabsorption.

BACKGROUND: Matrix extracellular phosphoglycoprotein (MEPE), first isolated from tumour-derived tissue from a patient with oncogenic hypophosphataemia, is a putative phosphatonin that has received much less attention than fibroblast growth factor-23. To date, its effect on renal tubular phosphate reabsorption remains undefined. METHODS: A renal clearance study was performed in anaesthetized rats infused intravenously with a range of doses of MEPE. RESULTS: MEPE had no effect on glomerular filtration rate (inulin clearance) but caused rapid, dose-dependent increases in absolute and fractional phosphate excretion, wholly attributable to reduced phosphate reabsorption. At a maximal dose, MEPE increased fractional phosphate excretion more than 2-fold, whereas no change was observed in time controls. CONCLUSION: The results lend support to the hypothesis that MEPE contributes to the phosphaturia of oncogenic hypophosphataemia and of hypophosphataemic rickets.

Simultaneous determination of anions in nanoliter volumes.

BACKGROUND: The study of renal tubular transport requires the ability to accurately measure ion concentrations in samples taken from single tubules. Sample collection and analysis are laborious, so methods allowing determination of multiple ion species in a small volume sample are advantageous. This article describes a method for the simultaneous analysis of anions at physiologic concentrations in nanoliter volumes of tubular fluid. METHOD: The analysis is performed using capillary zone electrophoresis. Diluted samples are moved along a capillary by bulk transport and separated according to charge and size. Peaks corresponding to anions are obtained by ultraviolet (UV) detection; peak area is proportional to ion concentration. RESULTS: The anions chloride, nitrate, citrate, phosphate, and bicarbonate were separated in less than 4 minutes, and iothalamate in less than 5 minutes. Simultaneous quantitative analysis was performed for chloride, phosphate, and bicarbonate, demonstrating detection limits of 12 fmol for chloride, 12 fmol for phosphate, and 72 fmol for bicarbonate. A comparison between this method and a flow-through microfluorimeter analysis of chloride showed good agreement between the two micro-methods. Illustrative data from proximal and distal tubular fluid samples obtained by micropuncture (volume 30-70 nL) are given, as are results from urine samples. RESULTS: Results for chloride, phosphate, and bicarbonate in control material are in close agreement with the certified values, while values in tubular fluid are in accordance with previously published results. CONCLUSION: This method provides a straightforward means of analyzing multiple anions in small volume biological samples.

Clinical predictors of bloodstream infections and mortality in hospitalized Malawian children.

BACKGROUND: In sub-Saharan Africa, bloodstream infections (BSI) are a major cause of pediatric mortality. Because of limited resources and facilities in these developing countries, treatment often must be based solely on clinical observations and patient history and includes the use of broad spectrum antimicrobials, a factor in the emergence of antibiotic resistance. METHODS: During July 28 through August 18, 1998 we analyzed clinical, epidemiologic and microbiologic data from a cohort of 225 hospitalized children in Malawi, Africa, to determine clinical indices associated with the presence/absence of BSI and/or mortality for use in settings with minimal microbiologic laboratory and intensive care facilities. RESULTS: BSI (n = 35 children) were associated with malnutrition, chronic cough, lethargy by history, lethargy on examination and oral thrush; 92% of children without these symptoms were BSI-negative. Mortality (21 of 173 children with known mortality status) was associated with malnutrition, lethargy on examination, prior receipt of antimalarials and acute decreased feeding. Of those with > or =2 of these indices 69% died; of those with <2 of the indices 94% survived. Infection with human immunodeficiency virus was not significantly related to either BSI or mortality status. CONCLUSIONS: Malnutrition, but not HIV, was strongly related to both BSI and mortality. Assessment of these BSI and mortality indices at hospital admission provides rapid, cost-free indication of which children are most/least in need of empiric antimicrobial therapy or intensive observation, thereby maximizing appropriate use of antimicrobials and limited facilities while minimizing inappropriate antimicrobial usage.

A randomized controlled trial of an educational intervention to improve phosphate levels in hemodialysis patients.

OBJECTIVE: To determine the effect of a dietetic educational intervention on phosphate and calcium levels of hemodialysis patients. DESIGN: Parallel-group randomized controlled trial. SETTING: Teaching hospital hemodialysis unit in London, England. PATIENTS: Fifty-six stable adult hemodialysis patients with hyperphosphatemia. INTERVENTION: An educational intervention and one-to-one teaching session given by a renal dietitian, attempting to improve patients' knowledge of phosphate management and their compliance with diet and medication. OUTCOME MEASUREMENT: Patients' serum phosphate, calcium, and calcium x phosphate products in the 3 months after the intervention, compared with those before the intervention. Results were also compared with a control group that had not undergone the intervention. RESULTS: In the intervention group, serum phosphate was significantly reduced after the education session, as compared with the results previously. In the control group, there was no significant change in serum phosphate level. The improved results were sustained over a period of 3 months. Serum calcium increased in the intervention group, but this result was not significant. There was an improvement in the calcium-phosphate product in the intervention group, but again this was not significant. CONCLUSION: Dietetic educational intervention can favorably alter patients' serum phosphate levels, with potential impact on morbidity and mortality.

Peripheral blood cell-specific cytokines in persons with untreated HIV infection in Malawi, Africa.

Human immunodeficiency virus (HIV) infection is the primary cause of morbidity and mortality in Malawi, Africa, because of its many effects on the immune system. Immune cells communicate through cytokines; therefore, we examined the relationships between HIV serostatus and cell-specific cytokine production for 40 asymptomatic, employed adults and 312 acutely ill, hospitalized patients in Malawi. We also measured the plasma HIV-1 RNA levels of 13 asymptomatic persons and 83 patients found to be HIV(+). We incubated peripheral whole blood with brefeldin-A +/- phorbol 12-myristate 13-acetate and ionomycin and then permeabilized, fixed, fluorescently stained, and examined the mononuclear cells with four-color, six-parameter flow cytometry. The percentage of lymphocytes expressing CD4 did not differ significantly between the HIV(+) and HIV(-) healthy adults (medians, 35.2 vs. 40.8%, respectively), but a wide array of cytokine parameters were lower in the HIV(+) than in the HIV(-) asymptomatic persons, for example, median percentages of T cells producing induced interleukin 2 (IL-2) (8.7 vs. 16.5%, respectively) and spontaneously producing IL-6 (0.7 vs. 11.0%, respectively). Also, four T cell parameters reflecting type 2-to-type 1 cytokine balances (T2/T1) were higher in the HIV(+), versus HIV(-), asymptomatic persons. Unlike the healthy adults, for patients with mycobacteremia/fungemia or malaria, the HIV(+) patients had higher median percentages of T cells and CD8(+) T cells producing induced interferon gamma than did the HIV(-) PATIENTS: For both asymptomatic and acutely ill persons, HIV-1 plasma levels were positively correlated with T2/T1 parameters. Cell-specific cytokine effects of HIV infection may precede measurable effects on CD4 expression. Cytokine therapies, even beyond periodic administration of IL-2, may improve the responses of HIV-infected persons to both HIV and coinfections.

Clinical and immune impact of Mycobacterium bovis BCG vaccination scarring.

The World Health Organization recommends Mycobacterium bovis BCG vaccination in areas of high tuberculosis prevalence. BCG's clinical and immune effects, not necessarily Mycobacterium tuberculosis specific, are unclear. BCG vaccine scarring often is used as a surrogate marker of vaccination or of effective vaccination. We evaluated BCG scarring status in relation to clinical findings and outcome in 700 hospitalized Malawians, of whom 32 had M. tuberculosis bloodstream infections (BSI) (10 of whom had cellular immune studies done) and of whom 48 were infants <6 months old and therefore recently vaccinated (19 of whom had immune studies). In the patients >/=6 months old, scarring was not related to the presence of pulmonary symptoms (35 versus 30%), chronic cough or fever, mortality, or M. tuberculosis BSI. In M. tuberculosis BSI patients, scarring was unrelated to mortality, vital signs, or clinical symptoms but those with scarring had higher proportions of memory and activated T cells and more type 2-skewed cytokine profiles. Infants with either BCG scarring (n = 10) or BCG lesional inflammation (n = 5) had no symptoms of sepsis, but 18 of 33 infants without BCG vaccination lesions did. Those with BCG lesions had localized infections more often than did those without BCG lesions. These infants also had lower median percentages of lymphocytes spontaneously making interleukin-4 (IL-4) or tumor necrosis factor alpha (TNF-alpha) and lower ratios of T cells spontaneously making IL-4 to T cells making IL-6. Thus, we found that, in older patients, BCG vaccine scarring was not associated with M. tuberculosis-specific or nonspecific clinical protection. Those with M. tuberculosis BSI and scarring had immune findings suggesting previous M. tuberculosis antigen exposure and induction of a type 2 cytokine pattern with acute reexposure. It is unlikely that this type 2 pattern would be protective against mycobacteria, which require a type 1 response for effective containment. In infants <6 months old, recent BCG vaccination was associated with a non-M. tuberculosis-specific, anti-inflammatory cytokine profile. That the vaccinated infants had a greater frequency of localized infections and lesser frequency of sepsis symptoms suggests that this postvaccination cytokine pattern may provide some non-M. tuberculosis-specific clinical benefits.

Spontaneous cytokine production and its effect on induced production.

Cytokines regulate cellular immune activity and are produced by a variety of cells, especially lymphocytes, monocytes, and macrophages. Multiparameter flow cytometry is often used to examine cell-specific cytokine production after in vitro phorbol 12-myristate 13-acetate and ionomycin induction, with brefeldin A or other agents added to inhibit protein secretion. Spontaneous ex vivo production reportedly rarely occurs. We examined the spontaneous production of interleukin 2 (IL-2), IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) by peripheral-blood B lymphocytes, T cells, CD8(-) T cells, CD8(+) T cells, CD3(-) CD16/56(+) lymphocytes (natural killer [NK] cells), CD3(+) CD16/56(+) lymphocytes (natural T [NT] cells), and/or monocytes of 316 acutely ill hospitalized persons and 62 healthy adults in Malawi, Africa. We also evaluated the relationship between spontaneous and induced cytokine production. In patients, spontaneous TNF-alpha production occurred most frequently, followed in descending order by IFN-gamma, IL-8, IL-4, IL-10, IL-6, and IL-2. Various cells of 60 patients spontaneously produced TNF-alpha; for 12 of these patients, TNF-alpha was the only cytokine produced spontaneously. Spontaneous cytokine production was most frequent in the immunoregulatory cells, NK and NT. For IL-2, IL-4, IL-6, IL-8, and IL-10, spontaneous cytokine production was associated with greater induced production. For TNF-alpha and IFN-gamma, the relationships varied by cell type. For healthy adults, IL-6 was the cytokine most often produced spontaneously. Spontaneous cytokine production was not unusual in these acutely ill and healthy persons living in an area where human immunodeficiency virus, mycobacterial, malaria, and assorted parasitic infections are endemic. In such populations, spontaneous, as well as induced, cell-specific cytokine production should be measured and evaluated in relation to various disease states.

Vitamin A levels and immunity in humans.

In animal studies, vitamin A deficiency induces a shift from type 2 (humoral) to type 1 (cellular) cytokines; there are no similar data for humans. Control of human immunodeficiency virus (HIV) and Mycobacterium tuberculosis infections requires type 1 cytokine (cellular) immunity. These infections and vitamin A deficiency are highly prevalent in Africa. We therefore examined the interactions among serum vitamin A levels, immune parameters, HIV infection status, Mycobacterium bovis BCG vaccine scarring (as an indicator of a type 1 cytokine profile), and clinical findings for 70 hospitalized children in Malawi, Africa. Directly conjugated monoclonal antibodies and flow cytometry were used to assess cell-specific cytokine production by peripheral blood monocytes and lymphocyte subpopulations. The statistical techniques employed included nonparametric statistics and logistic regression analyses. Thirty percent of the participants had severe vitamin A deficiency (<10 microg/dl), 34% had moderate deficiency (10 to <20 microg/dl), and 36% had normal levels (> or = 20 microg/dl). Vitamin A levels were lower for HIV-positive than for HIV-negative children (median, 10 and 17 microg/dl, respectively). Vitamin A-deficient children (<20 microg/dl) were more likely than non-vitamin A-deficient children to have higher proportions of natural killer (NK) cells (median, 8.3 and 5.2%, respectively) and lower ratios of interleukin-10-producing monocytes to tumor necrosis factor alpha-producing monocytes after induction (median, 1.0 and 2.3, respectively). Vitamin A-deficient children were also more likely than non-vitamin A-deficient children to exhibit respiratory symptoms (47% versus 12%) and visible BCG vaccine scars (83% versus 48%), which are indicative of a type 1 response to vaccination. Vitamin A status did not vary with gender, age, incidence of malaria parasitemia, blood culture positivity, or rates of mortality (6% of vitamin A-deficient children died versus 20% of non-vitamin A-deficient children). Lower vitamin A levels were associated with a relative type 1 cytokine dominance and proportionately more NK cells, both of which may be somewhat beneficial to persons who are exposed to HIV, M. tuberculosis, or other type 1 pathogens.