Cervical cancer prevention in Southern Africa: A review of national cervical cancer screening guidelines in the Southern African development community.

BACKGROUND: Cervical cancer poses a significant burden, particularly in low-and-middle income countries (LMIC) with limited access to healthcare. High-income countries have made progress in prevention, while LMIC face unacceptably high incidence and mortality rates, often lacking official screening recommendations. We analysed the presence and content of cervical cancer screening guidelines for the secondary prevention of cervical cancer in the Southern African Development Community (SADC) and compared it to the current World Health Organization (WHO) guidelines for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. METHODS: A review of national cervical cancer guidelines across the SADC region was conducted. Data was obtained from government websites, international cancer control platforms, and WHO resources. Search terms included "cervical cancer" and "cervical cancer control guidelines", amongst others. There were no limitations on publication years, and the most recent versions of the guidelines were analysed, regardless of language. Each guideline was assessed for specific screening and treatment recommendations, in relation to the current WHO guidelines. Points were assigned for each data element. RESULTS: While most countries contributed data to this analysis there was a notable absence of adherence to the WHO guidelines. The most common screening method was naked eye visual inspection. There was a consensus on the age of screening initiation. Most countries recommended treatment by cryotherapy and loop excision. CONCLUSION: Effective cervical cancer screening programmes, guided by evidence-based recommendations, can enhance early intervention and outcomes. This study highlights the need for standardized and evidence-based cervical cancer screening guidelines in the SADC region, to reduce the burden of cervical cancer and improve the health outcomes of women in these areas.

Increased Belief Instability in Psychotic Disorders Predicts Treatment Response to Metacognitive Training.

BACKGROUND AND HYPOTHESIS: In a complex world, gathering information and adjusting our beliefs about the world is of paramount importance. The literature suggests that patients with psychotic disorders display a tendency to draw early conclusions based on limited evidence, referred to as the jumping-to-conclusions bias, but few studies have examined the computational mechanisms underlying this and related belief-updating biases. Here, we employ a computational approach to understand the relationship between jumping-to-conclusions, psychotic disorders, and delusions. STUDY DESIGN: We modeled probabilistic reasoning of 261 patients with psychotic disorders and 56 healthy controls during an information sampling task-the fish task-with the Hierarchical Gaussian Filter. Subsequently, we examined the clinical utility of this computational approach by testing whether computational parameters, obtained from fitting the model to each individual's behavior, could predict treatment response to Metacognitive Training using machine learning. STUDY RESULTS: We observed differences in probabilistic reasoning between patients with psychotic disorders and healthy controls, participants with and without jumping-to-conclusions bias, but not between patients with low and high current delusions. The computational analysis suggested that belief instability was increased in patients with psychotic disorders. Jumping-to-conclusions was associated with both increased belief instability and greater prior uncertainty. Lastly, belief instability predicted treatment response to Metacognitive Training at the individual level. CONCLUSIONS: Our results point towards increased belief instability as a key computational mechanism underlying probabilistic reasoning in psychotic disorders. We provide a proof-of-concept that this computational approach may be useful to help identify suitable treatments for individual patients with psychotic disorders.

Introduction of an Alcohol-Related Electronic Screening and Brief Intervention (eSBI) Program to Reduce Hazardous Alcohol Consumption in Namibia's Antiretroviral Treatment (ART) Program.

Alcohol is the most widely abused substance in Namibia and is associated with poor adherence and retention in care among people on antiretroviral therapy (ART). Electronic screening and brief interventions (eSBI) are effective in reducing alcohol consumption in various contexts. We used a mixed methods approach to develop, implement, and evaluate the introduction of an eSBI in two ART clinics in Namibia. Of the 787 participants, 45% reported some alcohol use in the past 12 months and 25% reported hazardous drinking levels. Hazardous drinkers were more likely to be male, separated/widowed/divorced, have a monthly household income > $1000 NAD, and report less than excellent ART adherence. Based on qualitative feedback from participants and providers, ART patients using the eSBI for the first time found it to be a positive and beneficial experience. However, we identified several programmatic considerations that could improve the experience and yield in future implementation studies.

The cardiopulmonary exercise test grey zone; optimising fitness stratification by application of critical difference.

BACKGROUND: Cardiorespiratory fitness can inform patient care, although to what extent natural variation in CRF influences clinical practice remains to be established. We calculated natural variation for cardiopulmonary exercise test (CPET) metrics, which may have implications for fitness stratification. METHODS: In a two-armed experiment, critical difference comprising analytical imprecision and biological variation was calculated for cardiorespiratory fitness and thus defined the magnitude of change required to claim a clinically meaningful change. This metric was retrospectively applied to 213 patients scheduled for colorectal surgery. These patients underwent CPET and the potential for misclassification of fitness was calculated. We created a model with boundaries inclusive of natural variation [critical difference applied to oxygen uptake at anaerobic threshold (V˙O2-AT): 11 ml O2 kg-1 min-1, peak oxygen uptake (V˙O2 peak): 16 ml O2 kg-1 min-1, and ventilatory equivalent for carbon dioxide at AT (V̇E/V̇CO2-AT): 36]. RESULTS: The critical difference for V˙O2-AT, V˙O2 peak, and V˙E/V˙CO2-AT was 19%, 13%, and 10%, respectively, resulting in false negative and false positive rates of up to 28% and 32% for unfit patients. Our model identified boundaries for unfit and fit patients: AT <9.2 and ≥13.6 ml O2 kg-1 min-1, V˙O2 peak <14.2 and ≥18.3 ml kg-1 min-1, V˙E/V˙CO2-AT ≥40.1 and <32.7, between which an area of indeterminate-fitness was established. With natural variation considered, up to 60% of patients presented with indeterminate-fitness. CONCLUSIONS: These findings support a reappraisal of current clinical interpretation of cardiorespiratory fitness highlighting the potential for incorrect fitness stratification when natural variation is not accounted for.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial.

BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.

Revision interposition arthroplasty of the elbow.

Between 1996 and 2008, nine patients with severe post-traumatic arthritis underwent revision of a failed interposition arthroplasty of the elbow with a further interposition procedure using an allograft of tendo Achillis at a mean of 5.6 years (0.7 to 13.1) after the initial procedure. There were eight men and one woman with a mean age of 47 years (36 to 56). The mean follow-up was 4.7 years (2 to 8). The mean Mayo Elbow Performance score improved from 49 (15 to 65) pre-operatively to 73 (55 to 95) (p = 0.04). The mean Disability of the Arm, Shoulder and Hand score was 26 (7 to 42). One patient was unavailable for clinical follow-up and one underwent total elbow replacement three months post-operatively. Of the remaining patients, one had an excellent, two had good, three fair and one a poor result. Subjectively, five of the nine patients were satisfied. Four continued manual labour. Revision interposition arthroplasty is an option for young, active patients with severe post-traumatic arthritis who require both mobility and durability of the elbow.

Outcome of sliding inguinal hernia repair.

PURPOSE: Sliding inguinal hernias represent a small proportion of inguinal hernias but become more common with advancing age. The most recent review is based on a series published over 50 years ago. There are, however, many case reports of unusual presentations in girls. METHODS: We performed a review of a prospectively kept electronic record of all operations performed at Logan Hospital since 2003 in order to document the clinical characteristics of sliding inguinal hernias in the twenty-first century. RESULTS: Thirty-one males underwent predominantly anterior repair of a sliding hernia after a median of 9 months of symptoms (2.9% of all hernia repairs-32/1,092). Approximately two-thirds of hernias were left sided. There were five minor and two technical complications. Follow-up ranged from 3 weeks to 3 years. Two recurrences have been repaired. CONCLUSIONS: Sliding inguinal hernias continue to test the surgeon's understanding of the inguinal canal's anatomy and technical expertise with a significant rate of technical complications and recurrence.

Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience.

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin-fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen.

Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis.

The blood protein fibrinogen as a ligand for integrin and non-integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Studies in animal models and in human disease have demonstrated that extravascular fibrinogen that is deposited in tissues upon vascular rupture is not merely a marker, but a mediator of diseases with an inflammatory component, such as rheumatoid arthritis, multiple sclerosis, sepsis, myocardial infarction and bacterial infection. The present article focuses on the recent discoveries of specific cellular targets and receptors for fibrinogen within tissues that have extended the role of fibrinogen from a coagulation factor to a regulator of inflammation and immunity. Fibrinogen has the potential for selective drug targeting that would target its proinflammatory properties without affecting its beneficial effects in hemostasis, since it interacts with different receptors to mediate blood coagulation and inflammation. Strategies to target receptors for fibrinogen and fibrin within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in a variety of human diseases associated with fibrin deposition.

Association analysis of the chromosome 4p-located G protein-coupled receptor 78 (GPR78) gene in bipolar affective disorder and schizophrenia.

The orphan G protein-coupled receptor 78 (GPR78) gene lies within a region of chromosome 4p where we have previously shown linkage to bipolar affective disorder (BPAD) in a large Scottish family. GPR78 was screened for single-nucleotide polymorphisms (SNPs) and a linkage disequilibrium map was constructed. Six tagging SNPs were selected and tested for association on a sample of 377 BPAD, 392 schizophrenia (SCZ) and 470 control individuals. Using standard chi(2) statistics and a backwards logistic regression approach to adjust for the effect of sex, SNP rs1282, located approximately 3 kb upstream of the coding region, was identified as a potentially important variant in SCZ (chi(2) P=0.044; LRT P=0.065). When the analysis was restricted to females, the strength of association increased to an uncorrected allele P-value of 0.015 (odds ratios (OR)=1.688, 95% confidence intervals (CI): 1.104-2.581) and uncorrected genotype P-value of 0.015 (OR=5.991, 95% CI: 1.545-23.232). Under the recessive model, the genotype P-value improved further to 0.005 (OR=5.618, 95% CI: 1.460-21.617) and remained significant after correcting for multiple testing (P=0.017). No single-marker association was detected in the SCZ males, in the BPAD individuals or with any other SNP. Haplotype analysis of the case-control samples revealed several global and individual haplotypes, with P-values <0.05, all but one of which contained SNP rs1282. After correcting for multiple testing, two haplotypes remained significant in both the female BPAD individuals (P=0.038 and 0.032) and in the full sample of affected female individuals (P=0.044 and 0.033). Our results provide preliminary evidence for the involvement of GPR78 in susceptibility to BPAD and SCZ in the Scottish population.

Role of leucocytes in damage to the vascular endothelium during ischaemia-reperfusion injury.

During this investigation, a model of tourniquet-induced forearm ischaemia-reperfusion injury is employed to investigate the role of leucocytes in damage to the vascular endothelium during ischaemia-reperfusion injury. Leucocyte entrapment is investigated by measuring the concentration of leucocytes in venous blood leaving the arm. Neutrophil and monocyte leucocyte subpopulations are isolated by density gradient centrifugation techniques. Cell surface expression of CD11b and the intracellular production of hydrogen peroxide are measured via flow cytometry. Plasma concentrations of elastase and von Willebrand factor (vWF) are measured using enzyme-linked immunosorbemt assay (ELISA) techniques. During ischaemia-reperfusion, there was an increase in CD11b cell surface expression on neutrophils (P=0.040) and monocytes (P=0.049), and a decrease in peripheral blood leucocytes (P=0.019). There was an increase in the intracellular production of hydrogen peroxide by leucocyte subpopulations (P=0.027 [neutrophils], P=0.091 [monocytes]) and in the plasma elastase concentration (P=0.05). There was also a trend to increasing plasma concentration of vWF (P=0.0562), which was measured as a marker of endothelial damage. Ischaemia-reperfusion results in increased adhesiveness, entrapment and activation of leucocytes. Even following a mild ischaemic insult, this leucocyte response was followed immediately by evidence of endothelial damage. These results may have important implications for understanding the development of chronic diseases that involve mild ischaemic episodes.

Coonrad-Morrey total elbow arthroplasty for tumours of the distal humerus and elbow.

We reviewed 20 patients who had undergone a Coonrad-Morrey total elbow arthroplasty after resection of a primary or metastatic tumour from the elbow or distal humerus between 1980 and 2002. Eighteen patients underwent reconstruction for palliative treatment with restoration of function after intralesional surgery and two after excision of a primary bone tumour. The mean follow-up was 30 months (1 to 192). Five patients (25%) were alive at the final follow-up; 14 (70%) had died of their disease and one of unrelated causes. Local control was achieved in 15 patients (75%). The mean Mayo Elbow Performance Score improved from 22 (5 to 45) to 75 points (55 to 95). Four reconstructions (20%) failed and required revision. Seven patients (35%) had early complications, the most frequent being nerve injury (25%). There were no infections or wound complications although 18 patients (90%) had radiotherapy, chemotherapy or both. The Coonrad-Morrey total elbow arthroplasty provides good relief from pain and a good functional outcome after resection of tumours of the elbow. The rates of complications involving local recurrence of tumour (25%) and nerve injury (25%) are of concern.

The impact of psychological disturbances on immediate memory.

The current study tested the hypothesis that attention mediates the impact of psychological disturbances (i.e. depression, loss of self-control, and bizarre thinking) on immediate memory. A hypothesized model, in which psychological disturbances indirectly impacted immediate memory via attention, was tested using structural equations modeling (EQS). The participants included heterogeneous groups of brain-damaged and psychiatric subjects both with and without age-corrected observed variables. These groups did not vary with regard to the relationships within the model, and all models had good fit indices [comparative fit index (CFI)>0.98]. Competing models with paths directly from psychological disturbances to verbal, spatial, and general immediate memory were not significant, and these competing models did not result in a better fitting model. Therefore, the best fitting, most parsimonious model was the hypothesized one. These results corroborate the hypothesis of an indirect relationship between psychological disturbances and immediate memory via attention.

A conservative femoral replacement for total hip arthroplasty. A prospective study.

Between 1985 and 1993, 146 patients (162 hips) had total hip replacement (THR) using a conservative uncemented femoral component. The mean age of the patients was 50.8 years and the mean follow-up was 6.2 years (2 to 13). One patient was lost to follow-up, one died within two years of surgery and one had a revision procedure after a fracture sustained in a road-traffic accident. For the remaining 159, Kaplan-Meier survival analysis was calculated for the incidence of revision because of mechanical loosening or osteolysis. Survival without mechanical loosening at both five and ten years was 98.2%. Survival without osteolysis was 99% at five and 91% at ten years. The Harris hip score improved from a mean of 66.3 before to 90.4 at follow-up. Of particular note is the lack of thigh pain in this group. Radiological analysis showed that 139 stems (88%) had no measurable subsidence, 8 (5%) had less than 2 mm and 12 (7%) had more than 2 mm. Two of the eight and one of the 12 were revised for mechanical loosening. Nine hips were revised for late loosening associated with osteolysis. No reaming of the femoral canal was associated with statistically significant less blood loss compared with a comparable control group of uncemented implants (p < 0.0001). Our study suggests that using a conservative femoral implant does not protect against wear debris but the reliable mechanical stability (98.2%) makes this an attractive design of implant particularly for young patients.

Soluble adhesion molecules in clinical ischaemic injury.

BACKGROUND: Neutrophil adhesion is a prerequisite for ischaemic injury. In vitro research has shown that soluble adhesion molecules have an inhibitory effect on neutrophil binding AIMS: To determine whether the circulating forms of adhesion molecules are consumed during skeletal muscle ischaemic injury in man. METHODS: The response of the circulating forms of adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and L-selectin to ischaemia and reperfusion was investigated in 23 patients during surgery involving aortic cross-clamping and in 20 volunteers with tourniquet-induced forearm ischaemia. RESULTS: In the aortic model the levels of circulating ICAM-1 fell from an initial value of 250 +/- 20 to 210 +/- 13 ng/ml (p < 0.05) and soluble L-selectin fell from 642 +/- 62 to 487 +/- 49 ng/ml during ischaemia (p < 0.05). There was a similar pattern of reduced levels of circulating adhesion molecules in the model of forearm ischaemia. However the recovery of these molecules during the reperfusion period differed between the two models. CONCLUSIONS: Soluble L-selectin and soluble ICAM-1 appear to be utilised during clinical models of ischaemia. This supports previous in vitro studies suggesting a role in competitive inhibition and these circulating molecules may be clinically important inhibitors of leukocyte adhesion.

Semiconstrained total elbow arthroplasty in the context of treated previous infection.

Previous infection has been considered a strict contraindication to implantation or reimplantation of an elbow prosthesis. The purpose of this study was to investigate whether these patients can in fact be successfully treated with a prosthetic arthroplasty given previous treatment of the infection. Ten consecutive prosthetic arthroplasties performed in patients with documented infections in the elbow were retrospectively reviewed. Seven of the patients had infectious complications of total elbow arthroplasties that led to resection. Two patients had previous infections from septic joints and 1 from open reduction internal fixation. The median interval of time from infection treatment to final implant was 45 months (3.8 years). All arthroplasties were performed by the same surgeon with a modified Coonrad-Morrey, semiconstrained prosthesis. Patients were monitored for clinical signs of infection including radiographic and serologic studies and clinical evaluation based on the Mayo Elbow Performance Score. Mean surveillance was 4 years (range 2.8 to 5.4 years). Eight of the 10 cases have not shown signs of infection at the latest assessment. Two have had recurrent infections. The time interval from the original infection to latest implantation did not correlate with infection recurrence. Among those 8 without recurrent infection, 7 had excellent and 1 had satisfactory results according to the Mayo Elbow Performance Score. The recurrent infections were rated as failures. The average score was 32 before and 81 after surgery. The average pain score was 15 before surgery, and the average postoperative pain score was 40. Salvage of previously infected elbows with prosthetic arthroplasty can provide excellent results in a significant proportion of patients. Although the procedure offers superior functional outcomes compared with the alternative treatment options, it is technically demanding.

Maternal stress in caring for children with feeding disabilities: implications for health care providers.

The purposes of this study were to compare the stress experienced by mothers of children with feeding disorders to the stress experienced by mothers of children with other childhood disabilities, to compare the stress experienced by mothers of children who are tube-fed with that of mothers of children with disabilities who do not require tube feeding, to ascertain the types of stressors that mothers in both groups experience, and to determine their coping resources. Subjects were mothers of children with disabilities who had recently been discharged or were receiving outpatient care from a private rehabilitation facility in a Midwestern city. The Short Form of the Questionnaire on Resources and Stress instrument and open-ended questions developed by the researchers were used. Results were analyzed using analysis of variance. Results indicate that mothers of children requiring tube feeding experienced significantly greater stress than mothers of children with disabilities who do not require tube feedings. Mothers of children requiring tube feeding also receive less support from family and friends. To assist dietitians, other health care professionals, and university instructors in developing family-centered treatment programs, we recommend including fathers, friends, or relatives in the care and feeding process; discovering ways to include the tube-fed child in family mealtime activities; increasing public awareness of tube-feeding issues; organizing support groups; and educating dietetics students about the unique stresses experienced by mothers of children who are tube-fed.