Compatibility and stability of an admixture of multiple anaesthetic drugs for opioid-free anaesthesia.

The ability to combine and use drugs in a single infusion device may be useful in resource-limited settings. This study examined the chemical stability of an opioid-sparing mixture of ketamine, lidocaine and magnesium sulphate when combined in a single syringe. High-performance liquid chromatography and atomic absorption spectrophotometry were performed on six syringes containing the three-drug mixture. Since most opioid-sparing techniques typically rely on a 24-hour infusion regime, we tested stability at the initial admixing and 24 hours later. Stability was defined as a measured drug concentration within 10% of expected, with the absence of precipitation or pH alterations. Pharmacokinetic simulations were conducted to further show that the achieved plasma drug concentrations were well within an effective analgesic range. All mixed drug concentration measurements were within the required 10% reference limit. No obvious precipitation or interaction occurred, and pH remained stable. Drug stability was maintained for 24 hours. Pharmacokinetic simulations showed that ketamine and lidocaine were within their minimum analgesic effect concentrations. Our results show that this three-drug mixture is chemically stable for up to 24 hours after mixing, with a pharmacokinetic simulation illustrating safe, clinically useful predicted plasma concentrations when using the described admixture.

Ethyl formate + nitrogen fumigant: a new, safe, and environmentally friendly option for treating a 20 ft shipping container loaded with general freight.

The use of shipping containers for cargo transportation has the potential to transport insect pests from infested to non-infested areas. Fumigation is required as an appropriate biosecurity measure to exterminate insect pests. Fumigation trials were conducted in a 20 ft general purpose (GP) shipping container. Four species of mixed-age cultures, Lasioderma serricorne (F.), Sitophilus oryzae (L.), Trogoderma variabile (Ballion), and Rhyzopertha dominica (F.) were used for bioassays. Ninety g m-3 of ethyl formate + nitrogen formed non-flammable ethyl formate fumigant formulation was released into the container. The fumigation yielded sufficient concentration × time (Ct) products at a range of 437.54-449.19 g h m-3 in the container for exterminating all life stages. Ethyl formate left no residue in treated drinks. This study demonstrated that on site generation of a non-flammable ethyl formate and nitrogen fumigant can be achieved and this new application technology ensures that ethyl formate distributes evenly in the container within 30 min after application and with a variation of <3%. The research further demonstrated that an ethyl formate + nitrogen application can be used as a pre-shipment treatment for controlling all the stages of insect pests in a shipping container. After a fumigation holding period and ventilation of 15 min, ethyl formate was successfully removed from the container at 0.5-35ppm in different locations. The levels of ethyl formate in the workspace were <0.5 ppm during application, fumigation, and aeriation, which is about 5% of the 100 ppm level for ethyl formate.

Commercial trials evaluating the novel use of ethyl formate for in-transit fumigation of shipping containers.

The use of shipping containers for cargo transportation has the potential to transport insect pests from infested to non-infested areas. Therefore, fumigation is required as an appropriate biosecurity measure to exterminate these pests. In-transit fumigation trials were conducted in two 20 ft shipping containers during a two-day journey in both September and December 2017. Ethyl formate (90 g m-3) was purged with nitrogen (EF + N2) into the containers. Ethyl formate concentration inside containers and the surrounding environment were monitored at timed intervals throughout the journey. Fumigation achieved sufficient concentration × time (Ct) products in the containers during the journey, which can exterminate all stages of most common insect pests. The Ct products in-transit were greater than those in a shipping container being fumigated in a stationary position at a dose rate of 90 g m-³ for 24 hours exposure. Levels of EF in the environment between 1-15 m downwind from the containers and driver's cabin were less than 0.5 ppm at each of the timed intervals, 200 times below 100 ppm of EF Threshold Limit Value (TLV). Our study indicates that in-transit EF + N2 technology has the potential to deliver cost savings in the fumigation process through reduction of the Labor cost, elimination of the time a container and cargo must remain stationary in a fumigation yard and a significant decrease in total supply chain time (between container packing and receival).

Requiem for Nigro or is anal squamous carcinoma still a surgical problem: Abdominoperineal excision rather than a defunctioning stoma?

BACKGROUND: Combined multimodal treatment (CMT) is the preferred treatment for anal squamous carcinoma with radical surgery reserved for treatment failure. Some patients require a defunctioning stoma prior to CMT. Successful closure of such a stoma is unlikely. Abdominoperineal excision (APE) may be suitable as primary treatment in these patients. METHOD: A retrospective review of all patients with anal squamous carcinoma was undertaken. Patients who required defunctioning colostomies prior to CMT were analysed for potential resectability of tumour prior to CMT and rate of permanent stoma. OBJECTIVE: To evaluate organ preservation in the treatment of anal squamous cancer and the closure rate of pre-treatment, temporary diverting colostomy, thereby assessing whether APE could be offered as primary treatment in those requiring a pre-treatment colostomy. RESULTS: One hundred and twenty-five patients were included of which 58 were males. The mean age was 56 years. 107 were treated with curative intent. Six received primary APE and 12 salvage APE. Thirty (22 males) required pretreatment diverting colostomies. Three (10%) stomas were successfully reversed. Forty-eight (38%) of the 125 completed treatment with a permanent colostomy. Six patients who needed a stoma prior to CMT were deemed resectable. CONCLUSION: Organ preservation was not possible in about a third of patients. Defunctioning stomas prior to CMT were likely to be permanent. We propose that APE could be considered as an alternative in selective cases where the tumour is resectable with low morbidity and a stoma is indicated.

Comparative study of extralevator vs. conventional abdominoperineal excision in a single centre in the developing world.

ABSTRACT: Abdominoperineal excision (APE) is used to resect cancers in the distal rectum and anus where sphincterpreserving surgery is not possible. It is associated with increased local recurrence rates compared to anterior resection. The extralevator abdominoperineal excision (ELAPE) was developed to reduce local recurrence and was widely adopted without sound evidence. AIM: To compare the short-term (2 years) outcomes of patients managed with ELAPE to those with conventional APE in a single institution in a developing country. METHOD: A prospective database on all patients treated with prone ELAPE from 2010 to 2014 was compared to patients treated with conventional APE. Patient demographics, tumour characteristics, intra-operative tumour perforation, involvement of the circumferential resection margin (CRM), surgical complications and mortality are reported. RESULTS: Fifty-six patients were treated with APE of which 29 were male. Median age was 56. Thirty underwent conventional APE (16 male; 14 female) and 26 underwent ELAPE (15 male; 11 female). The groups were similar in age, tumour histology, height above anal verge clinical staging and response to neoadjuvant treatment. Perineal closure techniques in both cohorts were similar. There was no difference in intra-operative tumour perforation, involvement of the CRM, perineal wound complications or 30-day mortality in the 2 groups. CONCLUSION: There is no difference in the important short-term outcomes of conventional APE when compared to ELAPE.

Refeeding enteroclysis as an alternative to parenteral nutrition for enteric fistula.

AIM: Refeeding enteroclysis is one method of giving artificial nutritional support to patients with enterocutaneous fistula. This study compares the results of this technique with parenteral nutrition or nutrition given via a proximal stoma. METHOD: All patients admitted to our intestinal failure unit with a proximal enteric fistula and managed with refeeding enteroclysis over a 4-year period were included and compared with a matched group of patients managed without using this technique. RESULTS: Twenty patients (15 men) with a proximal enteric fistula received chyme refeeding down the distal limb of the fistula. This was established at a mean of 14 days after admission to the unit and total parenteral nutrition could be weaned off by 20 days. The mean output from the proximal limb was 1800 ml and the mean volume refed down the distal limb was 1220 ml per day. Additional enteric feed was given to 12 patients. No patient was given pharmacological agents to delay gastrointestinal transit or additional intravenous water and electrolyte for most of the time after refeeding was established. There were no complications or deaths related to chyme refeeding. CONCLUSION: Refeeding enteroclysis is feasible in selected patients with a proximal enteric fistula or stoma. Adequate nutrition, water and electrolyte balance can be achieved without resorting to parenteral infusions.

The effect of overbooking on idle dental chair capacity in the Pretoria region of the Gauteng Oral Health Services.

An analysis of annual reports revealed that on average 20% of patient appointments with oral hygienists in the Department of Health in the Pretoria region were not utilised due to patient noncompliance (i.e. broken appointments). Many solutions have been considered to address the high rate of noncompliance and the resulting idle chair capacity. One solution selected to overcome some of the negative consequences of broken appointments was deliberate overbooking. The aim of our study was to determine the effect of overbooking on idle dental chair capacity by measuring the utilisation rate over a three month period (July to September) after 25% overbooking was introduced in the Pretoria region. A statistical analysis was conducted on our results to determine an overbooking rate that would ensure full utilisation of the available dental chair capacity. The available time units over the three month study period amounted to 1365, allocated to 1427 patients resulting in an overal overbooking rate of 4.54%. The overall utilisation rate was found to be 79.2%. The calculated regression line estimated that there would be full utilisation of dental chair capacity at an overbooking rate of 26.7%. Overbooking at the levels applied in this study had a minimal overall effect on idle dental chair capacity. Our results confirm the need for careful planning and management in addressing noncompliance. In a manner similar to the clinical situation, organisational development requires a correct diagnosis in order that an appropriate and effective intervention may be designed.

A prospective observational study of preoperative natriuretic peptide testing in adult non-cardiac surgical patients in hospitals in Western Cape Province, South Africa.

BACKGROUND: International guidelines recommend risk stratification to identify high-risk non-cardiac surgical patients. It is also recommended that all patients aged ≥45 years with significant cardiovascular disease should have preoperative natriuretic peptide (NP) testing. Abnormal preoperative B-type NPs have a strong association with postoperative cardiac complications. In South African hospitals, it is not known how many patients with significant cardiovascular disease scheduled for intermediate- to high-risk surgery will have raised NPs. OBJECTIVES: To determine the prevalence of abnormal (raised) NPs in non-cardiac surgical patients with cardiac clinical risk factors. A secondary objective was to develop a model to identify surgical patients who may benefit from preoperative NP screening. METHODS: The inclusion criteria were patients aged ≥45 years presenting for elective, non-obstetric, intermediate- to high-risk non-cardiac surgery with at least one of the following cardiovascular risk factors: a history of ischaemic heart disease or peripheral vascular disease (coronary equivalent); a history of stroke or transient ischaemic attack; a history of congestive cardiac failure; diabetes mellitus currently on an oral hypoglycaemic agent or insulin; and serum creatinine level >175 µmol/L (>2.0 mg/dL). Blood samples for N-terminal-prohormone B-type NP (NT-proBNP) were collected before induction of anaesthesia. The preoperative prognostic threshold for abnormal (raised) NT-proBNP was ≥300 pg/mL. A generalised linear mixed model was used to determine the association between the risk factors and an abnormal NT-proBNP level. RESULTS: Of 172 patients, 63 (37%) had an elevated preoperative NT-proBNP level. The comorbidities independently associated with elevated preoperative NT-proBNP were coronary artery disease or peripheral vascular disease, congestive cardiac failure, and a creatinine level >175 µmol/L CONCLUSIONS: We strongly recommend that non-cardiac surgical patients aged ≥45 years undergoing intermediate- or high-risk noncardiac surgery with a history of coronary artery disease/peripheral vascular disease, congestive cardiac failure or elevated creatinine have preoperative NP testing as part of risk stratification.

Multivisceral resection of locally advanced colorectal cancer in an African referral centre.

BACKGROUND: Colorectal cancer (CRC) is common and often presents with advanced disease in Africa. Multivisceral resection (MVR) improves survival in locally advanced (T4b) CRC. The aim was to describe the management and outcomes of patients with clinical T4b CRC without metastatic disease who underwent MVR. METHODS: A retrospective review of patients with T4 CRC who underwent MVR between January 2008 and December 2013. RESULTS: Four hundred and ninety-four patients were included. Of the 158 with suspected T4 cancer, 44 had MVR, of which one was excluded due to metastases. The mean age was 64 years. The male to female ratio was 1:1. The most commonly resected extra-colorectal structure was the abdominal wall (21%). The median survival was 68 months (SD 13.9). The 5-year disease free (DFS) and overall survival (OS) were 46% and 55%, respectively. Survival of patients with colon and rectum cancer was similar. Intraoperative tumour spillage, vascular/perineural invasion, and anastomotic leakage were independent predictors of survival. CONCLUSION: Multivisceral resection of locally advanced (T4b) CRC is feasible in the African context. Complete resection improves survival and should be the goal.

Malignant neuroendocrine tumour in an adult female diagnosed with Currarino syndrome.

SUMMARY: Currarino syndrome is a rare, autosomal dominant condition of caudal anomalies, usually diagnosed in childhood. Adult presentation is rare and malignant transformation of the associated presacral mass even more so. We report a case of a 60-year-old female diagnosed with a malignant neuroendocrine tumour in the presacral mass in Currarino syndrome and describe the surgical management and pathological findings.

Data Centre Profile: The Provincial Health Data Centre of the Western Cape Province, South Africa.

INTRODUCTION: The Western Cape Provincial Health Data Centre (PHDC) consolidates person-level clinical data across government services, leveraging sustained investments in patient registration systems, a unique identifier, and maturation of administrative and clinical digital health systems. OBJECTIVES: The PHDC supports clinical care directly through tools for clinicians which integrate patient data or identify patients in need of interventions, and indirectly through supporting operational and epidemiological analyses. METHODS: The PHDC is housed entirely within government. Data are processed from a range of source systems, usually daily, through distinct harmonisation and curation, beneficiation, and reporting processes. Linkage is predominantly through the unique identifier which doubles as a pervasive folder number, augmented by other identifiers. Further data processing includes triangulation of multiple data sources for enumerating health conditions, with assignment of certainty levels for each enumeration. Outputs include patient-specific email alerts, a web-based consolidated patient clinical viewing platform, filterable line-listings of patients with specific conditions and associated characteristics and outcomes, management reports and dashboards, and data releases in response to operational and research data requests. Strict architectural, administrative and governance processes ensure privacy protection. RESULTS: In the past decade 8 million unique people are recorded as having sought healthcare in the provincial public sector health services, with current utilisation at 15 million attendances or admissions a year. Cross-sectional enumeration of health conditions includes over 430 000 people with HIV, 500 000 with hypertension, 235 000 with diabetes. Annually 110 000 pregnancies and 54 000 patients with tuberculosis are enumerated. Over 50 data requests are processed each year for internal and external requesters in accordance with data request and release governance processes. CONCLUSIONS: The single consolidated environment for person-level health data in the Western Cape has created new opportunities for supporting patient care, while improving the governance around access to and release of sensitive patient data.

Incidence of myocardial injury after non-cardiac surgery: Experience at Groote Schuur Hospital, Cape Town, South Africa.

BACKGROUND: Myocardial injury after non-cardiac surgery (MINS) is a newly recognised entity identified as an independent risk factor associated with increased 30-day all-cause mortality. MINS increases the risk of death in the perioperative period by ~10-fold. More than 80% of patients with MINS are asymptomatic, so the majority of diagnoses are missed. Awareness of MINS is therefore important for perioperative physicians. OBJECTIVES: To investigate the incidence of MINS after elective elevated-risk non-cardiac surgery at Groote Schuur Hospital, Cape Town, South Africa (SA). METHODS: Patients aged ≥45 years undergoing elective elevated-risk non-cardiac surgery were enrolled via convenience sampling. The new fifth-generation high-sensitivity cardiac troponin T blood test was used postoperatively to identify MINS. Preoperative troponin levels were not measured. RESULTS: Among 244 patients included in the study, the incidence of MINS was 4.9% (95% confidence interval (CI) 2.8 - 8.5), which was not significantly different from that in a major international prospective observational study (VISION) (8.0% (95% CI 7.5 - 8.4)); p=0.080. CONCLUSIONS: Our SA cohort had a lower cardiovascular risk profile but a similar incidence of MINS to that described in international literature. The impact of MINS on morbidity and mortality is therefore likely to be proportionally higher in SA than in published international studies. The limited sample size and lower event rate weaken our conclusions. Larger studies are required to establish patient and surgical risk factors for MINS, allowing for revision of cardiovascular risk prediction models in SA.

On the geometrically exact low-order modelling of a flexible beam: formulation and numerical tests.

This paper proposes a low-order geometrically exact flexible beam formulation based on the utilization of generic beam shape functions to approximate distributed kinematic properties of the deformed structure. The proposed nonlinear beam shapes approach is in contrast to the majority of geometrically nonlinear treatments in the literature in which element-based-and hence high-order-discretizations are adopted. The kinematic quantities approximated specifically pertain to shear and extensional gradients as well as local orientation parameters based on an arbitrary set of globally referenced attitude parameters. In developing the dynamic equations of motion, an Euler angle parametrization is selected as it is found to yield fast computational performance. The resulting dynamic formulation is closed using an example shape function set satisfying the single generic kinematic constraint. The formulation is demonstrated via its application to the modelling of a series of static and dynamic test cases of both simple and non-prismatic structures; the simulated results are verified using MSC Nastran and an element-based intrinsic beam formulation. Through these examples, it is shown that the nonlinear beam shapes approach is able to accurately capture the beam behaviour with a very minimal number of system states.

Reducing stock-outs of essential tuberculosis medicines: a system dynamics modelling approach to supply chain management.

The under-performance of supply chains presents a significant hindrance to disease control in developing countries. Stock-outs of essential medicines lead to treatment interruption which can force changes in patient drug regimens, drive drug resistance and increase mortality. This study is one of few to quantitatively evaluate the effectiveness of supply chain policies in reducing shortages and costs. This study develops a systems dynamics simulation model of the downstream supply chain for amikacin, a second-line tuberculosis drug using 10 years of South African data. We evaluate current supply chain performance in terms of reliability, responsiveness and agility, following the widely-used Supply Chain Operation Reference framework. We simulate 141 scenarios that represent different combinations of supplier characteristics, inventory management strategies and demand forecasting methods to identify the Pareto optimal set of management policies that jointly minimize the number of shortages and total cost. Despite long supplier lead times and unpredictable demand, the amikacin supply chain is 98% reliable and agile enough to accommodate a 20% increase in demand without a shortage. However, this is accomplished by overstocking amikacin by 167%, which incurs high holding costs. The responsiveness of suppliers is low: only 57% of orders are delivered to the central provincial drug depot within one month. We identify three Pareto optimal safety stock management policies. Short supplier lead time can produce Pareto optimal outcomes even in the absence of other optimal policies. This study produces concrete, actionable guidelines to cost-effectively reduce stock-outs by implementing optimal supply chain policies. Preferentially selecting drug suppliers with short lead times accommodates unexpected changes in demand. Optimal supply chain management should be an essential component of national policy to reduce the mortality rate.

Ketonuria in pregnancy--with special reference to calorie-restricted food intake in obese diabetics.

Early morning ketonuria, as judged by Ketostix testing, occurred in 19% of urine samples from insulin-independent diabetic pregnant women eating 1000 calorie diets, in 14% from diabetics on higher calorie diets, and in 7% of urines from nondiabetic pregnant women. Ketostix test was never found to be positive in blood, even when it was 2+ in urine samples, and acetoacetate levels were always below 1 mmol/L. Enzymatic estimations of acetoacetate (AA) and beta-hydroxybutyrate (BB) in urine and plasma samples revealed (1) no significant differences in range or mean between the groups receiving different restricted diets or full diets, the highest value observed for plasma AA being 0.34 mmol/L; (2) that Ketostix became positive at a concentration of AA above 1 mmol/L and that such a value in urine corresponded to plasma levels of between 0.06 and 0.1 mmol/L, i.e., double the normal; and (3) a 50-100-fold increase in urine AA when blood levels exceeded 0.08 mmol/L. Neonates born to diabetic mothers with ketonuria had no fetal distress or asphyxia neonatorum. The lowest Apgar score at 5 min was 8; 80% of neonates had a score of 10. Hence, positive Ketostix tests in urine samples do not indicate toxic levels in the blood, and a 1000 calorie diet for obese pregnant diabetics appears to be safe as regards neonatal outcome.

The management of non-insulin-dependent diabetes during pregnancy.

We propose a rational regimen for management of non-insulin-dependent pregnant diabetics (NIDD), using appropriately constituted calorie-restricted diets with the oral agents metformin and glibenclamide as may be necessary, with rapid recourse to insulin if the latter do not produce excellent control of blood glucose. Using this regimen between June 1974 and December 1983 we have managed 423 new diabetics (ND, diagnosed during pregnancy) with a perinatal mortality (PNM) of 14 per 1000 and 268 established diabetics (known diabetics, KD) with a PNM of 70/1000 (57/1000 since 1978). A further 80 NIDDs were 'untreated', i.e., not seen by us until near term; these suffered a PNM of 313/1000. Side-effects of the drugs have been few and mild, they are not teratogenic; 'starvation ketosis' does not occur; neonatal hypoglycaemia is preventable by using continuous insulin infusion during delivery. We suggest that the regimen outlined here is acceptable to the patients, is safe, gives excellent results and furthermore teaches the diabetic mother proper dietary control and combats lifelong obesity. It should be useful especially in developing countries in which pregnant, overweight NIDDs are common. Precise control of the blood glucose is essential.

The use of topical, un-buffered sodium hypochlorite in the management of burn wound infection.

BACKGROUND: Burn wound infections are a major cause of morbidity and mortality. The bactericidal action of sodium hypochlorite has been known for centuries and it has been in clinical practice for over 70 years. Whereas a buffered sodium hypochlorite solution is not universally available, an un-buffered solution is cheap and easy to prepare. AIM: The aim of this study was to determine the optimum concentration with regard to safety and efficacy, as well as shelf life of an un-buffered sodium hypochlorite solution for the topical management of burn wound infections. METHODS: Human fibroblasts were exposed to serial dilutions of un-buffered sodium hypochlorite solutions for 30 min and assessed for viability. Isolates of Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pyogenes were exposed to the same dilutions of un-buffered sodium hypochlorite to establish the minimum bactericidal concentration. The pH, osmolality and electrolyte concentrations were measured. These experiments were repeated with solution stored at room temperature for 6 consecutive days. RESULTS: 24% of fibroblasts were viable after exposure to a 0.025% solution and 98.9% with a 0.003% solution. The MBC for the P. aeruginosa isolates was 0.003%, for S. aureus was 0.006% and for S. pyogenes was 0.0015%. This remained constant for 6 consecutive days. The un-buffered 0.0025% solution has a pH of 10, an osmolality of 168 sodium concentration of 89 mmol/dl and chloride of 84 mmol/dl. This remained stable for 14 days. CONCLUSIONS: An un-buffered solution of sodium hypochlorite with a concentration of 0.006% would be suitable for the topical management of burn wound infections caused by common pathogens. It has a shelf life of at least 6 days.

Simple repair of a giant inguinoscrotal hernia.

We present a case of a giant inguinoscrotal hernia that extended almost to the patient's knees. Operative repair was through a standard transverse inguinal incision. No debulking or abdominal enlargement procedure had to be performed. The repair was done with a tension-free, onlay, prosthetic mesh repair.

A 10-year retrospective analysis of pregnancy outcome in pregestational Type 2 diabetes: comparison of insulin and oral glucose-lowering agents.

AIMS: To review the use of oral glucose-lowering agents (OGLA) in pregnant women with Type 2 diabetes mellitus. METHODS: Retrospective analysis of outcomes and their predictors in singleton pregnancies > or = 24 weeks managed at Groote Schuur hospital, Cape Town, South Africa from 1991 to 2000. There were 379 pregnancies, subdivided into three groups according to therapy: OGLA alone, converted from OGLA to insulin, insulin alone or converted from diet alone to insulin. The OGLA used were metformin and glibenclamide. RESULTS: Mean glycated haemoglobin (HbA(1c)) was similar at booking and throughout pregnancy in all groups. In the OGLA alone, converted from OGLA to insulin and insulin alone/converted from diet alone to insulin groups, fetal anomaly rates were comparable: 5.7%, 2.0% and 0.0%, P = 0.2, respectively; whereas perinatal mortality rates (per 1000 births) were: 125, 28, 33, P = 0.003, respectively. Booking HbA(1c) was independently associated with fetal anomaly [odds ratio (OR) 1.48; 95% confidence interval (CI) 1.11, 1.97; P = 0.006]. The specific OGLA used in the first trimester was not associated with the occurrence of fetal anomaly. Last HbA(1c) (OR 1.65; 95% CI 1.16, 2.42; P = 0.005) and fetal anomaly (OR 15.18; 95% CI 2.43, 93.37; P = 0.005) were independently associated with perinatal mortality. Conversion from OGLA to insulin was protective for perinatal mortality compared with OGLA alone treatment (OR 0.220; 95% CI 0.061, 0.756; P = 0.024). No perinatal mortality was observed in women on metformin alone. CONCLUSIONS: These data suggest that metformin and glibenclamide are not teratogenic but that it is advisable to replace OGLA, in particular glibenclamide, with insulin when women book for pregnancy care to reduce perinatal mortality rates.