Working title: high dose rate intra-cavitary brachytherapy with cobalt 60 source for locally advanced cervical cancer: the Zimbabwean experience

Background and purpose
Cervical cancer is the fourth commonest cancer in women in the world with the highest regional incidence and mortality seen in Southern, Eastern and Western Africa. It is the commonest cause of cancer morbidity and mortality among Zimbabwean women. Most patients present with locally advanced disease that is no longer amenable to surgery. Definitive concurrent chemoradiation (CCRT), which is the use of external beam radiotherapy (EBRT) and weekly cisplatin, includes use of intracavitary brachytherapy, as the standard treatment. In the setting of this study, cobalt-60 (Co60)-based high dose rate brachytherapy (HDR-BT) has been in use since 2013. This study sought to review practices pertaining to use of brachytherapy in Zimbabwe, including timing with external beam radiotherapy, adverse effects and patient outcomes.

Methods
A retrospective analysis of data from records of patients with histologically confirmed cervical cancer treated with HDR-BT at the main radiotherapy centre in Zimbabwe from January 2013 to December 2014 was done. Outcome measures were local control, overall survival as well as gastro-intestinal and genito-urinary toxicity.

Results
A total of 226 patients were treated with HDR-BT during the study period, with a 97% treatment completion rate. All patients received between 45-50Gy of pelvic EBRT. Seventy-four percent received concurrent platinum-based chemotherapy. In 52% of the patients, HDR-BT was started when they were still receiving EBRT. The commonest fractionation schedule used was the 7Gy × 3 fractions, once a week (87%). Clinical complete tumour response was achieved in 75% at 6 weeks post treatment, 23% had partial response. Follow-up rates at 1 year and 2 years were 40 and 19% respectively. Disease free survival at 1 year and 2 years was 94 and 95% respectively. Vaginal stenosis was the commonest toxicity recorded, high incidence noted with increasing age. Four patients developed vesico-vaginal fistulae and two patients had rectovaginal fistulae.

Conclusion
One hundred and seventeen patients patients started HDR-BT during EBRT course, with a treatment completion rate of 97%. The overall treatment duration was within 56 days in the majority of patients. Early local tumour control was similar for all the HDR-BT fractionation regimes used in the study, with a high rate (75%) of complete clinical response at 6 weeks post-treatment. Prospective studies to evaluate early and long-term outcomes of HDR-BT in our setting are recommended.

Placental pathology and maternal factors associated with stillbirth: An institutional based case-control study in Northern Tanzania

Objective
To determine the placental pathologies and maternal factors associated with stillbirth at Kilimanjaro Christian Medical Centre, a tertiary referral hospital in Northern Tanzania.

Methods
A 1:2 unmatched case-control study was carried out among deliveries over an 8-month period. Stillbirths were a case group and live births were the control group. Respective placentas of the newborns from both groups were histopathologically analyzed. Maternal information was collected via chart review. Mean and standard deviation were used to summarize the numerical variables while frequency and percentage were used to summarize categorical variables. Crude and adjusted logistic regressions were done to test the association between each variable and the risk of stillbirth.

Results
A total of 2305 women delivered during the study period. Their mean age was 30 ± 5.9 years. Of all deliveries, 2207 (95.8%) were live births while 98 (4.2%) were stillbirths. Of these, 96 stillbirths (cases) and 192 live births (controls) were enrolled. The average gestational age for the enrolled cases was 33.8 ±3.2 weeks while that of the controls was 36.3±3.6 weeks, (p-value 0.244). Of all stillbirths, nearly two thirds 61(63.5%) were males while the females were 35(36.5%). Of the stillbirth, 41were fresh stillbirths while 55 were macerated. The risk of stillbirth was significantly associated with lower maternal education [aOR (95% CI): 5.22(2.01–13.58)], history of stillbirth [aOR (95%CI): 3.17(1.20–8.36)], lower number of antenatal visits [aOR (95%CI): 6.68(2.71–16.48), pre/eclampsia [aOR (95%CI): 4.06(2.03–8.13)], and ante partum haemorrhage [OR (95%CI): 2.39(1.04–5.53)]. Placental pathology associated with stillbirth included utero-placental vascular pathology and acute chorioamnionitis.

Conclusions
Educating the mothers on the importance of regular antenatal clinic attendance, monitoring and managing maternal conditions during antenatal periods should be emphasized. Placentas from stillbirths should be histo-pathologically evaluated to better understand the possible aetiology of stillbirths.

Death of 43 Indonesian women with ovarian cancer: A case series

Background: Ovarian cancer is a gynecological cancer with a higher mortality than other gynecological cancers.

Case report: There were 43 cases of Indonesian women who died of ovarian cancer in 2015-2017. Patients were first diagnosed at the age of 40-59 years (65.11%), of which had normal BMI (62.72%) and mostly in stage III (39.53%). The histology was 88.3% epithelial ovarian cancer with the most subtypes of mucinous carcinoma (25.5%). The majority were referral patients (62.7%), but due to its malignancy, many died before receiving ovarian cancer treatment (40.74%). Of the 43 patients, 17 patients received chemotherapy, and 10 patients received a combination of surgical therapy and chemotherapy. Most of the deaths were caused by primary disease (69.77%). Patients with stages III and IV, as well as patients receiving surgery or chemotherapy alone had shorter survival times.

Conclusion: Most ovarian cancer patients are first diagnosed at stage III with the mucinous carcinoma subtype. Most deaths are caused by primary ovarian cancer. The therapy that provides the longest survival is a combination of surgery and chemotherapy.

How do Supply- and Demand-side Interventions Influence Equity in Healthcare Utilisation? Evidence from Maternal Healthcare in Senegal

The launch of the Millennium Development Goals in 2000, followed by the Sustainable Development Goals in 2015, and the increasing focus on achieving universal health coverage has led to numerous interventions on both supply- and demand-sides of health systems in low- and middle-income countries. While tremendous progress has been achieved, inequities in access to healthcare persist, leading to calls for a closer examination of the equity implications of these interventions. This paper examines the equity implications of two such interventions in the context of maternal healthcare in Senegal. The first intervention on the supply-side focuses on improving the availability of maternal health services while the second intervention, on the demand-side, abolished user fees for facility deliveries. Using three rounds of Demographic Health Surveys
covering the period 1992 to 2010 and employing three measures of socioeconomic status (SES) based on household wealth, mothers’ education and rural/urban residence – we find that although both interventions increase utilisation of maternal health services, the rich benefit more from the supply-side intervention, thereby increasing inequity, while the poor benefit more from the demand-side intervention i.e. reducing inequity. Both interventions positively influence facility deliveries in rural areas although the increase in facility deliveries after the demand-side intervention is more than the increase after the supply-side intervention. There is no significant difference in utilisation based on mothers’ education. Since people from different SES categories are likely to respond differently to interventions on the supply- and demand-side of the health system, policymakers involved in the design of health programmes should pay closer attention to concerns of inequity and elite capture that may unintentionally result from these interventions

Efficacy of Trans-abdominis Plane Block for Post Cesarean Delivery Analgesia in Low-income Countries: a Phase Three Feasibility Study.

Background: Optimal pain control in a parturient woman undergoing caesarean section is essential for preventing complications such as venous thrombo-embolism and improving maternal satisfaction, early
functional recovery, mother-baby bond and breastfeeding. Intentional pain assessment and adequate management to acceptable pain severity using multimodal methods can be achieved in low-middle
income countries (LMICs).

Aim: Is to assess the efficacy of transversus abdominis plane (TAP) block and satisfaction post-cesarean delivery analgesia at Kilimanjaro Christian Medical Centre in Low-Income countries.
Methods: The study population consisted of 72 participants who met criteria posted for elective and emergency caesarean section. They were blindly assigned into two groups: group A was the interventional group which received TAP block and standard pain management according to local protocols and consisted of 41 participants and group B was the control group which received standard pain management without TAP block and consisted of 31 participants. In Group A 30ml of 0.25% bupivacaine single shot was deposited in the TAP plane bilaterally for postoperative analgesia. Participants were randomized using a parallel method. Their demographics were recorded before surgery and visual analogue scale was used to assess postoperative pain at rest and on movement, and maternal satisfaction at 0hrs, 6hrs, 12hrs and 24hrs.
Results: Total of 72 patients were analyzed using NRS with pain score at 0hr, 6hr and 12hr was significantly low by about 50% in Intervened group as compared to control group with (p-value (2 tail) of <0.001 however at 24 hrs. was 0.272. Participant in group A had extra movements at 0hr, 6hrs and 12hrs with p-value <0.001 as compare to control cut had no significant difference when coughing. Maternal
satisfaction with pain management was 95.1% with no reported adverse event.

Conclusions: Trans Abdominis Plane block when used as part of multimodal pain management is more effective in managing post-cesarean pain resulting in less physical limitation and high maternal satisfaction.

High Prevalence of Antibiotic-Resistant Gram-Negative Bacteria Causing Surgical Site Infection in a Tertiary Care Hospital of Northeast India

Background and objective
Surgical site infections (SSI) are the most common healthcare-associated infections in low- and middle-income countries associated with substantial morbidity and mortality and impose heavy demands on healthcare resources. We aimed to study the microbiological profile of SSI pathogens and their antibiotic-resistant patterns in a tertiary care teaching hospital serving mostly rural population

Methods
A prospective, hospital-based cross-sectional study on pathogen profile and drug resistance was conducted from January 2015 to December 2016. Study subjects were the patients who developed signs of SSI after undergoing surgical procedures at three surgical wards (General Surgery, Orthopedics, and Obstetrics & Gynecology). The selection of the patients was based on CDC Module. Standard bacteriological methods were applied for isolation of pathogens and antibiotic-susceptibility testing based on CLSI (Clinical Laboratory Standard Institute) guidelines.

Results
Out of 518 enrolled subjects, 197 showed growth after aerobic culture yielding 228 pathogen isolates; 12.2% of samples showed polymicrobial growth. Escherichia coli (22.4%) and Klebsiella species (20.6%) were the predominant isolated bacteria followed by Staphylococcus species (18.4%), Pseudomonas species (12.3%), and Enterococcus species (6.6%). Gram-negative bacteria (GNB) were highly resistant to ampicillin (90.1%) and cefazolin (85.9%). High resistance was also observed to mainstay drugs like ceftriaxone (48.4%), cefepime (61%), amoxycillin-clavulanic acid (43.4%), and ciprofloxacin/levofloxacin (37.7%). Among the Gram-positive cocci, Staphylococcus aureus showed 85-96% resistance to penicillin and 65-74% to ampicillin. But GPCs were relatively less resistant to quinolones (16-18%) and macrolides (21.5%). S. aureus was 100% sensitive to vancomycin and clindamycin but vancomycin-resistant Enterococci was encountered in 3/15 (20%) isolates.

Conclusion
GNBs were responsible for more than two-thirds of aerobic-culture positive SSI and showed high resistance to the commonly used antibiotics thus leaving clinicians with few choices. This necessitates periodic surveillance of causative organisms and their antibiotic-susceptibility pattern to help in formulating hospital antibiotic policy. The antibiotic stewardship program is yet to be adopted in our hospital.

Surgical candidacy and treatment initiation among women with cervical cancer at public referral hospitals in Kampala, Uganda: a descriptive cohort study

Objectives This study aimed to report the proportion of women with a new diagnosis of cervical cancer recommended for curative hysterectomy as well as associated factors. We also report recommended treatments by stage and patterns of treatment initiation.

Design This was an observational cohort study. Inperson surveys were followed by a phone call.

Setting Participants were recruited at the two public tertiary care referral hospitals in Kampala, Uganda.

Participants Adult women with a new diagnosis of cervical cancer were eligible: 332 were invited to participate, 268 met the criteria and enrolled, and 255 completed both surveys.

Primary and secondary outcomes measures The primary outcome of interest was surgical candidacy; a secondary outcome was treatment initiation. Descriptive and multivariate statistical analyses examined the associations between predictors and outcomes. Sensitivity analyses were performed to examine outcomes in subgroups, including stage and availability of radiation.

Results Among 268 participants, 76% were diagnosed at an advanced stage (IIB–IVB). In total, 12% were recommended for hysterectomy. In adjusted analysis, living within 15 km of Kampala (OR 3.10, 95% CI 1.20 to 8.03) and prior screening (OR 2.89, 95% CI 1.22 to 6.83) were significantly associated with surgical candidacy. Radiotherapy availability was not significantly associated with treatment recommendations for early-stage disease (IA–IIA), but was associated with recommended treatment modality (chemoradiation vs primary chemotherapy) for locally advanced stage (IIB–IIIB). Most (67%) had started treatment. No demographic or health factor, treatment recommendation, or radiation availability was associated with treatment initiation. Among those recommended for hysterectomy, 55% underwent surgery. Among those who had initiated treatment, 82% started the modality that was recommended.

Conclusion Women presented to public referral centres in Kampala with mostly advanced-stage cervical cancer and few were recommended for surgery. Most were able to initiate treatment. Lack of access to radiation did not significantly increase the proportion of early-stage cancers recommended for hysterectomy.

Effectiveness of interventions for improving timely diagnosis of breast and cervical cancers in low and middle-income countries: a systematic review protocol

Introduction
Breast and cervical cancers pose a major public health burden globally, with disproportionately high incidence, morbidity and mortality in low- and middle-income countries (LMICs). The majority of women diagnosed with cancer in LMICs present with late-stage disease, the treatment of which is often costlier and less effective. While interventions to improve the timely diagnosis of these cancers are increasingly being implemented in LMICs, there is uncertainty about their role and effectiveness. The aim of this review is to systematically synthesise available evidence on the nature and effectiveness of interventions for improving timely diagnosis of breast and cervical cancers in LMICs.

Methods
and analysis A comprehensive search of published and relevant grey literature will be conducted. The following electronic databases will be searched: MEDLINE (via PubMed), Cochrane Library, Scopus, CINAHL, Web of Science and the International Clinical Trials Registry Platform (ICTRP). Evidence will be synthesised in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). Two reviewers will independently screen the search outputs, select studies using predefined inclusion criteria and assess each included study for risk of bias. If sufficient data are available and studies are comparable in terms of interventions and outcomes, a meta-analysis will be conducted. Where studies are not comparable and a meta-analysis is not appropriate, a narrative synthesis of findings will be reported.

Ethics and dissemination
As this will be a systematic review of publicly available data, with no primary data collection, it will not require ethical approval. Findings will be disseminated widely through a peer-reviewed publication and forums such as conferences, workshops and community engagement sessions. This review will provide a user-friendly evidence summary for informing further efforts at developing and implementing interventions for addressing delays in breast and cervical cancer diagnosis in LMICs.

Potential impact of midwives in preventing and reducing maternal and neonatal mortality and stillbirths: a Lives Saved Tool modelling study

Background
Strengthening the capacity of midwives to deliver high-quality maternal and newborn health services has been highlighted as a priority by global health organisations. To support low-income and middle-income countries (LMICs) in their decisions about investments in health, we aimed to estimate the potential impact of midwives on reducing maternal and neonatal deaths and stillbirths under several intervention coverage scenarios.

Methods
For this modelling study, we used the Lives Saved Tool to estimate the number of deaths that would be averted by 2035, if coverage of health interventions that can be delivered by professional midwives were scaled up in 88 countries that account for the vast majority of the world’s maternal and neonatal deaths and stillbirths. We used four scenarios to assess the effects of increasing the coverage of midwife-delivered interventions by a modest amount (10% every 5 years), a substantial amount (25% every 5 years), and the amount needed to reach universal coverage of these interventions (ie, to 95%); and the effects of coverage attrition (a 2% decrease every 5 years). We grouped countries in three equal-sized groups according to their Human Development Index. Group A included the 30 countries with the lowest HDI, group B included 29 low-to-medium HDI countries, and group C included 29 medium-to-high HDI countries.

Findings
We estimated that, relative to current coverage, a substantial increase in coverage of midwife-delivered interventions could avert 41% of maternal deaths, 39% of neonatal deaths, and 26% of stillbirths, equating to 2·2 million deaths averted per year by 2035. Even a modest increase in coverage of midwife-delivered interventions could avert 22% of maternal deaths, 23% of neonatal deaths, and 14% of stillbirths, equating to 1·3 million deaths averted per year by 2035. Relative to current coverage, universal coverage of midwife-delivered interventions would avert 67% of maternal deaths, 64% of neonatal deaths, and 65% of stillbirths, allowing 4·3 million lives to be saved annually by 2035. These deaths averted would be particularly in the group B countries, which currently account for a large proportion of the world’s population and have high mortality rates compared with group C.

Interpretation
Midwives can help to substantially reduce maternal and neonatal mortality and stillbirths in LMICs. However, to realise this potential, midwives need to have skills and competencies in line with recommendations from the International Confederation of Midwives, to be part of a team of sufficient size and skill, and to work in an enabling environment. Our study highlights the potential of midwives but there are many challenges to the achievement of this potential. If increased coverage of midwife-delivered interventions can be achieved, health systems will be better able to provide effective coverage of essential sexual, reproductive, maternal, newborn, and adolescent health interventions.

Funding
New Venture Fund.

Feasibility of HPV-based cervical cancer screening in rural areas of developing countries with the example of the North Tongu District, Ghana

Cervical cancer gains increasing recognition as a preventable threat to women’s health, as expressed by WHO Director General Dr. Ghebreyesus in his recent call for its elimination. Developing countries carry the global burden and despite existing recommendations for secondary prevention screening programs their implementation remains a barrier. This doctoral thesis aims to evaluate the feasibility of an HPV-based cervical cancer screening approach in the North Tongu District, Ghana.
Methods This work studied (i) the methodological validity of self-sampling specimens from cervical cancer patients for HPV oncoprotein testing before its use in a screening population, (ii) the HPV prevalence among 2002 women, 18-65 years of age, in the general population of the North Tongu Disctrict, Ghana, through a cross-sectional population-based study with self-sampling collection in rural communities, and (iii) the natural history of HPV infection by longitudinal comparison of HPV type-specific persistence and clearance for 104 women over a four years’ time period. Results Using self-sampling cervicovaginal lavage specimens for HPV oncoprotein detection was methodologically feasible with 95% sensitivity for HPV16/18 positive cervical cancer. However self-sampling cervicovaginal scraping specimens did not reveal reliable HPV oncoprotein test results during the cross-sectional assessment. The high-risk HPV prevalence found among women living in the North Tongu District, Ghana was 32.3% and 27.3% among women in the WHO-recommended screening age range of 30-49 years. Sample collection in the rural communities was successful. Infection associated risk factors were (i) increasing age, (ii) increasing number of sexual partners and (iii) marital status, in particular not being married. Over the four years’ time period 6.7% of the women observed had persistent high-risk HPV infection, while 93.3% cleared their initial infection and 21.2% acquired new infections.
Discussion The high-risk HPV prevalence found among the general population and women 30-49 years is high and therefore requires careful planning and good infrastructure to triage high-risk HPV positive women and reduce the number of women needing treatment. Using HPV oncoprotein triage from the same self-collected specimen is not reliable at this point, stratification by sociodemographic factors risks stigmatization and retesting for HPV persistence necessitates a well-functioning recall system and HPV genotyping.
Conclusion The high HPV prevalence found demands substantial governmental support and investment to build well-functioning screening infrastructure that offers necessary triage and treatment options for women high-risk HPV positive with increased risk for cervical cancer. Integrating local infrastructure and capacity is promising but requires regional assessment rather than one-size-fit-all approaches.