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Background: Cervical cancer continues to disproportionately burden women in low/middle-income countries like Ghana. We examined treatment patterns and histopathological outcomes among women screened using visual inspection with acetic acid (VIA) and/or mobile colposcopy who subsequently underwent thermal ablation, large loop excision of the transformation zone (LLETZ), or cold knife conization at the Cervical Cancer Prevention and Training Centre, Battor. We also assessed the prevalence of cervical intraepithelial neoplasia 2+ (CIN2+) or micro-invasive disease and their associated factors for women who underwent excisional treatments. The treatment choices for cervical precancerous lesions suitable for resource-limited settings have also been described from the perspective of a center that manages a heterogenous population., Methods: We conducted an analysis of secondary data collected between June 2016 and June 2023 among women with positive findings on VIA or mobile colposcopy who subsequently underwent thermal ablation or large loop excision of the transformation zone (LLETZ). The prevalence of histopathology outcomes, including no dysplasia, CIN1 - 3, and micro-invasive disease, were estimated with 95% confidence intervals (CIs). Factors associated with histopathological findings were modeled using multinomial logistic regression., Results: For the study period, 14 (10.6%) of the total 132 participants underwent cervical lesion treatment at outreach locations, all via thermal ablation. The remaining 118 (89.4%) were treated at the Catholic Hospital, Battor using LLETZ (n = 66, 55.9%), thermal ablation (n = 51, 43.2%), and cold knife conization (n = 1, 0.9%). Among 65 women with histopathology reports, the most frequent histopathological finding was no dysplasia (47.7%; 95% CI, 35.1 - 60.5), followed by CIN2 and CIN3 (20.0%; 95% CI, 11.1 - 31.8 each), CIN1 (7.7%; 95% CI, 2.5 - 17.0) and micro-invasion (4.6%; 95% CI, 1.0 - 12.9). Those with micro-invasive disease were significantly older than those with CIN1, CIN2, and CIN3 (p = 0.036, 0.022, 0.009, respectively), but not significantly older than those who showed no dysplasia (p = 0.088). For each unit increase in age, the likelihood of CIN3 was relatively significantly reduced compared to no dysplasia (crude relative risk ratio [RRR] = 0.93; 95% CI, 0.86 - 0.99). This association was neither observed with the remaining histopathological groups nor for parity and persisted after controlling for parity (adjusted RRR = 0.92; 95% CI, 0.85 - 0.99; p = 0.025)., Conclusion: This paper largely demonstrates treatment options available to women and practitioners in LMICs. The high combined prevalence of high-grade precancerous lesions and micro-invasive disease underscores the need to increase cervical cancer awareness that would enhance screening attendance and hasten efforts at moving from opportunistic to organized screening in Ghana. This will enhance early cervical lesion detection and treatment, while simultaneously re-evaluating and cutting down on unnecessary treatment., (© 2024. The Author(s).)

Background: There is increasing evidence of a higher risk and poorer prognosis of cervical cancer among women with diabetes mellitus (DM) compared to the general population. These are mediated by higher susceptibility to persistent high-risk human papillomavirus (hr-HPV) infection due to dysfunctional clearance in an immunocompromised state. We aimed to determine the prevalence of hr-HPV infection and cervical lesions in a cohort of women with DM in Ghana. We further disaggregated the prevalence according to DM type and explored factors associated with hr-HPV infection., Methods: This retrospective descriptive cross-sectional study assessed 198 women with DM who underwent cervical screening via concurrent hr-HPV DNA testing and visual inspection with acetic acid in an outpatient department of the National Diabetes Management and Research Centre in Korle-Bu Teaching Hospital, Accra from March to May 2022. Univariate and multivariable binary logistic regression were used to explore factors associated with hr-HPV positivity., Results: Among 198 women with DM (mean age, 60.2 ± 12.1 years), the overall hr-HPV prevalence rate was 21.7% (95% CI, 16.1-28.1), disaggregated as 1.5% (95% CI, 0.3-4.4) each for HPV16 and HPV18 and 20.7% (95% CI, 15.3-27.0) for other HPV genotype(s). Respective hr-HPV prevalence rates were 37.5% (95% CI, 15.2-64.6) for type 1 DM, 19.8% (95% CI, 13.9-26.7) for type 2 DM, and 25.0% (95% CI, 8.7-49.1) for unspecified/other DM types. Past use of the combined contraceptive pill independently increased the risk of hr-HPV infection by approximately three times (adjusted odds ratio [aOR] = 2.98; 95% CI, 1.03 - 8.64; p-value = 0.045), whereas each unit increase in FBG level increased the odds of hr-HPV infection by about 15% (aOR = 1.15; 95% CI, 1.02 - 1.30; p-value = 0.021)., Conclusion: Our study points to a high prevalence of hr-HPV among women with DM and highlights a need for glycemic control among them as this could contribute to lowering their odds of hr-HPV infection. The low overall rates of HPV vaccination and prior screening also indicate a need to build capacity and expand the scope of education and services offered to women with DM as regards cervical precancer screening., (© 2024. The Author(s).)

Background: Little attention has been given to the risk of high-risk human papillomavirus (hr-HPV) infection and cervical precancerous lesions among female migrant head porters (kayayei) in Ghana, as a vulnerable group, and to promote cervical screening in these women. This pilot study aimed to determine the prevalence of hr-HPV infection and cervical lesions among kayayei in Accra, the capital of the Greater Accra Region of Ghana and to describe our approach to triaging and treating these women., Methods: This descriptive cross-sectional cohort study involved the screening of 63 kayayei aged ≥ 18 years at the Tema Station and Agbogbloshie markets in March 2022 and May 2022. Concurrent hr-HPV DNA testing (with the MA-6000 platform) and visual inspection with acetic acid (VIA) was performed. We present prevalence estimates for hr-HPV DNA positivity and VIA 'positivity' as rates, together with their 95% confidence intervals (CIs). We performed univariate and multivariable nominal logistic regression to explore factors associated with hr-HPV infection., Results: Gross vulvovaginal inspection revealed vulval warts in 3 (5.0%) and vaginal warts in 2 (3.3%) women. Overall, the rate of hr-HPV positivity was 33.3% (95% CI, 21.7-46.7), whereas the VIA 'positivity' rate was 8.3% (95% CI, 2.8-18.4). In the univariate logistic regression analysis, none of the sociodemographic and clinical variables assessed, including age, number of prior pregnancies, parity, past contraceptive use, or the presence of abnormal vaginal discharge showed statistically significant association with hr-HPV positivity. After controlling for age and past contraceptive use, only having fewer than two prior pregnancies (compared to having ≥ 2) was independently associated with reduced odds of hr-HPV infection (adjusted odds ratio, 0.11; 95% CI, 0.02-0.69)., Conclusion: In this relatively young cohort with a high hr-HPV positivity rate of 33.3% and 8.3% of women showing cervical lesions on visual inspection, we posit that kayayei may have an increased risk of developing cervical cancer if their accessibility to cervical precancer screening services is not increased., (© 2024. The Author(s).)

Introduction: Women living with HIV (WLHIV) have higher prevalence and persistence rates of high-risk human papillomavirus (hr-HPV) infection with a six-fold increased risk of cervical cancer. Thus, more frequent screening is recommended for WLHIV., Objectives: This retrospective descriptive cross-sectional study was conducted to investigate and compare the prevalence of hr-HPV infection and abnormal findings on mobile colposcopy in two cohorts of WLHIV following cervical screening in rural and urban settings in Ghana., Methods: Through the mPharma 10 000 Women Initiative, WLHIV were screened via concurrent hr-HPV DNA testing (MA-6000; Sansure Biotech Inc., Hunan, China) and visual inspection (Enhanced Visual Assessment [EVA] mobile colposcope; MobileODT, Tel Aviv, Israel) by trained nurses. The women were screened while undergoing routine outpatient reviews at HIV clinics held at the Catholic Hospital, Battor (rural setting) and Tema General Hospital (urban setting), both in Ghana., Results: Two-hundred and fifty-eight WLHIV were included in the analysis (rural, n = 132; urban, n = 126). The two groups were comparable in terms of age, time since HIV diagnosis, and duration of treatment for HIV. The hr-HPV prevalence rates were 53.7% (95% CI, 45.3-62.3) and 48.4% (95% CI, 39.7-57.1) among WLHIV screened in the rural vs urban settings ( p -value = .388). Abnormal colposcopy findings were found in 8.5% (95% CI, 5.1-11.9) of the WLHIV, with no significant difference in detection rates between the two settings ( p -value = .221). Three (13.6%) of 22 women who showed abnormal colposcopic findings underwent loop electrosurgical excision procedure (LEEP), leaving 19/22 women from both rural and urban areas with pending treatment/follow-up results, which demonstrates the difficulty faced in reaching early diagnosis and treatment, regardless of their area of residence. Histopathology following LEEP revealed CIN III in 2 WLHIV (urban setting, both hr-HPV negative) and CIN I in 1 woman in the rural setting (hr-HPV positive)., Conclusions: There is a high prevalence of hr-HPV among WLHIV in both rural and urban settings in this study in Ghana. Concurrent HPV DNA testing with a visual inspection method (colposcopy/VIA) reduces loss to follow-up compared to performing HPV DNA testing as a standalone test and recalling hr-HPV positive women for follow up with a visual inspection method. Concurrent HPV DNA testing and a visual inspection method may also pick up precancerous cervical lesions that are hr-HPV negative and may be missed if HPV DNA testing is performed alone., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Human papillomavirus (HPV) DNA testing is more sensitive than cytology for detecting cervical precancer; however, increasing reports of high-risk HPV (hr-HPV)-negative cases of cervical intraepithelial neoplasia (CIN) and even malignancy motivate the use of combined testing. We present our experience with 'tritesting', defined as the performance of HPV DNA testing, cytology and visual inspection in a single session at the Cervical Cancer Prevention and Training Centre, Ghana. We further determined the prevalence rates of hr-HPV infection, abnormal cytology and cervical lesions among women screened using tritesting., Methods: This descriptive retrospective cross-sectional study assessed all women screened via tritesting between April 2019 to April 2023. HPV DNA testing was performed using the Sansure MA-6000, GeneXpert or AmpFire platforms. Visual inspection was performed using enhanced visual assessment mobile colposcopy or visual inspection with acetic acid. Liquid-based cytology was performed using cervical samples taken with a Cervex-Brush® and fixed in PreservCyt, while samples for conventional cytology were taken using an Ayre spatula and cytobrush., Results: Among 236 women screened (mean age, 39.1 years (standard deviation, 10.9)), the overall prevalence rates of hr-HPV infection and cervical lesions were 17.8% (95% confidence interval (CI), 13.1-23.3) and 11.9% (95% CI, 8.0-16.7), respectively. Cytology yielded findings of atypical squamous cells of undetermined significance or worse in 2.5% (95% CI, 0.9-5.5) of women. Histopathology following loop electrosurgical excision procedure revealed CIN I (tritest positive) and CIN III (hr-HPV-positive, visual inspection 'positive', cytology-negative) in one woman each. Factors independently associated with hr-HPV infection among 'tritested' women were age ≥ 39 years, tertiary level of education and current contraceptive use. Twenty-seven out of 39 hr-HPV-positive women (69.2%; 95% CI, 52.4-83.0) showed a type 3 transformation zone and would have needed to be recalled for a cytologic sample to be taken in a 'see and triage' approach with HPV DNA testing and a visual inspection method., Conclusion: This study brings tritesting into the spotlight, as an alternative to other methods, particularly for women who prefer this due to the advantage of a single visit to a health facility and being more cost-effective, if they have to travel long distances to access cervical screening services., Competing Interests: The authors declare that they have no conflict of interest., (© the authors; licensee ecancermedicalscience.)

Background: Cervical precancer screening in low-resource settings is largely opportunistic with low coverage. Many women in these settings, where the burden of cervical cancer is highest, only visit health institutions when pregnant or after delivery. We explored screening during antenatal and postnatal visits aimed at increasing coverage., Methods: Pregnant women (in any trimester) attending antenatal care (ANC) and women attending postnatal care (PNC; 6-10 weeks) clinics were screened at Catholic Hospital, Battor and at outreach clinics from February to August 2022 (08/02/2022 to 02/08/2022). At the same visit, cervical specimens were obtained for high-risk human papillomavirus (hr-HPV) DNA testing (with the Sansure MA-6000 PCR platform) followed by either visual inspection with acetic acid (VIA) or mobile colposcopy with the enhanced visual assessment system., Results: Two hundred and seventy and 107 women were screened in the antenatal and postnatal groups, respectively. The mean ages were 29.4 (SD, 5.4) in the ANC group and 28.6 (SD, 6.4) years in the PNC group. The overall hr-HPV prevalence rate was 25.5% (95% confidence interval (CI), 21.1-29.9) disaggregated as 26.7% (95% CI, 21.4-31.9) in the ANC group and 22.4% (95% CI, 14.5-30.3) in the PNC group ( p = 0.3946). Overall, 58.9% of pregnant women (28.3% hr-HPV+) and 66.4% of postnatal women (22.5% hr-HPV+) only visited a health facility when pregnant or after delivery (at Child Welfare Clinics). The VIA 'positivity' rate for all screened women was 5.3% (95% CI, 3.1-7.6), disaggregated into 5.2% (95% CI, 2.5-7.8) in the ANC group and 5.7% (95% CI, 1.3-10.1) in the PNC group ( p -value = 0.853)., Conclusion: A significant number of women in Ghana only visit a health facility during pregnancy or after delivery. ANC and PNC clinics would offer opportunities to increase coverage in cervical precancer screening in low-resource settings. Relying on community nurses ensures that such programs are readily integrated into routine care of women and no opportunity is missed., Competing Interests: The authors declare that they have no conflict of interest., (© the authors; licensee ecancermedicalscience.)

Background: The need for cervical cancer screening has been emphasised in at-risk cohorts of women to reduce their risk of cervical cancer. Some women with decreased risk of acquiring human papillomavirus (HPV) infections, such as Catholic nuns, receive less attention and on occasion are missed in cervical cancer screening programmes. This study aimed to determine the high-risk HPV (hr-HPV) prevalence in such a cohort to emphasise the need for cervical precancer screening among all women. To improve compliance, we employed self-sampling., Methods: This descriptive cross-sectional cohort study involved the data of 105 Catholic nuns subjected to cervical screening using self-samples in the Greater Accra, Volta, and Central regions of Ghana between June 4, 2022 and June 30, 2022. hr-HPV testing was performed on self-samples using the MA-6000 HPV DNA platform. Screen-positive nuns underwent follow-up pap smears and EVA colposcopy. In addition to descriptive analysis, univariate and multivariable nominal logistic regression was used to explore the relationship between hr-HPV positivity and selected continuous and categorical factors., Findings: 105 nuns from three convents were screened with hr-HPV DNA testing (MA-6000). Twenty-five tested positive for hr-HPV (prevalence of 23.8% (95% CI, 15.7-32.0) [HPV 18 only (n = 2, 1.9%), non-HPV 16/18 genotypes ( others ) (n = 22, 21.0%), and mixed infection with HPV 16 and other genotype(s) (n = 1, 1.0%)]. Pap smears for all 25 hr-HPV-positives came in as negative for intraepithelial lesions or malignancy, whereas EVA mobile colposcopy showed minor abnormal findings in two (8.0%; 95% CI, 1.0-26.0), both of whom were managed conservatively., Interpretation: Our findings suggest that the hr-HPV prevalence in this cohort of nuns is similar to that of the general population. To meet the World Health Organization's target for cervical cancer elimination, it is important that all women are given access to cervical cancer screening and preventative services. Further, increasing 'anonymity' and privacy among nuns through self-sampling may be crucial to expanding choice, coverage, and uptake of screening in support of their health rights., Funding: None., Competing Interests: All authors report no competing interests., (© 2023 The Author(s).)

In response to calls by the World Health Organization for cervical precancer screening services in low-resource settings to lean toward HPV DNA testing, a number of testing platforms have been made available. This study aimed to evaluate the operational parameters of four HPV testing systems in previous (careHPV) and current (GeneXpert, AmpFire, and MA-6000) use in a secondary healthcare setting in terms of 'appropriateness', ease of use, throughput, and diagnostic yield. This descriptive retrospective cohort analysis included 6056 women who presented to our facility between June 2016 and March 2022 for cervical precancer screening via HPV testing. A large majority of this cohort underwent AmpFire testing (55.8%), followed by careHPV (23.3%), MA-6000 (14.7%), and GeneXpert (6.1%). MA-6000 showed the highest hr-HPV positivity rate of 26.4% (95% CI, 23.6-29.5), followed by AmpFire (17.2%; 95% CI, 15.9-17.5). GeneXpert and careHPV showed similar hr-HPV positivity rates of 14.8% (95% CI, 11.3-18.8) and 14.8% (95% CI, 13.0-16.8), respectively. For the AmpFire and MA-6000 platforms, which utilize similar detection and reporting formats, we found a significant excess detection rate of 9.2% (95% CI, 6.1-12.4; p-value <0.0001) for MA-6000 compared to AmpFire. At the genotype level, MA-6000 also detected significantly higher rates of HPV 16 and other hr-HPV types (both p-values <0.001) than AmpFire; there was no difference in detection for HPV 18. Based on our experiences and preliminary analysis, we believe that the choice of HPV testing platform cannot be accomplished with a one-size-fits-all approach. Factors worth considering are the financial implications of platform acquisition, costs to clients, and throughput when screening programs are not sufficiently large. We describe our successes and challenges with the different platforms which we believe will be helpful to centers in low-income countries as they transition into using HPV DNA testing for cervical precancer screening., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Effah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Worldwide, about 20-25 million people are affected by sickle cell disease (SCD), with 60% of patients living in sub-Saharan Africa. Despite recent therapeutic advancements resulting in improved life expectancy among SCD patients, the prevalence of high-risk human papillomavirus (hr-HPV) and cervical lesions have not been studied in women with SCD. We determined the prevalence of hr-HPV and cervical lesions among women with SCD and recommended strategies for reducing cervical cancer incidence in this cohort., Methods: Through the mPharma 10,000 Women Initiative, women with SCD attending routine visits at the Ghana Institute of Clinical Genetics SCD clinic were screened by trained nurses. Screening was performed via concurrent MA-6000 hr-HPV DNA testing and enhanced visual assessment (EVA) mobile colposcopy from mobileODT., Results: Among 168 participants screened (mean age, 43.0 years), the overall prevalence rates of hr-HPV infection and cervical lesions were 28.6% (95% CI, 21.7-35.4) and 3.6% (95% CI, 0.8-6.4), respectively. The hr-HPV prevalence rates stratified by haemoglobin genotype were 29.4% (95% CI, 19.7-39.1) and 28.6% (95% CI, 18.5-38.7) for genotypes SS and SC, respectively. None of the five women with the SF genotype tested hr-HPV positive, and the only patient with Sbthal genotype tested hr-HPV positive. Two women were EVA 'positive' but hr-HPV negative, whereas four were EVA positive and hr-HPV positive. Exploratory analysis revealed no significant associations between hr-HPV positivity and age, education level, marital status or parity., Conclusion: In the absence of a comprehensive national cervical screening programme aimed at including women with SCD as a special population, cervical cancer may increase in frequency among SCD patients. Thus, there is a need to build capacity and expand the scope of screening services for women with SCD., Competing Interests: The authors declare that they have no conflict of interest., (© the authors; licensee ecancermedicalscience.)

High-risk human papillomavirus (hr-HPV) testing for primary cervical precancer screening offers an opportunity to improve screening in low-middle income countries (LMICs). This study aimed to compare the analytic performances of the AmpFire and MA-6000 platforms for hr-HPV DNA testing in three groups of women screened for hr-HPV types in Ghana: group 1 with 33 GeneXpert-archived ThinPrep/liquid-based samples subjected to both tests, group 2 with 50 AmpFire-archived dry brush samples subjected to MA-6000 testing, and group 3 involving 143 cotton swab samples simultaneously subjected to both tests without archiving. The overall agreement rates were 73 %, 92 %, and 84 %, for groups 1-3, respectively, and 84 % (95 % CI, 78.6-88.6) for the entire group. Neither AmpFire nor MA-6000 was more likely to test hr-HPV positive in all three groups and the combined group. Group 1 showed fair agreement without statistical significance (κ = 0.224, 95 % CI, -0.118 to 0.565), while group 3 showed significant moderate agreement (κ = 0.591, 95% CI, 0.442-0.741). Group 2 showed an almost perfect significant level of agreement (κ = 0.802; 95 % CI, 0.616-0.987). Thus, both platforms showed statistically significant moderate to near-perfect agreement for detecting hr-HPV in cervicovaginal samples, with variation according to archiving conditions and duration between sample collection and retesting. For LMICs using these platforms for COVID-19 testing, as the COVID-19 pandemic subsides, the platforms can become available for running other tests such as hr-HPV DNA testing for cervical precancer screening., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cytology-based cervical cancer screening programs have been difficult to implement and scale up in developing countries. Thus, the World Health Organization recommends a 'see and treat' approach by way of hr-HPV testing and visual inspection. We aimed to evaluate concurrent HPV DNA testing and visual inspection in a real-world low-resource setting by comparing the detection rates of concurrent visual inspection with dilute acetic acid (VIA) or mobile colposcopy and hr-HPV DNA testing to standalone hr-HPV DNA testing (using the careHPV, GeneXpert, AmpFire, or MA-6000 platforms). We further compared their rates of loss to follow-up. This retrospective, descriptive cross-sectional study included all 4482 women subjected to cervical precancer screening at our facility between June 2016 and March 2022. The rates of EVA and VIA 'positivity' were 8.6% (95% CI, 6.7-10.6) and 2.1 (95% CI, 1.6-2.5), respectively, while the hr-HPV-positivity rate was 17.9% (95% CI, 16.7-19.0). Overall, 51 women in the entire cohort tested positive on both hr-HPV DNA testing and visual inspection (1.1%; 95% CI, 0.9-1.5), whereas a large majority of the women tested negative (3588/4482, 80.1%) for both and 2.1% (95% CI, 1.7-2.6) tested hr-HPV-negative but visual inspection 'positive'. In total, 191/275 (69.5%) participants who tested hr-HPV positive on any platform, as a standalone test for screening, returned for at least one follow-up visit. In light of factors such as poor socioeconomic circumstances, additional transportation costs associated with multiple screening visits, and lack of a reliable address system in many parts of Ghana, we posit that standalone HPV DNA testing with recall of hr-HPV positives will be tedious for a national cervical cancer prevention program. Our preliminary data show that concurrent testing (hr-HPV DNA testing alongside visual inspection by way of VIA or mobile colposcopy) may be more cost-effective than recalling hr-HPV-positive women for colposcopy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Effah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Cervical precancer screening programs are difficult to establish in low resource settings partly because of a lack of human resource. Our aiming was to overcome this challenge. We hypothesized that this could be done through task shifting to trained nurses., Design: Descriptive retrospective cross-sectional review., Setting: Training was at the Cervical Cancer Prevention and Training Center (CCPTC) and screening was carried out at the clinic and at outreaches / peripheral facilities., Participants: All women who reported to the clinic for screening or were recruited during outreaches., Interventions: All 4 nurses were trained for at least 2weeks (module 1). A total of 904 women were screened by the trained nurses using the EVA system. Quality assurance was ensured., Main Outcome Measures: Primary screening and follow-up were carried out by the trained nurses with quality assured through image sharing and meetings with peers and experienced gynaecologists., Results: 828 women had primary screening and 76 had follow-up screening. 739 (89.3%) were screened at the clinic and 89 (10.7%) at outreaches/peripheral facilities. Of all screened, 130 (14.5%) had cervical lesions, and 25 (2.8%) were treated, 12 (48.0%) by Loop Electrosurgical Excision Procedure (LEEP) performed by a gynaecologist, 11 (44.0%) with thermal coagulation by trained nurses except one, and 2 (8.0%) with cryotherapy by trained nurses., Conclusion: We demonstrate the utility of a model where nurses trained in basic colposcopy can be used to successfully implement a cervical precancer screening and treatment program in low-resource settings., Funding: None indicated., Competing Interests: Conflict of interest: The authors declare no conflict of interest, (Copyright © The Author(s).)