Maternal experiences of caring for an infant with neurological impairment after neonatal encephalopathy in Uganda: a qualitative study.

PURPOSE: The study investigated maternal experiences of caring for a child affected by neurological impairment after neonatal encephalopathy (NE) ("birth asphyxia") in Uganda. METHODS: Between September 2011 and October 2012 small group and one-on-one in-depths interviews were conducted with mothers recruited to the ABAaNA study examining outcomes from NE in Mulago hospital, Kampala. Data were analysed thematically with the aid of Nvivo 8 software. FINDINGS: Mothers reported caring for an infant with impairment was often complicated by substantial social, emotional and financial difficulties and stigma. High levels of emotional distress, feelings of social isolation and fearfulness about the future were described. Maternal health-seeking ability was exacerbated by high transport costs, lack of paternal support and poor availability of rehabilitation and counselling services. Meeting and sharing experiences with similarly affected mothers was associated with more positive maternal caring experiences. CONCLUSION: Mothering a child with neurological impairment after NE is emotionally, physically and financially challenging but this may be partly mitigated by good social support and opportunities to share caring experiences with similarly affected mothers. A facilitated, participatory, community-based approach to rehabilitation training may have important impacts on maximising participation and improving the quality of life of affected mothers and infants. Implications for Rehabilitation Caring for an infant with neurological impairment after NE in Uganda has substantial emotional, social and financial impacts on families and is associated with high levels of emotional stress, feelings of isolation and stigma amongst mothers. Improved social support and the opportunity to share experiences with other similarly affected mothers are associated with a more positive maternal caring experience. High transport costs, lack of paternal support and poor availability of counselling and support services were barriers to maternal healthcare seeking. Studies examining the feasibility, acceptability and impact of early intervention programmes are warranted to maximise participation and improve the quality of life for affected mothers and their infants

QUEnch assiSTed (QUEST) MRI Used as a Novel Approach to Identify Reactive Oxygen Species as a Result of Experimental TBI

Introduction: Traumatic brain injury (TBI) generates reactive oxygen species (ROS), promoting inflammatory processes and impeding TBI recovery. Within the VA population, over 70% of military personnel that sustain a TBI receive opioid-based pain relief, however, opiates may actually exacerbate post-TBI complications through its documented recruitment of oxidative and inflammatory systems. Thus, we hypothesize that TBI and opioid treatment act synergistically to worsen post-TBI oxidative stress. Methods: Mice were exposed to either TBI or sham injury and administered morphine or saline in the acute post-injury period. Afterwards, neuroimaging was conducted using a novel technique, QUEnch assiSTed (QUEST) MRI, which compares standard MRI signals across mice that acutely receive an antioxidant “quench” therapy and those receiving saline as control. Therefore, differential MRI signals between these groups are an index of ROS generation. Changes in hippocampus and cortex signals were measured, as these structures are most commonly affected by TBI. Methylene blue and α-lipoic acid were used as antioxidants in the quenching step as they halt mitochondrial ROS production and scavenge excess ROS, respectively. Results: No significant changes in ROS levels were detected as a result of TBI, opioid exposure or their combination using QUEST MRI in either the cortex or hippocampus. Conclusions and Future Directions: While QUEST imaging did not yield significant changes between experimental groups, future work will include ex-vivo biochemical ROS analyses from harvested tissues, which will provide higher resolution quantification of oxidative processes than that of QUEST MRI

A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope

Globular clusters with their large populations of millisecond pulsars (MSPs) are believed to be potential emitters of high-energy gamma-ray emission. Our goal is to constrain the millisecond pulsar populations in globular clusters from analysis of gamma-ray observations. We use 546 days of continuous sky-survey observations obtained with the Large Area Telescope aboard the Fermi Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular clusters. Steady point-like high-energy gamma-ray emission has been significantly detected towards 8 globular clusters. Five of them (47 Tucanae, Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices $(0.7 < \Gamma <1.4)$ and clear evidence for an exponential cut-off in the range 1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral indices $(1.0 < \Gamma < 1.7)$, however the presence of an exponential cut-off can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC 6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral properties. From the observed gamma-ray luminosities, we estimate the total number of MSPs that is expected to be present in these globular clusters. We show that our estimates of the MSP population correlate with the stellar encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters, commensurate with previous estimates. The observation of high-energy gamma-ray emission from a globular cluster thus provides a reliable independent method to assess their millisecond pulsar populations that can be used to make constraints on the original neutron star X-ray binary population, essential for understanding the importance of binary systems in slowing the inevitable core collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J. Kn\"odlseder, N. Webb, B. Pancraz

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Dermoscopy, with and without visual inspection, for the diagnosis of melanoma in adults

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of ‘tests’ to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other highresolution image analysis techniques. Objectives: To determine the diagnostic accuracy of dermoscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults, and to compare its accuracy with that of visual inspection alone. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary ROC methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. Main results: A total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases) were included, providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as ‘High’ concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic. The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in-person (dermoscopy added to visual inspection) and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) of 4.6; 95% CI 2.4, 9.0, P<0.001). Accuracy was compared for (a) in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas) versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas) and for (b) image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas) versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a) 4.7 (95% CI: 3.0 to 7.5; P < 0.001) and (b) 5.6 (95% CI: 3.7 to 8.5; P < 0.001). These effects correspond to predicted differences in sensitivity of (a) 16% (95% CI: 8%, 23%) (92% for dermoscopy+visual inspection vs 76% for visual inspection) and (b) 35% (95% CI 24% to 46%) (81% for dermoscopy vs 47% for visual inspection) at a fixed specificity of 80%; and topredicted differences in specificity of (a) 20% (95% CI 7%, 33) (95% for dermoscopy plus visual inspection vs 75% for visual inspection) and (b) 40% (95% CI 27, 57) (82% for dermoscopy vs 42% for visual inspection) at a fixed sensitivity of 80%. Using the median prevalence of disease in each set of studies ((a) 12% for in-person and (b) 24% for image-based) for a hypothetical population of 1000 lesions, an increase in sensitivity of (a) 16% (in-person) and (b) 35% (image-based) from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a) 19 and (b) 81 with (a) 176 and (b) 152 false positive results. An increase in specificity of (a) 20% (in-person) and (b) 40% (image-based) at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a) 176 and (b) 304 with (a) 24 and (b) 48 melanomas missed. The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis) had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34, 5.6; P=0.17) or image-based (RDOR 1.4, 95% CI 0.60, 3.3; P=0.22) evaluations. This result was supported by subgroup analysis according to algorithm used. Higher accuracy for observers reported as having high experience and for those classed as ‘expert consultants’ in comparison to those considered to have less experience in dermoscopy was observed, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. Authors' conclusions: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care is limited however it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in-person are lacking

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk

Dermoscopy, with and without visual inspection, for the diagnosis of melanoma in adults

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of ‘tests’ to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other highresolution image analysis techniques. Objectives: To determine the diagnostic accuracy of dermoscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults, and to compare its accuracy with that of visual inspection alone. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary ROC methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. Main results: A total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases) were included, providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as ‘High’ concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic. The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in-person (dermoscopy added to visual inspection) and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) of 4.6; 95% CI 2.4, 9.0, P<0.001). Accuracy was compared for (a) in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas) versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas) and for (b) image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas) versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a) 4.7 (95% CI: 3.0 to 7.5; P < 0.001) and (b) 5.6 (95% CI: 3.7 to 8.5; P < 0.001). These effects correspond to predicted differences in sensitivity of (a) 16% (95% CI: 8%, 23%) (92% for dermoscopy+visual inspection vs 76% for visual inspection) and (b) 35% (95% CI 24% to 46%) (81% for dermoscopy vs 47% for visual inspection) at a fixed specificity of 80%; and topredicted differences in specificity of (a) 20% (95% CI 7%, 33) (95% for dermoscopy plus visual inspection vs 75% for visual inspection) and (b) 40% (95% CI 27, 57) (82% for dermoscopy vs 42% for visual inspection) at a fixed sensitivity of 80%. Using the median prevalence of disease in each set of studies ((a) 12% for in-person and (b) 24% for image-based) for a hypothetical population of 1000 lesions, an increase in sensitivity of (a) 16% (in-person) and (b) 35% (image-based) from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a) 19 and (b) 81 with (a) 176 and (b) 152 false positive results. An increase in specificity of (a) 20% (in-person) and (b) 40% (image-based) at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a) 176 and (b) 304 with (a) 24 and (b) 48 melanomas missed. The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis) had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34, 5.6; P=0.17) or image-based (RDOR 1.4, 95% CI 0.60, 3.3; P=0.22) evaluations. This result was supported by subgroup analysis according to algorithm used. Higher accuracy for observers reported as having high experience and for those classed as ‘expert consultants’ in comparison to those considered to have less experience in dermoscopy was observed, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. Authors' conclusions: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care is limited however it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in-person are lacking

Visual inspection for the diagnosis of cutaneous melanoma in adults

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. History-taking and visual inspection of a suspicious lesion by a clinician is usually the first in a series of ‘tests’ to diagnose skin cancer. Establishing the accuracy of visual inspection alone is critical to understating the potential contribution of additional tests to assist in the diagnosis of melanoma. Objectives: To determine the diagnostic accuracy of visual inspection for the detection of cutaneous invasive melanoma and intraepidermal melanocytic variants in adults with limited prior testing and in those referred for further evaluation of a suspicious lesion. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Test accuracy studies of any design that evaluated visual inspection in adults with lesions suspicious for melanoma, compared with a reference standard of, either histological confirmation or clinical follow-up. Studies reporting data for ‘clinical diagnosis’ where dermoscopy may or may not have been used were excluded. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. We investigated the impact of: in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise. Main results: Forty-nine publications reporting on a total of 51 study cohorts with 34,351 lesions (including 2499 cases) were included, providing 134 datasets for visual inspection. Across almost all study quality domains, insufficient information was provided in the majority of study reports to allow the risk of bias to be judged, while concerns regarding applicability of study findings were scored as ‘High’ in three of four domains assessed. Selective participant recruitment, lack of detail regarding the threshold for deciding on a positive test result, and lack of detail on observer expertise were particularly problematic. Attempts to analyse studies by degree of prior testing were hampered by a lack of relevant information and by the restricted inclusion of lesions selected for biopsy or excision. Accuracy was generally much higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio of 8.54, 95% CI 2.89, 25.3, P<0.001). Meta-analysis of in-person evaluations that could be clearly placed on the clinical pathway showed a general trade-off between sensitivity and specificity, with the highest sensitivity (92.4%, 95% CI 26.2, 99.8%) and lowest specificity (79.7%, 95% CI 73.7, 84.7%) observed in participants with limited prior testing (n = 3 datasets). Summary sensitivities were lower for those referred for specialist assessment but with much higher specificities (e.g. sensitivity 76.7% (95% CI 61.7, 87.1%) and specificity 95.7% (95% CI 89.7, 98.3%) for lesions selected for excision, n = 8 datasets). These differences may be related to differences in the spectrum of included lesions, differences in the definition of a positive test result, or to variations in observer expertise. We did not find clear evidence that accuracy is improved by the use of any algorithm to assist diagnosis in all settings. Attempts to examine the effect of observer expertise in melanoma diagnosis were hindered due to poor reporting. Authors' conclusions: Visual inspection is a fundamental component of the assessment of a suspicious skin lesion; however, the evidence suggests that melanomas will be missed if visual inspection is used on its own. The evidence to support its accuracy in the range of settings in which it is used is flawed and very poorly reported. Although published algorithms do not appear to improve accuracy, there is insufficient evidence to suggest that the ‘no algorithm’ approach should be preferred in all settings. Despite the volume of research evaluating visual inspection, further prospective evaluation of the potential added value of using established algorithms according to the prior testing or diagnostic difficulty of lesions may be warranted

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug$11, HIV test $4, and$14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3$100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation