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Purpose: This study explores the attributes of true positive and false positive rates in screening mammogram test sets assessed by breast screening radiologists in order to identify the combined impact of prior images, breast density and lesion features with experience factors linked to diagnostic performance., Methods: 869 radiologists' first-time readings across nine mammogram BREAST test sets with 361 normal and 179 cancer mammograms were collected between 2014 and 2023. Participants viewed digital mammograms on diagnostic monitors and localized abnormal lesions. The performances of readers in normal and cancer cases were compared with the ground truth and analyzed in four quartiles of breast density, lesion types and the availability of prior images using Man-Whitney U and Kruskal Wallis tests. The general linear model was applied to determine independent and significant covariates that affected the true positives and false positives. The correlation of the readers' experience with the performances in different case and lesion features was explored using Spearman test., Results: The combination of lesion appearance and the availability of prior images had a significant impact on false positive results (P=0.033). The model that included lesion appearance, breast density, and no prior image status significantly influenced case true positives of readers (P=0.026). Meanwhile, the model considering only lesion appearance and breast density (P=0.002) had a significant effect on lesion true positives. There was a positive correlation observed between the number of cases read per week and readers' performances, including TP rates and lesion sensitivity across various lesion types (P<0.05). Radiologists reading over 100 cases weekly achieved 80 % true positive rate for architectural distortion, asymmetric density, and masses, while this threshold increased to over 150 cases for calcifications. Detecting mixed lesion types required reading more than 60 cases weekly. Radiologists with over 5 years' experience achieved 70-75 % accuracy in localizing cancer lesions., Conclusion: Findings highlight the significant combined impact of breast density, prior image availability, lesion characteristics, and breast screening readers' experience on breast cancer detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aims: To establish the impact that access to prior mammograms has on radiologists' performance and the influence of radiologists' characteristics and breast density on their subsequent performance., Methods: Eight participants independently interpreted 72 digital screening mammograms in two reading sessions using the Royal Australian and New Zealand College of Radiologist's classification. In the first reading session, participants were given access to current and prior mammograms. In the second reading session six months later, participants only had access to the current mammograms. Radiologists' specificity, sensitivity, lesion sensitivity, Receiver Operating Characteristic (ROC) curve, and Jacknife Alternative Free-response ROC (JAFROC) were calculated. A Paired T-test was used to compare readings with and without prior mammograms, and to assess if breast density influenced participants performance. Independent Sample T-test was used to compare performance across radiologists' characteristics. A relative risk analysis was conducted to assess the probability of false positives and false negatives when prior mammograms were available., Results: Access to prior mammograms improved specificity in dense and non-dense breasts (p≤0.01) and reduced false positives (p = 0.01) but had no effect on sensitivity (p = 0.37), lesion sensitivity (p = 0.67), ROC (p = 0.16), and JAFROC (p = 0.24). Prior mammogram also reduced the probability of false positives (RR = 0.38; 95%CI:0.26-0.57, p<0.0001) without affecting the false negative rate (RR = 1.14; 95%CI:0.88-1.49, p = 0.30). The impact of prior mammograms on performance was not influenced by breast density or radiologists' characteristics., Conclusions: Access to prior mammograms improves radiologists' specificity and reduces false positives without affecting sensitivity and the false negative rate regardless of radiologists' characteristics and breast density., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Rationale and Objectives: Integrating learning spacing in medicine has shown promise in enhancing knowledge retention and diagnostic proficiency. While studies demonstrate the effectiveness of spaced learning in various fields, limited research exists on its application in radiological training. This study aims to investigate the impact of intervals in spaced training on radiologists' and trainees' diagnostic performance via mammogram test sets., Methods: 54 radiologists and 101 radiology trainees completed 207 and 458 first-time readings of 9 mammogram test sets between 2019 and 2023. Each test set comprised of 60 mammograms (20 cancer and 40 normal), sourced retrospectively from BreastScreen Australia. Each radiologist evaluated mammograms using the BIRADS lexicon. Readers' performance was compared with truth data and evaluated in terms of specificity, case sensitivity, lesion sensitivity, ROC AUC and JAFROC FOM. The progress of readers' performances in following test sets after the first one was analyzed using Wilcoxon Signed Rank test. The association of participants' performances and the intervals among test sets' completions was investigated using Pearson's test., Results: Significant positive correlations were found between intervals and radiologists' improvement in specificity and JAFROC FOM (P < 0.05). The separation of 4 to 10 days showed the most improvement among radiologists across all metrics, while intervals exceeding 90 days related to highest increase in case sensitivity (5.15%), lesion sensitivity (6.55%), ROC AUC (3.05%) and JAFROC FOM (6.3%). Trainees completing test sets in one day showed positive correlations with their ROC AUC (R=0.45; P = 0.008) and JAFROC FOM (R=0.43; P = 0.02), while those taking a longer time to complete showed negative impacts on case sensitivity (P = 0.009) and ROC AUC (P = 0.02). Remarkable progress in trainees was found in case sensitivity (6.15%), lesion sensitivity (11.6%), ROC AUC (3.5%) and JAFROC FOM (4.35%) with test set intervals of 31-90 days., Conclusions: Radiologists demonstrated superior performance when the training test sets were spaced over longer intervals, whereas trainees exhibited proficiency with shorter time separations. By optimizing the spacing of reviewing and practicing radiological concepts, mammogram readers can bolster memory retention and diagnostic decision-making skills., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing Interests All authors have no conflicts of interest related to the work described in the study., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

G protein-coupled receptors (GPCRs) are the largest group of membrane receptors in the central nervous system and one of the key proteins for signal transduction between cells. Currently, many drugs available on the market act via GPCRs and these receptors remain attractive targets for the treatment of brain disorders, including alcohol use disorder (AUD). Here, we describe the most recent literature, with a primary focus on the past 5 years, on GPCR targets with the potential for reducing behaviours associated with excessive alcohol intake. Specifically, we focus on preclinical evidence of compounds with attractive pharmacological profiles and potential for future clinical investigation for the treatment of AUD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives This study explored the familiarity, perceptions and confidence of Australian radiology clinicians involved in reading screening mammograms, regarding artificial intelligence (AI) applications in breast cancer detection. Methods Sixty-five radiologists, breast physicians and radiology trainees participated in an online survey that consisted of 23 multiple choice questions asking about their experience and familiarity with AI products. Furthermore, the survey asked about their confidence in using AI outputs and their preference for AI modes applied in a breast screening context. Participants' responses to questions were compared using Pearson's χ 2 test. Bonferroni-adjusted significance tests were used for pairwise comparisons. Results Fifty-five percent of respondents had experience with AI in their workplaces, with automatic density measurement powered by machine learning being the most familiar AI product (69.4%). The top AI outputs with the highest ranks of perceived confidence were 'Displaying suspicious areas on mammograms with the percentage of cancer possibility' (67.8%) and 'Automatic mammogram classification (normal, benign, cancer, uncertain)' (64.6%). Radiology and breast physicians preferred using AI as second-reader mode (75.4% saying 'somewhat happy' to 'extremely happy') over triage (47.7%), pre-screening and first-reader modes (both with 26.2%) (P  < 0.001). Conclusion The majority of screen readers expressed increased confidence in utilising AI for highlighting suspicious areas on mammograms and for automatically classifying mammograms. They considered AI as an optimal second-reader mode being the most ideal use in a screening program. The findings provide valuable insights into the familiarities and expectations of radiologists and breast clinicians for the AI products that can enhance the effectiveness of the breast cancer screening programs, benefitting both healthcare professionals and patients alike.

Although the value of adding AI as a surrogate second reader in various scenarios has been investigated, it is unknown whether implementing an AI tool within double reading practice would capture additional subtle cancers missed by both radiologists who independently assessed the mammograms. This paper assesses the effectiveness of two state-of-the-art Artificial Intelligence (AI) models in detecting retrospectively-identified missed cancers within a screening program employing double reading practices. The study also explores the agreement between AI and radiologists in locating the lesions, considering various levels of concordance among the radiologists in locating the lesions. The Globally-aware Multiple Instance Classifier (GMIC) and Global-Local Activation Maps (GLAM) models were fine-tuned for our dataset. We evaluated the sensitivity of both models on missed cancers retrospectively identified by a panel of three radiologists who reviewed prior examinations of 729 cancer cases detected in a screening program with double reading practice. Two of these experts annotated the lesions, and based on their concordance levels, cases were categorized as 'almost perfect,' 'substantial,' 'moderate,' and 'poor.' We employed Similarity or Histogram Intersection (SIM) and Kullback-Leibler Divergence (KLD) metrics to compare saliency maps of malignant cases from the AI model with annotations from radiologists in each category. In total, 24.82% of cancers were labeled as "missed." The performance of GMIC and GLAM on the missed cancer cases was 82.98% and 79.79%, respectively, while for the true screen-detected cancers, the performances were 89.54% and 87.25%, respectively (p-values for the difference in sensitivity < 0.05). As anticipated, SIM and KLD from saliency maps were best in 'almost perfect,' followed by 'substantial,' 'moderate,' and 'poor.' Both GMIC and GLAM (p-values < 0.05) exhibited greater sensitivity at higher concordance. Even in a screening program with independent double reading, adding AI could potentially identify missed cancers. However, the challenging-to-locate lesions for radiologists impose a similar challenge for AI., (© 2024. The Author(s).)

This paper investigates the adaptability of four state-of-the-art artificial intelligence (AI) models to the Australian mammographic context through transfer learning, explores the impact of image enhancement on model performance and analyses the relationship between AI outputs and histopathological features for clinical relevance and accuracy assessment. A total of 1712 screening mammograms ( n = 856 cancer cases and n = 856 matched normal cases) were used in this study. The 856 cases with cancer lesions were annotated by two expert radiologists and the level of concordance between their annotations was used to establish two sets: a 'high-concordances subset' with 99% agreement of cancer location and an 'entire dataset' with all cases included. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of Globally aware Multiple Instance Classifier (GMIC), Global-Local Activation Maps (GLAM), I&H and End2End AI models, both in the pretrained and transfer learning modes, with and without applying the Contrast Limited Adaptive Histogram Equalization (CLAHE) algorithm. The four AI models with and without transfer learning in the high-concordance subset outperformed those in the entire dataset. Applying the CLAHE algorithm to mammograms improved the performance of the AI models. In the high-concordance subset with the transfer learning and CLAHE algorithm applied, the AUC of the GMIC model was highest (0.912), followed by the GLAM model (0.909), I&H (0.893) and End2End (0.875). There were significant differences ( p < 0.05) in the performances of the four AI models between the high-concordance subset and the entire dataset. The AI models demonstrated significant differences in malignancy probability concerning different tumour size categories in mammograms. The performance of AI models was affected by several factors such as concordance classification, image enhancement and transfer learning. Mammograms with a strong concordance with radiologists' annotations, applying image enhancement and transfer learning could enhance the accuracy of AI models.

Provision of online and remote specialist education and general continued professional education in medicine is a growing field. For radiology specifically, the ability to access web-based platforms that house high resolution medical images, and the high fidelity of simulated activities is increasingly growing due to positive changes in technology. This study investigates the differences in providing a self-directed specialist radiology education system in two modes: at clinics and in-person workshops. 335 Australian radiologists completed 562 readings of mammogram test sets through the web-based interactive BREAST platform with 325 at conference workshops and 237 at their workplaces. They engaged with test sets with each comprising of 60 mammogram cases (20 cancer and 40 normal). Radiologists marked the location of any cancers and had their performance measured via 5 metrics of diagnostic accuracy. Results show that the location of engagement with BREAST did not yield any significant difference in the performances of all radiologists and the same radiologists between two reading modes (P > 0.05). Radiologists who read screening mammograms for BreastScreen Australia performed better when they completed the test sets at designated workshops (P < 0.05), as was also the case for radiologists who read > 100 cases per week (P < 0.05). In contrast, radiologists who read less mammograms frequently recorded better performances in specificity and JAFROC at clinics (P < 0.05). Findings show that remotely accessed online education for specialised training and core skills building in radiology can provide a similar learning opportunity for breast radiologists when compared to on-site dedicated workshops at scientific meetings. For readers with high volumes of mammograms, a workshop setting may provide a superior experience while clinic setting is more helpful to less experienced readers., (© 2022. The Author(s).)

Objective: The study aims to evaluate the diagnostic efficacy of radiologists and radiology trainees in digital breast tomosynthesis (DBT) alone vs DBT plus synthesized view (SV) for an understanding of the adequacy of DBT images to identify cancer lesions., Methods: Fifty-five observers (30 radiologists and 25 radiology trainees) participated in reading a set of 35 cases (15 cancer) with 28 readers reading DBT and 27 readers reading DBT plus SV. Two groups of readers had similar experience in interpreting mammograms. The performances of participants in each reading mode were compared with the ground truth and calculated in term of specificity, sensitivity, and ROC AUC. The cancer detection rate in various levels of breast density, lesion types and lesion sizes between 'DBT' and 'DBT + SV' were also analyzed. The difference in diagnostic accuracy of readers between two reading modes was assessed using Man-Whitney U test. p < 0.05 indicated a significant result., Results: There was no significant difference in specificity (0.67- vs -0.65; p = 0.69), sensitivity (0.77- vs -0.71; p = 0.09), ROC AUC (0.77- vs -0.73; p = 0.19) of radiologists reading DBT plus SV compared with radiologists reading DBT. Similar result was found in radiology trainees with no significant difference in specificity (0.70- vs -0.63; p = 0.29), sensitivity (0.44- vs -0.55; p = 0.19), ROC AUC (0.59- vs -0.62; p = 0.60) between two reading modes. Radiologists and trainees obtained similar results in two reading modes for cancer detection rate with different levels of breast density, cancer types and sizes of lesions ( p > 0.05)., Conclusion: Findings show that the diagnostic performances of radiologists and radiology trainees in DBT alone and DBT plus SV were equivalent in identifying cancer and normal cases., Advances in Knowledge: DBT alone had equivalent diagnostic accuracy as DBT plus SV which could imply the consideration of using DBT as a sole modality without SV.

Purpose: This study aims to investigate the diagnostic performances of Australian and Shanghai-based Chinese radiologists in reading full-field digital mammogram (FFDM) and digital breast tomosynthesis (DBT) with different levels of breast density., Approach: Eighty-two Australian radiologists interpreted a 60-case FFDM set, and 29 radiologists also reported a 35-case DBT set. Sixty Shanghai radiologists read the same FFDM set, and 32 radiologists read the DBT set. The diagnostic performances of Australian and Shanghai radiologists were assessed using truth data (cancer cases were biopsy proven) and compared overall in specificity, case sensitivity, lesion sensitivity, receiver operating characteristics (ROC) area under the curve, and jack-knife free-response receiver operating characteristics (JAFROC) figure of merit, and they were stratified by case characteristics using the Mann-Whitney U test. The Spearman rank test was used to explore the association between radiologists' performances and their work experience in mammogram interpretation., Results: There were significantly higher performances of Australian radiologists compared with Shanghai radiologists in low breast density for case sensitivity, lesion sensitivity, ROC, and JAFROC in the FFDM set ( P < 0.0001 ); in high breast density, Shanghai radiologists' performances in lesion sensitivity and JAFROC were also lower than Australian radiologists ( P < 0.0001 ). In the DBT test set, Australian radiologists performed better than Shanghai radiologists in cancer detection in both low and high breast density. The work experience of Australian radiologists was positively linked to their diagnostic performances, whereas this association was not statistically significant in Shanghai radiologists., Conclusion: There were significant variations in reading performances between Australian and Shanghai radiologists in FFDM and DBT across different levels of breast density, lesion types, and lesion sizes. An effective training initiative tailored to suit local readers is essential to enhancing the diagnostic accuracy of Shanghai radiologists., (© 2023 Society of Photo-Optical Instrumentation Engineers (SPIE).)

Background: This study aims to investigate the diagnostic efficacy of radiologists when reading screening mammograms in the absence of previous images, and with the presence of prior images from the same and different vendors., Methods: 612 radiologists' readings across 9 test sets, consisting of 540 screening mammograms (361-normal and 179-cancer) with 245 cases having prior images obtained from same vendor as current images, 129 from a different vendor and 166 cases having no prior images, were retrospectively analysed. True positive (sensitivity), true negative (specificity) and area under ROC curve (AUC) values of radiologists were calculated for three groups of cases (without prior images (NP), with prior images from same vendor (SP), and with prior images from different vendor (DP)). Logistic regression was used to estimate the odds ratio (OR) of true positive, true negative and true cancer localization among case groups with different levels of breast density and lesion characteristics., Results: Radiologists obtained 12.8% and 10.3% higher sensitivity in NP and DP than SP (0.803-and-0.785 vs. 0.712; p < 0.0001). Specificity in NP and DP cases were 4.8% and 2.0% lower than SP cases (0.749 and 0.771 vs. 0.787). The AUC values for NP and DP were significantly higher than SP cases across different levels of breast density (0.814-and-0.820 vs. 0.782; p < 0.0001). The odds ratio (OR) of true positive for NP relative to SP was 1.6 ( p < 0.0001) and DP relative to SP was 1.5 ( p < 0.0001). Radiologists were more like to detect architectural distortion in DP than SP cases (OR = 3.2; p < 0.0001), whilst the OR for abnormal calcifications was 2.85 ( p < 0.0001)., Conclusions: Cases without previous mammograms or with prior mammograms obtained from different vendors were more likely to benefit radiologists in cancer detection, whilst prior mammograms undertaken from the same vendor were more useful for radiologists in evaluating normal cases.

The development of screening mammography over 30 years has remarkedly reduced breast cancer-associated mortality by 20%-30% through detection of small cancer lesions at early stages. Yet breast screening programmes may function differently in each nation depending on the incidence rate, national legislation, local health infrastructure and training opportunities including feedback on performance. Mammography has been the frontline breast cancer screening tool for several decades; however, it is estimated that there are 15% to 35% of cancers missed on screening which are owing to perceptual and decision-making errors by radiologists and other readers. Furthermore, mammography screening is not available in all countries and the increased speed in the number of new breast cancer cases among less developed countries exceeds that of the developed world in recent decades. Studies conducted through the BreastScreen Reader Assessment Strategy (BREAST) training tools for breast screening readers have documented benchmarking and significant variation in diagnostic performances in screening mammogram test sets in different countries. The performance of the radiologists from less well-established breast screening countries such as China, Mongolia and Vietnam were significant lower in detecting early-stage cancers than radiologists from developed countries such as Australia, USA, Singapore, Italy. Differences in breast features and cancer presentations, discrepancies in the level of experiences in reading screening mammograms, the availability of high-quality national breast screening program and breast image interpretation training courses between developed and less developed countries are likely to have impact on the variation of readers' performances. Hence dedicated education training programs with the ability to tailor to different reader cohorts and different population presentations are suggested to ameliorate challenges in exposure to a range of cancer cases and improve the interpretation skills of local radiologists. Findings from this review provide a good understanding of the radiologist' performances and their improvement using the education interventions, primarily the BREAST program, which has been deployed in a large range of developing and developed countries in the last decade. Self-testing and immediate feedback loops have been shown to have important implications for benchmarking and improving the diagnostic accuracy in radiology worldwide for better breast cancer control., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Trieu, Mello-Thoms, Barron and Lewis.)

Much of young people's fertility health knowledge has been limited to avoiding sexually transmitted infections and preventing pregnancy thus lacking what is necessary to support future overall health as well as reproductive goals. This study assesses university students' knowledge related to fertility health factors to verify consistencies and discrepancies in fertility health knowledge, with a sub-assessment focusing on men's knowledge. The Fertility Health Knowledge survey was delivered to 17,189 students at three American universities. Twenty percent or 546 of the 2,692 participants were male. The 30-question survey addresses knowledge of modifiable and non-modifiable risk factors on fertility health in men and women, and four questions regarding fertility intentions. Across all 30 questions, 63% of female responses were correct and 61% of male responses were correct. For 10 questions, less than 70% of males and females answered correctly, with men answering correctly more often than females for six of the questions. Males exhibited more knowledge regarding male fertility. Knowledge of fertility health was consistently limited, regardless of site or demographics. Men demonstrated improved overall fertility health knowledge and more knowledge regarding male factors. There are still considerable gaps in knowledge of modifiable risk factors that may impact fertility health and future overall health. Fertility health promotion through education should be comprehensive and widely available in secondary schools, colleges, and universities. As well, increased education regarding fertility health in primary care settings should become the norm-with male inclusion as a standard of their care.

Acute kidney injury induced by nephrotoxic agents is common, increasing in incidence and associated with considerable morbidity and mortality in developing countries. MicroRNAs are stable biomarkers that can be detected in extracellular fluids. This systematic scoping review aims to describe published research on urinary and circulating microRNAs in toxic acute kidney injury in both animal and human studies. We conducted a literature search, using EMBASE and Medline, for articles on urinary and circulating microRNA in nephrotoxic injuries to February 2020. A total of 21 publications studied acute kidney injury from 12 different toxic agents. Cisplatin was the most common nephrotoxic agent (n = 10), followed by antibiotics (n = 4). There were no randomized controlled trials. An increase in urinary miR-218 predicted acute kidney injury in six different studies, suggesting it is a promising biomarker for nephrotoxin-induced acute kidney injury. There were many factors that prevented a more comprehensive synthesis of microRNA performance including highly variable models, no consistent protocols for RNA isolation, cDNA synthesis and PCR amplification, and variability in normalization methods using reference controls. In conclusion, while microRNAs are promising biomarkers to study nephrotoxic acute kidney injury, the replication of most positive findings is not assessable due to deficient reporting of negative outcomes. A very narrow range of poisons have been studied, and more human data are required. In particular, further studies are needed on the most important causes of nephrotoxic injury, such as pesticides, chemicals, snake envenoming, and medicines other than aminoglycosides and cisplatin., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background and Purpose: Few surveys address fertility health in both men and women. This report details development of a fertility knowledge assessment tool for clinical and research settings that would sensitize young adults to habits that would promote healthy fertility., Methods: A pilot study ( N = 31) followed by a larger study of students at three schools ( N = 465, 335, & 375) at a midwestern university using a new 30-item survey., Results: Face and content validity of the survey tool were determined by a panel of experts. Internal consistency and reliability were acceptable for a new instrument ( α = .81 for the total group; α = .80 for each school., Conclusions: This instrument is a valid and reliable short screening tool that can be used to assess knowledge of fertility and possibly open discussions about fertility self-care., (© Copyright 2020 Springer Publishing Company, LLC.)

Problem: Smartphone applications are an increasingly useful part of patients' self-management of chronic health conditions. Asthma is a common chronic health condition for which good self-management by patients is very helpful in maintaining stability. User-centered design and intelligent systems that learn are steps forward in building applications that are more effective in providing quality care that is scalable and tailored to each patient., Methods: A literature and application store search to review historic and current asthma smart phone applications. User-centered design is a methodology that involves all stakeholders of a proposed system from the beginning of the design phase to the end of installation. One aspect of this user-centered approach involved conducting focus groups with patients and health care providers to determine what features they desire for use in applications and create a model to build smart infrastructure for a learning health care system. A simple prototype for an asthma smartphone application is designed and built with basic functionality., Outcomes: Only one publication in the literature review of asthma smartphone applications describes both user-centered design and intelligent learning systems. The authors have presented a set of user-desired attributes for a smart health care application and a possible data flow diagram of information for a learning system. A prototype simple user-centered designed asthma smartphone application that better assists patients in their care illustrates the value of the proposed architecture., Discussion: Our user-centered approach helped design and implement a learning prototype smart phone application to help patients better manage their asthma and provide information to clinical care providers. While popular in other industries, user-centered design has had slow adoption in the health care area. However, the popularity of this approach is increasing and will hopefully result in mobile application that better meets the needs of both patients and their care providers., Competing Interests: All authors declare that they have no conflicts of interest., (© 2020 The Authors. Learning Health Systems published by Wiley Periodicals, Inc. on behalf of the University of Michigan.)

This issue of Current Medical Research (CMR) includes studies that provide evidence that use of natural family planning (NFP) can be helpful for subfertile couples wishing to achieve a pregnancy, the effectiveness of a method of NFP during breastfeeding, and the effects of using NFP on marital relationships. This review also includes evidence on predicting the sex of a baby by timing intercourse, evidence that brain injuries can be reflected in changes in the menstrual cycle, and that women prefer methods of family planning that have no side effects. The issue ends with an in-depth review of new technologies that aid in the use of NFP. Topics covered include subfertile couples, breastfeeding, marriage, predicting the sex of a baby, brain injuries, and new technologies.

Purpose: To investigate if generic Wondfo ovulation sticks (WLH) are sufficiently sensitive to the luteinizing hormone (LH) surge in urine when used with the Marquette Fertility Algorithm. The electronic hormonal fertility monitor (EHFM) is highly accurate in detecting the LH surge but cost of the monitor and the accompanying test sticks has increased over the last several years. The EHFM is sensitive to detect the LH surge at 20 milli-international units per milliliter (mIU/mL); the WLH sticks are slightly less sensitive at 25 mIU/mL., Study Design and Methods: A convenience sample of women using the Marquette Method of Natural Family Planning with the EHFM to avoid pregnancy were recruited (N = 54). Each participant used the EHFM every morning after cycle day 6 and tested morning and evening urine with the WLH stick until the day following detection of the LH surge on the EHFM., Results: Forty-two women provided 219 cycles. Frequency of LH surge detection was 182/219 (83.1%) for EHFM and 203/219 (92.7%) for WLH sticks. Agreement between the EHFM and the WLH on the day of the LH surge was 97.7%. High fertility readings providing a warning of peak fertility at least 5 days before peak was 67% for the WLH; the EHFM was 47.7%. Paired sample correlations for high fertility was .174 (p = .014) and paired sample differences t was -4.729 (p = .000)., Clinical Implications: The WLH stick is sufficiently sensitive to use in place of the EFHM for determining peak fertility and with the Marquette Fertility algorithm. Even with minimal use, WLH sticks cost about half the price of the monitor strips and provide more flexibility of use. Cost differences increase with the number of sticks used per cycle. Further research with a larger sample is needed to verify results.

Adamantanyl benzamide 1 was identified as a potent P2X 7 R antagonist but failed to progress further due to poor metabolic stability. We describe the synthesis and SAR of a series of bioisosteres of benzamide 1 to explore improvements in the pharmacological properties of this lead. Initial efforts investigated a series of heteroaromatic bioisosteres, which demonstrated improved physicochemical properties but reduced P2X 7 R antagonism. Installation of bioisosteric fluorine on the adamantane bridgeheads was well tolerated and led to a series of bioisosteres with improved physicochemical properties and metabolic stability. Trifluorinated benzamide 34 demonstrated optimal physicochemical parameters, superior metabolic stability (ten times longer than lead benzamide 1), and an improved physicokinetic profile and proved effective in the presence of several known P2X 7 R polymorphisms.

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X 7 R antagonists., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Fibrogenesis imperfecta ossium is a rare disorder of bone usually characterized by marked osteopenia and associated with variable osteoporosis and osteosclerosis, changing over time. Histological examination shows that newly formed collagen is abnormal, lacking birefringence when examined by polarized light. The case presented demonstrates these features and, in addition, a previously undocumented finding of a persistent marked reduction of the serum C3 and C4. Osteoblasts established in culture from a bone biopsy showed abnormal morphology on electron microscopy and increased proliferation when cultured with benzoylbenzoyl-ATP and 1,25-dihydroxyvitamin D, contrasting with findings in normal osteoblasts in culture. A gene microarray study showed marked upregulation of the messenger RNA (mRNA) for G-protein-coupled receptor 128 (GPR 128), an orphan receptor of unknown function and also of osteoprotegerin in the patient's osteoblasts in culture. When normal osteoblasts were cultured with the patient's serum, there was marked upregulation of the mRNA for aquaporin 1. A single pathogenetic factor to account for the features of this disorder has not been defined, but the unique findings described here may facilitate more definitive investigation of the abnormal bone cell function., Competing Interests: The authors declare no conflict of interest.

The 18kDa translocator protein (TSPO) is a target for novel glioblastoma therapies due to its upregulation in this cancer and relatively low levels of expression in the healthy cortex. The pyrazolo[1,5-a]pyrimidine acetamides, exemplified by DPA-713 and DPA-714, are a class of high affinity TSPO ligands with selectivity over the central benzodiazepine receptor. In this study we have explored the potential anti-glioblastoma activity of a library of DPA-713 and DPA-714 analogues, and investigated the effect of amending the alkyl ether chain on TSPO affinity and functional potential. All ligands demonstrated nanomolar affinity for TSPO, but showed diverse functional activity, for example DPA-713 and DPA-714 did not affect the proliferation or viability of human T98G glioblastoma cells, while the hexyl ether and benzyl ether derivatives decreased proliferation of T98G cells without affecting proliferation in human fetal glial SVGp12 cells. These ligands also induced apoptosis and dissipated T98G mitochondrial membrane potential. This suggests that the nature of the alkyl ether chain of pyrazolo[1,5-a]pyrimidine acetamides has little influence on TSPO affinity but is important for functional activity of this class of TSPO ligands., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We show that changing the number and position of nitrogen atoms in the heteroatomic core of a pyrazolopyrimidine acetamide is sufficient to induce complex binding to wild type human TSPO. Only compounds with this complex binding profile lacked intrinsic effect on glioblastoma proliferation but positively modulated the antiproliferative effects of a synthetic TSPO ligand. To the best of our knowledge this is the first demonstration of allosteric-like interaction at the wild type human TSPO.

The translocator protein (TSPO) is an 18-kDa five-transmembrane protein, which is primarily found in the outer mitochondrial membrane. Levels of this protein are up-regulated in the most aggressive and common glioma, glioblastoma multiforme (GM). Levels of TSPO also correlate with GM clinical outcome, suggesting that TSPO may be a novel GM diagnostic imaging agent. Therapeutically, targeting the TSPO may provide a mechanism to abrogate the apoptotic-resistant, invasive and aggressive nature of GM and may also provide a way of targeting other anti-cancer treatments to GM sites. This review highlights recent progress in research on TSPO-based diagnostic imaging and therapeutics for GM., (© 2015 Authors; published by Portland Press Limited.)