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Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

The reference method for low-density lipoprotein-cholesterol (LDL-C) quantitation is β-quantification, a technically demanding method that is not convenient for routine use. Indirect calculation methods to estimate LDL-C, including the Friedewald equation, have been used since 1972. This calculation has several recognized limitations, especially inaccurate results for triglycerides (TG)4.5 mmol/l (400 mg/dl). In view of this, several other equations were developed across the world in different datasets.The purpose of this review was to analyze the best method to calculate LDL-C in clinical practice by reviewing studies that compared equations with measured LDL-C.We identified 45 studies that compared these formulae. The Martin/Hopkins equation uses an adjustable factor for TG:very low-density lipoprotein-cholesterol ratios, validated in a large dataset and demonstrated to provide more accurate LDL-C calculation, especially when LDL1.81 mmol/l (70 mg/dl) and with elevated TG. However, it is not in widespread international use because of the need for further validation and the use of the adjustable factor. The Sampson equation was developed for patients with TG up to 9 mmol/l (800 mg/dl) and was based on β-quantification and performs well on high TG, postprandial and low LDL-C samples similar to direct LDL-C.The choice of equation should take into the level of triglycerides. Further validation of different equations is required in different populations.

Data on the prevalence and mortality of paediatric sepsis in resource-poor settings are scarce. We aimed to assess the prevalence and in-hospital mortality of severe sepsis and septic shock treated in paediatric intensive care units (PICUs) in Brazil, and risk factors for mortality.We performed a nationwide, 1-day, prospective point prevalence study with follow-up of patients with severe sepsis and septic shock, using a stratified random sample of all PICUs in Brazil. Patients were enrolled at each participating PICU on a single day between March 25 and 29, 2019. All patients occupying a bed at the PICU on the study day (either admitted previously or on that day) were included if they were aged 28 days to 18 years and met the criteria for severe sepsis or septic shock at any time during hospitalisation. Patients were followed up until hospital discharge or death, censored at 60 days. Risk factors for mortality were assessed using a Poisson regression model. We used prevalence to generate national estimates.Of 241 PICUs invited to participate, 144 PICUs (capacity of 1242 beds) included patients in the study. On the day of the study, 1122 children were admitted to the participating PICUs, of whom 280 met the criteria for severe sepsis or septic shock during hospitalisation, resulting in a prevalence of 25·0% (95% CI 21·6-28·8), with a mortality rate of 19·8% (15·4-25·2; 50 of 252 patients with complete clinical data). Increased risk of mortality was associated with higher Pediatric Sequential Organ Failure Assessment score (relative risk per point increase 1·21, 95% CI 1·14-1·29, p0·0001), unknown vaccination status (2·57, 1·26-5·24; p=0·011), incomplete vaccination status (2·16, 1·19-3·92; p=0·012), health care-associated infection (2·12, 1·23-3·64, p=0·0073), and compliance with antibiotics (2·38, 1·46-3·86, p=0·0007). The estimated incidence of PICU-treated sepsis was 74·6 cases per 100 000 paediatric population (95% CI 61·5-90·5), which translates to 42 374 cases per year (34 940-51 443) in Brazil, with an estimated mortality of 8305 (6848-10 083).In this representative sample of PICUs in a middle-income country, the prevalences of severe sepsis or septic shock and in-hospital mortality were high. Modifiable factors, such as incomplete vaccination and health care-associated infections, were associated with greater risk of in-hospital mortality.Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Desenvolvimento Científico e Tecnológico.For the Portuguese translation of the abstract see Supplementary Materials section.

The gold standard for measuring LDL-C is impractical for routine use while direct measurements have numerous shortcomings. This study investigated the correlation of predictive equations with currently used enzymatic assays in populations where these have historically proven unreliable to determine whether equations may be used interchangeably. No reference measure was available for comparison in this study.We examined two analytical datasets from different platforms to evaluate the correlation of predictive equations for LDL-C (Friedewald, Sampson-NIH2, Martin-Hopkins, Extended Martin-Hopkins, Hattori and Anandaraja) with direct LDL-C assays in a large paediatric (n = 7598) and an adult cohort with uncontrolled diabetes (n = 57165). Non-parametric statistics were used for comparison.In the paediatric cohort, the Sampson-NIH2 equation correlated best with the direct LDL-C assays with the most values falling within desirable bias (35.9-44%) and TEDifferent measurement platforms influence the results of predictive equations and directly measured LDL-C. We propose utilising the Martin-Hopkins equation as an alternative to dLDL-C assays in adults with diabetes and for screening purposes in paediatric populations to avoid underestimating cardiovascular risk.

Background: Due to the heat and moisture exchanger's (HME) breathing resistance, laryngectomized patients cannot always use an (optimal) HME during physical exercise. We propose a novel HME cassette concept with adjustable “bypass,” to provide adjustment between different breathing resistances within one device. Methods: Under standardized conditions, the resistance and humidification performance of a high resistance/high humidification HME (XM) foam in a cassette with and without bypass were compared to a lower resistance/lesser humidification HME (XF) foam in a closed cassette. Results: With a bypass in the cassette, the resistance and humidification performance of XM foam were similar to those of XF foam in the closed cassette. Compared to XM foam in the closed cassette, introducing the bypass resulted in a 40% resistance decrease, whereas humidification performance was maintained at 80% of the original value. Conclusions: This HME cassette prototype allows adjustment between substantially different resistances while maintaining appropriate humidification performances.

Introduction The focus on paediatric radiation dose reduction supports reevaluation of paediatric imaging protocols. This is particularly important in the neonates where chest radiographs are frequently requested to assess respiratory illness and line placement. This study aims to assess the impact of neonatal chest radiographic protocols on patient dose in four hospitals in different countries. Methods Exposure parameters, collimation, focus to skin distance (FSD) and radiation dose from 200 neonatal chest radiographs were registered prospectively. Inclusion criteria consisted of both premature and full-term neonates weighing between 1000 and 5000 g. Only data from the examinations meeting diagnostic criteria and approved for the clinical use were included. Radiation dose was assessed using dose area product (DAP). Results The lowest DAP value (4.58 mGy cm2) was recorded in the Norwegian hospital, employing a high kVp, low mAs protocol using a DR system. The Canadian hospital recorded the highest DAP (9.48), using lower kVp and higher mAs with a CR system, including the addition of a lateral projection. The difference in the mean DAP, weight, field of view (FOV) and kVp between the hospitals is statistically significant (p Conclusion Use of non-standardised imaging protocols in neonatal chest radiography results in differences in patient dose across hospitals included in the study. Using higher kVp, lower mAs and reducing the number of lateral projections to clinically relevant indications result in a lower DAP measured in the infant sample studied. Further studies to examine image quality based on exposure factors and added filtration are recommended. Implications for practice Reevaluation of paediatric imaging protocols presents an opportunity to reduce patient dose in a population with increased sensitivity to ionising radiation.

OBJECTIVE: To examine the association between cultivable vaginal Lactobacillus and fecundability in Kenyan women attempting non-medically assisted conception DESIGN: Prospective preconception cohort SETTING: Nairobi and Mombasa, Kenya PATIENTS: Women trying to conceive who reported ≤3 months of pre-enrollment conception attempt time EXPOSURE: Cultivable Lactobacillus (primary), Lactobacillus morphotypes on Gram stain (secondary) MAIN OUTCOME MEASURES: Participants reported first day of last menstrual period and recent sexual behavior, underwent pregnancy testing, and provided vaginal specimen samples for Lactobacillus culture and Gram stain at ≤6 monthly preconception visits. The outcome was fecundability – the per-menstrual cycle probability of pregnancy. Associations between 1) cultivable Lactobacillus and 2) Lactobacillus morphotypes on Gram stain at the visit prior to each pregnancy test and fecundability were estimated using proportional probabilities models to generate fecundability ratios (FRs). RESULTS: 458 women contributed 1,376 menstrual cycles. At enrollment, 65.3% (n=299) of participants had cultivable Lactobacillus, 47.4% (n=217) had cultivable hydrogen peroxide producing Lactobacillus, and 64.6% (n=296) had Lactobacillus detected on Gram stain. In unadjusted analysis, there was no association between cultivable Lactobacillus at the visit prior and fecundability (FR 0.92, 95%CI 0.73–1.16); results were similar after adjustment for age, frequency of condomless sex, and study site (adjusted FR 0.92, 95%CI 0.72–1.18). Lactobacillus on Gram stain at the visit prior was associated with modestly higher fecundability (adjusted FR 1.18, 95%CI 0.92–1.51). CONCLUSIONS: Cultivable Lactobacillus was not associated with fecundability while Lactobacillus morphotypes detected on Gram stain were somewhat associated with increased fecundability. The relationship between vaginal Lactobacillus and fecundity may be species-specific.

This pilot study explored the value of localized index node removal after neoadjuvant immunotherapy in patients with stage III melanoma, for use as a response indicator to guide the extent of completion lymph node dissection. Promising technology.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines – oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health – in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

We report on a study that aimed at establishing a large soil–fungal culture collection spanning a wide taxonomic diversity and systematically screening the collection for bacterial associations. Fungal cultures were isolated from soil samples obtained from a natural grassland in eastern Germany and bacterial associations were assessed by PCR-amplification and sequencing of bacterial 16S rRNA. In addition, intraspecies genetic diversities of a subset of the isolated species were estimated by double-digest restriction associated DNA sequencing. A total of 688 fungal cultures, representing at least 106 fungal species from 36 different families, were obtained and even though clonal isolates were identified in almost all fungal species subjected to ddRAD-seq, relatively high genetic diversities could be observed in some of the isolated species. A total of 69% of the fungal isolates in our collection were found to be associated with bacteria and the most commonly identified bacterial genera were Pelomonas, Enterobacter and Burkholderia. Our results indicate that bacterial associations commonly occur in soil fungi, even if antibiotics are being applied during the isolation process, and provide a basis for the use of our culture collection in ecological experiments that want to acknowledge the importance of intraspecies genetic diversity.

STUDY QUESTION Is bacterial vaginosis (BV) associated with fecundability? SUMMARY ANSWER Women with BV may be at increased risk for sub-fecundity. WHAT IS KNOWN ALREADY While BV has been associated with poor IVF outcomes, the association between vaginal microbiota disruption and non-medically assisted conception has not been thoroughly explored. STUDY DESIGN, SIZE, DURATION Kenyan women with fertility intent were enrolled in prospective cohort that included monthly preconception visits with vaginal fluid specimen collection and pregnancy testing. Four hundred fifty-eight women attempting pregnancy for ≤3 menstrual cycles at enrollment were eligible for this fecundability analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS At monthly preconception visits, participants reported the first day of last menstrual period and sexual behavior, underwent pregnancy testing and provided vaginal specimens. Discrete time proportional probabilities models were used to estimate fecundability ratios (FRs) and 95% CI in menstrual cycles with and without BV (Nugent score ≥ 7) at the visit prior to each pregnancy test. We also assessed the association between persistent BV (BV at two consecutive visits) and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE Participants contributed 1376 menstrual cycles; 18.5% (n = 255) resulted in pregnancy. After adjusting for age, frequency of condomless sex and study site, BV at the visit prior to pregnancy testing was associated with a 17% lower fecundability (adjusted FR (aFR) 0.83, 95% CI 0.6–1.1). Persistent BV was associated with a 43% reduction in fecundability compared to cycles characterized by optimal vaginal health (aFR 0.57, 95% CI 0.4–0.8). LIMITATIONS, REASONS FOR CAUTION Detection of vaginal microbiota disruption using Gram stain and a point-of-care test for elevated sialidase identified a non-optimal vaginal environment, but these non-specific methods may miss important relationships that could be identified by characterizing individual vaginal bacteria and bacterial communities using molecular methods. In addition, results may be subject to residual confounding by condomless sex as this was reported for the prior month rather than for the fertile window during each cycle. WIDER IMPLICATIONS OF THE FINDINGS Given the high global prevalence of BV and infertility, an association between BV and reduced fecundability could have important implications for a large number of women who wish to conceive. Multi-omics approaches to studying the vaginal microbiota may provide key insights into this association and identify potential targets for intervention. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a National Institutes of Health grant (NICHD R01 HD087346-R.S.M.). R.S.M. received additional support for mentoring (NICHD K24 HD88229). E.M.L. was supported by pre- and post-doctoral fellowships (NIAID T32 AI07140, NICHD F32 HD100202). Data collection and management were made possible using REDCap electronic data capture tools hosted at the University of Washington’s Institute of Translational Health Science supported by grants from NCATS/NIH (UL1 TR002319). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. R.S.M. receives research funding, paid to the University of Washington, from Hologic Corporation, and has received honoraria for consulting from Lupin Pharmaceuticals. L.E.M. receives research funding, paid to the University of Washington, from Hologic Corporation, and has received honoraria for service on scientific advisory boards from Hologic and Nabriva Therapeutics. TRIAL REGISTRATION NUMBER N/A.

Summary Knowledge of the structure of a problem, such as relationships between stimuli, enables rapid learning and flexible inference. Humans and other animals can abstract this structural knowledge and generalize it to solve new problems. For example, in spatial reasoning, shortest-path inferences are immediate in new environments. Spatial structural transfer is mediated by cells in entorhinal and (in humans) medial prefrontal cortices, which maintain their co-activation structure across different environments and behavioral states. Here, using fMRI, we show that entorhinal and ventromedial prefrontal cortex (vmPFC) representations perform a much broader role in generalizing the structure of problems. We introduce a task-remapping paradigm, where subjects solve multiple reinforcement learning (RL) problems differing in structural or sensory properties. We show that, as with space, entorhinal representations are preserved across different RL problems only if task structure is preserved. In vmPFC and ventral striatum, representations of prediction error also depend on task structure., Highlights • Entorhinal cortex represents the task structure (rules) of an RL task • As in physical space, this representation is divorced from sensory signals • Spatial patterns of prediction error signals depended on task structure • Such relational representations of task structure might underlie generalisation, How do we generalize knowledge between problems that are only loosely related but have a similar structure? Baram et al. take inspiration from the generalization properties of entorhinal cortex in rodent spatial tasks to show that entorhinal and ventromedial prefrontal cortices generalize the structure of reinforcement learning tasks in humans.

Objectives Accurate tumour localisation is essential for breast-conserving surgery of non-palpable tumours. Current localisation technologies are associated with disadvantages such as logistical challenges and migration issues (wire guided localisation) or legislative complexities and high administrative burden (radioactive localisation). We present MAgnetic MArker LOCalisation (MaMaLoc), a novel technology that aims to overcome these disadvantages using a magnetic marker and a magnetic detection probe. This feasibility study reports on the first experience with this new technology for breast cancer localisation. Materials and methods Fifteen patients with unifocal, non-palpable breast cancer were recruited. They received concurrent placement of the magnetic marker in addition to a radioactive iodine seed, which is standard of care in our clinic. In a subset of five patients, migration of the magnetic marker was studied. During surgery, a magnetic probe and gammaprobe were alternately used to localise the markers and guide surgery. The primary outcome parameter was successful transcutaneous identification of the magnetic marker. Additionally, data on radiologist and surgeon satisfaction were collected. Results Magnetic marker placement was successful in all cases. Radiologists could easily adapt to the technology in the clinical workflow. Migration of the magnetic marker was negligible. The primary endpoint of the study was met with an identification rate of 100%. Both radiologists and surgeons reflected that the technology was intuitive to use and that it was comparable to radioactive iodine seed localisation. Conclusion Magnetic marker localisation for non-palpable breast cancer is feasible and safe, and may be a viable non-radioactive alternative to current localisation technologies.

Globally, ∼1 in 15 men of reproductive age are infertile, yet the precise mechanisms underlying their gamete failure are unknown. Although a semen analysis is performed to determine fertilizing potential, the diagnostic suitability of this analysis has been questioned in several reports, as many men, classified as infertile according to their semen analysis, subsequently turn out to be fertile. Herein, we have used a quantitative (phospho)-proteomic analysis, using enrichment on titanium dioxide followed by ion-trap mass spectrometry (LC-MS/MS), to compare the semen of infertile versus fertile males. One protein, namely outer dense fiber 1 (ODF1), was dramatically reduced in infertile males. Using specific antibodies, we then screened the gametes of a cohort of suspected infertile men and demonstrated a reduction in the amount of ODF1 compared with fertile controls. Stress treatment of sperm deficient in ODF1 caused the head to decapitate, suggesting why these gametes fail to initiate fertilization. Interestingly, electron micrographs of ODF1-deficient spermatozoa revealed an abnormal connecting piece, indicating several developmental defects with both the implantation plate and the thin laminated fibers. In some cases, the implantation plate appeared to be reduced in size or was overburdened by granular material near the connecting piece. Hence, a strong reduction ODF1 is a marker of idiopathic male infertility and a potential driver of this condition.

Open microfluidic cell culture systems are powerful tools for interrogating biological mechanisms. We have previously presented a microscale cell culture system, based on spontaneous capillary flow of biocompatible hydrogels, that is integrated into a standard cell culture well plate, with flexible cell compartment geometries and easy pipet access. Here, we present two new injection molded open microfluidic devices that also easily insert into standard cell culture well plates and standard culture workflows, allowing seamless adoption by biomedical researchers. These platforms allow culture and study of soluble factor communication among multiple cell types, and the microscale dimensions are well-suited for rare primary cells. Unique advances include optimized evaporation control within the well, manufacture with reproducible and cost-effective rapid injection molding, and compatibility with sample preparation workflows for high resolution microscopy (following well-established coverslip mounting procedures). In this work, we present several use cases that highlight the usability and widespread utility of our platform including culture of limited primary testis cells from surgical patients, microscopy readouts including immunocytochemistry and single molecule fluorescence in situ hybridization (smFISH), and coculture to study interactions between adipocytes and prostate cancer cells.

For bacterial genome sequencing, libraries from different strains are usually multiplexed in a single run. Normalized libraries are most often pooled in equal volumes, as recommended by next-generation sequencing platform manufacturers. This equal-volume strategy is well suited for multiplexing isolates from the same species. However, for runs involving multiple microbial species, an equimolar library pooling is more adapted because of the variation in bacterial genome size. To demonstrate its utility in clinical microbiology, we compared both equal-volume and equimolar strategies using a menu comprising 13 bacterial species involved in healthcare-associated infections. We show that equimolar pooling limits the retesting risk due to insufficient coverage depth, particularly when interspecies genome size difference is more than 2-fold. The use of this alternative strategy for multiplexing pathogenic bacteria should lead to more cost effective whole-genome sequencing applications in clinical microbiology.

It is proposed that a cognitive map encoding the relationships between entities in the world supports flexible behavior, but the majority of the neural evidence for such a system comes from studies of spatial navigation. Recent work describing neuronal parallels between spatial and non-spatial behaviors has rekindled the notion of a systematic organization of knowledge across multiple domains. We review experimental evidence and theoretical frameworks that point to principles unifying these apparently disparate functions. These principles describe how to learn and use abstract, generalizable knowledge and suggest that map-like representations observed in a spatial context may be an instance of general coding mechanisms capable of organizing knowledge of all kinds. We highlight how artificial agents endowed with such principles exhibit flexible behavior and learn map-like representations observed in the brain. Finally, we speculate on how these principles may offer insight into the extreme generalizations, abstractions, and inferences that characterize human cognition.

Emerging evidence suggests that transcranial alternating current stimulation (tACS) is an effective, frequency-specific modulator of endogenous brain oscillations, with the potential to alter cognitive performance. Here, we show that reduction in response latencies to solve complex logic problem indexing fluid intelligence is obtained through 40 Hz-tACS (gamma band) applied to the prefrontal cortex. This improvement in human performance depends on individual ability, with slower performers at baseline receiving greater benefits. The effect could have not being explained by regression to the mean, and showed task and frequency specificity: it was not observed for trials not involving logical reasoning, as well as with the application of low frequency 5 Hz-tACS (theta band) or non-periodic high frequency random noise stimulation (101-640 Hz). Moreover, performance in a spatial working memory task was not affected by brain stimulation, excluding possible effects on fluid intelligence enhancement through an increase in memory performance. We suggest that such high-level cognitive functions are dissociable by frequency-specific neuromodulatory effects, possibly related to entrainment of specific brain rhythms. We conclude that individual differences in cognitive abilities, due to acquired or developmental origins, could be reduced during frequency-specific tACS, a finding that should be taken into account for future individual cognitive rehabilitation studies.

Human caring has long been considered the primary domain of nurses and the primary function of nursing practice. Results related to the study of a Caring Science, Mindful Practice Massive Open Online Course (MOOC), suggest that Watson's Caring Science tenets are meaningful and useful for professionals who work in disciplines outside of nursing. Further study was needed to explore the degree to which Caring Science might be useful and applicable to the practices of non-nurse professionals. The study that is the focus of this article explored perceived usefulness of Watson's Caring Science for professionals from a wide array of disciplines who teach and work in online settings. Results confirm applicability and usefulness across disciplines and in diverse settings. Results also suggest that nurse-mediated Caring Science education and training may help establish common ground upon which further interprofessional and transdisciplinary understanding and collaboration may be built.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6–110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6–72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

Supplemental Digital Content is Available in the Text., Introduction: HIV-1 is transmitted through semen from men to their sexual partners. Genital infections can increase HIV-1 RNA shedding in semen, but shedding also occurs in the absence of typical pathogens. We hypothesized that higher bacterial concentrations in semen would be associated with higher HIV-1 RNA levels. Methods: We analyzed semen samples from 42 HIV-1–seropositive Kenyan men using quantitative polymerase chain reaction (PCR) to assess bacterial concentrations and real-time PCR to measure HIV-1 RNA levels. Generalized estimation equations were used to evaluate associations between these 2 measures. Broad-range 16S rRNA gene PCR with pyrosequencing was performed on a subset of 13 samples to assess bacterial community composition. Results: Bacteria were detected in 96.6% of 88 samples by quantitative PCR. Semen bacterial concentration and HIV-1 RNA levels were correlated 0.30 (P = 0.01). The association between bacterial concentration and HIV-1 RNA detection was not significant after adjustment for antiretroviral therapy (ART) (adjusted odds ratio: 1.27, 95% CI: 0.84 to 1.91). Factors associated with semen bacterial concentration included insertive anal sex (adjusted beta 0.92, 95% CI: 0.12 to 1.73) and ART use (adjusted beta: −0.77, 95% CI: −1.50 to 0.04). Among 13 samples with pyrosequencing data, Corynebacterium spp., Staphylococcus spp., and Streptococcus spp. were most frequently detected. Conclusion: Most of these HIV-1–infected men had bacteria in their semen. ART use was associated with undetectable semen HIV-1 RNA and lower semen bacterial concentrations, whereas insertive anal sex was associated with higher bacterial concentrations. Additional studies evaluating the relationship between semen bacteria, inflammation, mucosal immunity, and HIV-1 shedding are needed to understand implications for HIV-1 transmission.

Knowledge of the regulation of testicular retinoic acid synthesis is crucial for understanding its role in spermatogenesis. Bisdichloroacetyldiamines strongly inhibit spermatogenesis. We reported previously that one of these compounds, WIN 18,446, potently inhibited spermatogenesis in rabbits by inhibiting retinoic acid synthesis. To understand how WIN 18,446 inhibits retinoic acid synthesis, we characterized its effects on human retinal dehydrogenase ALDH1A2 in vitro as well as its effects on retinoid metabolism in vivo using mice. WIN 18,446 strongly and irreversibly inhibited ALDH1A2 in vitro. In vivo, WIN 18,446 treatment completely abolished spermatogenesis after 4 weeks of treatment and modestly reduced adiposity in mice fed a chow diet. Effects of WIN 18,446 on retinoid concentrations were tissue-dependent. Although lung and liver retinyl ester concentrations were lower in WIN 18,446-treated animals, adipose retinyl ester levels were increased following the treatment. Interestingly, animals treated with WIN 18,446 had significantly higher circulating retinol concentrations compared with control mice. The effect on spermatogenesis by WIN 18,446 was not prevented by simultaneous treatment with retinoic acid, whereas effects on other tissues were partially or completely reversed. Cessation of WIN 18,446 treatment for 4 weeks reversed most retinoid-related phenotypes except for inhibition of spermatogenesis. Our data suggest that WIN 18,446 may be a useful model of systemic acquired retinoic acid deficiency. Given the effects observed in our study, inhibition of retinoic acid biosynthesis may have relevance for the treatment of obesity and in the development of novel male contraceptives.

Laryngectomized patients suffer from respiratory complaints due to insufficient warming and humidification of inspired air in the upper respiratory tract. Improvement of pulmonary humidification with significant reduction of pulmonary complaints is achieved by the application of a heat and moisture exchanger (HME) over the tracheostoma. The aim of this study was to determine whether the new Provox HMEs (XM-HME and XF-HME) have a better water exchange performance than their predecessors (R-HME and L-HME, respectively; Atos Medical, Hörby, Sweden). The other aim was to assess the short-term clinical feasibility of these HMEs. The XM-HME and XF-HME were weighed at the end of inspiration and at the end of expiration at different breathing volumes produced by a healthy volunteer. The associations between weight changes, breathing volume and absolute humidity were determined using both linear and non-linear mixed effects models. Study-specific questionnaires and tally sheets were used in the clinical feasibility study. The weight change of the XM-HME is 3.6 mg, this is significantly higher than that of the R-HME (2.0 mg). The weight change of the XF-HME (2.0 mg) was not significantly higher than that of the L-HME (1.8 mg). The absolute humidity values of both XM- and XF-HME were significantly higher than that of their predecessors. The clinical feasibility study did not reveal any practical problems over the course of 3 weeks. The XM-HME has a significantly better water exchange performance than its predecessor (R-HME). Both newly designed HMEs did succeed in the clinical feasibility study.

Objectives: Genitourinary tract samples are required to investigate male HIV-1 infectivity. Because semen collection is often impractical, the acceptability, feasibility and validity of post-prostatic massage fluid/ urine (post-PMF/U) was evaluated for studying male genitourinary HIV-1 shedding. Methods: HIV-1-seropositive men were evaluated after 48 h of sexual abstinence. At each visit, a clinician performed prostatic massage, then post-PMF/U and blood were collected. Participants provided semen specimens 1 week later. An audio computer-assisted self-interview (ACASI) administered after each specimen collection evaluated acceptability, adherence to instructions and recent genitourinary symptoms. HIV-1 RNA was quantified using a real-time PCR assay. Detection and quantitation of HIV-1 RNA and stability over visits were compared for semen, post-PMF/U and blood. Results: Post-PMF/U was successfully obtained at 106 visits (64%) and semen at 136 visits (81%, p

Intralipid emulsion therapy is well-established for the treatment of local-anesthetic systemic toxicities. In recent years, its role has expanded as an important therapeutic agent in the reversal of other types of drug overdoses, including certain types of antipsychotics, antidepressants, antiarrhythmics, and calcium channel blockers. A literature review identified thirty-one case reports including forty-nine separate drug overdose cases involving ten separate drug classes which were successfully reversed with Intralipid. The present clinical case study describes an elderly unresponsive woman refractory to conventional treatments after ingesting a potentially lethal amount of 5.6 grams of diltiazem in a suicide attempt. After treatment with Intralipid over a twenty-four hour period, the patient's hemodynamic and metabolic derangements were corrected and stabilized completely. Intralipid emulsion rescue therapy provides another potential strategy for the reversal of many drug toxicities, most likely by providing a lipid layer safety net for drug overdose by passive diffusion. Clinicians are urged to embrace an expanded role of Intralipid emulsion rescue therapy, not only for local anesthetic drug toxicities, but also for other lipophilic drug overdoses.

Heat and moisture exchangers (HMEs) improve respiratory function after laryngectomy, but there is virtually no information on the benefit of traditional stoma cloths or other covers.Two sequential studies were performed: (1) an ex vivo test was used to compare the humidifying capacity of stoma cloths to other coverings; and (2) a 4-week randomized trial was then performed to assess patient acceptability of cloths both alone and with an HME (N = 18).The humidifying capacity of the coverings tested varied widely. For stoma cloths, a humidifying capacity of 13.7 mg/L was found to decrease to 8.5 mg/L if air-leaks around the cloth occurred. Patients who used HMEs disliked stoma cloths because they interfered with voicing, they became soiled more easily, and were less effective at reducing coughing and mucus production.Although less acceptable to patients who use an HME, stoma cloths do provide significant humidifying capacity and should be encouraged when HMEs are unavailable or inappropriate. © 2017 Wiley Periodicals, Inc. Head Neck 39: 921-931, 2017.

According to the Americans with Disabilities Act (1990), couples with blood-borne viruses that lead to infectious disease cannot be denied fertility treatment as long as the direct threat to the health and safety of others can be reduced or eliminated by a modification of policies or procedures. Three types of infectious patients are commonly discussed in the context of fertility treatment: those with human immunodeficiency virus (HIV), hepatitis C or hepatitis B. Seventy-five per cent of hepatitis C or HIV positive men and women are in their reproductive years, and these couples look to assisted reproductive techniques for risk reduction in conceiving a pregnancy. In many cases, only one partner is infected. Legal and ethical questions about treatment of infectious patients aside, the question most asked by clinical embryologists and andrologists is: "What are the laboratory protocols for working with gametes and embryos from patients with infectious disease?" The serostatus of each patient is the key that informs appropriate treatments. This guidance document describes protocols for handling gametes from seroconcordant and serodiscordant couples with infectious disease. With minor modifications, infectious patients with stable disease status and undetectable or low viral load can be accommodated in the IVF laboratory.

Intratesticular retinoic acid is necessary for spermatogenesis, but the relationship between intratesticular retinoic acid and sperm quality in man has not been studied. We hypothesized that intratesticular concentrations of retinoic acid would be lower in men with abnormal semen analyses compared to men with normal semen analyses. We recruited men requiring scrotal or penile surgery in a pilot observational study examining the relationship between sperm quality and intratesticular and serum retinoic acid. Twenty-four men provided two pre-operative blood and semen samples, and underwent a testicular biopsy during surgery. Serum and tissue all-trans and 13-cis retinoic acid and reproductive hormones were measured by LC/MS/MS and radioimmunoassays, respectively. Seven men had abnormal semen analyses by at least one WHO criteria and 17 men were normal. In men with abnormal semen, the median (25th, 75th percentile) intratesticular 13-cis retinoic acid was 0.14 (0.08, 0.25) pmol/gram tissue compared with 0.26 (0.18, 0.38) pmol/gram tissue in men with normal semen (p = 0.04). There were no significant differences in intratesticular all-trans retinoic acid or serum reproductive hormones between men with normal and abnormal semen analyses. Intratesticular 13-cis retinoic acid is significantly lower in men with abnormal semen analyses compared to men with normal semen analyses. Lower intratesticular 13-cis retinoic acid concentrations may be due to decreased biosynthesis or increased metabolism in the testes. Further investigation of the relationship between intratesticular 13-cis retinoic acid and poor sperm quality is warranted to determine if this association is present in infertile men.

During the past ten years, monoclonal antibodies (mAbs) have taken center stage in the field of targeted therapy and diagnosis. This increased interest in mAbs is due to their binding accuracy (affinity and specificity) together with the original molecular and structural rules that govern interactions with their cognate antigen. In addition, the effector properties of antibodies constitute a second major advantage associated with their clinical use. The development of molecular and structural engineering and more recently of in vitro evolution of antibodies has opened up new perspectives in the de novo design of antibodies more adapted to clinical and diagnostic use. Thus, efforts are regularly made by researchers to improve or modulate antibody recognition properties, to adapt their pharmacokinetics, engineer their stability, and control their immunogenicity. This review presents the latest molecular engineering results on mAbs with therapeutic and diagnostic applications.

Aims To evaluate if intra-operative guidance with ultrasonography (US) could improve surgical accuracy of palpable breast cancer excision, and to evaluate the performance of surgeons during training for US-guided excision. Materials and methods Thirty female patients undergoing breast-conserving surgery for palpable T1–T2 invasive breast cancer were recruited. Three individual breast surgeons, assisted by US, targeted and excised the tumours. The main objective was to obtain adequate resection margins with optimal resection volumes. The specimen volume, tumour diameter and histological margin status were recorded. The specimen volume was divided by the optimal resection volume, defined as the spherical tumour volume plus a 1.0-cm margin. The resulting calculated resection ratio (CRR) indicated the amount of excess tissue resected. Results All tumours were correctly identified during surgery, 29 of 30 tumours (96.7%) were removed with adequately negative margins, and one tumour was removed with focally positive margins. The median CRR was 1.0 (range, 0.4–2.8), implying optimal excision volume. For all breast surgeons, CRR improved during the training period. By the 8th procedure, all surgeons showed proficiency in performing intra-operative breast US. Conclusion Surgeons can easily learn the skills needed to perform intra-operative US for palpable breast tumour excision. The technique is non-invasive, simple, safe and effective for obtaining adequate resection margins. Within the first two cases, resections reached optimal volumes, thereby, presumably resulting in improved cosmetic outcomes. In a multicentre, randomised, clinical trial, intra-operative US guidance for palpable breast tumours will be evaluated for oncological and cosmetic outcomes.

Background. This study was designed to assess endotracheal climate in laryngectomized patients in a warm and dry environment and the effects of a heat and moisture exchanger (HME). Methods. Endotracheal temperature and humidity were measured in 11 laryngectomized patients with a regularly used HME (Provox Normal HME; R-HME), an HME with antimicrobial filter (Provox Micron HME; F-HME), and without HME (open stoma). Measurements were performed at 32 degrees C, 34 degrees C, and 38 degrees C (

PURPOSE: Lymphatic mapping for prostate cancer can be used to determine therapeutic strategies. Sentinel node visualization requires sufficient nodal tracer uptake. We evaluated the effect of an increase in particle concentration on preoperative and intraoperative sentinel node depiction. METHODS: Enrolled in the study were 50 consecutive patients with prostate cancer. The first 25 patients (group A) received nanocolloid with standard labelling (0.4 ml (99m)Tc per 0.1 mg nanocolloid). The last 25 patients (group B) received nanocolloid with a reduced labelling dilution volume (0.4 ml (99m)Tc per 0.2 mg nanocolloid). The aimed injected volume and dosage were the same for both groups (225 MBq in 0.4 ml). Intratumoral tracer injection was followed by planar lymphoscintigraphy (15 min and 2 h), SPECT/CT and laparoscopic sentinel lymphadenectomy. Lymph node visualization was evaluated using a four-point scoring system (0 nonvisualization to 3 intense visualization) and count quantification on the 2-h anterior lymphoscintigram. In addition to the gamma ray detection probe, a portable gamma camera was used for intraoperative sentinel node visualization. RESULTS: Preoperative visualization in group A was 88% (mean 2.0 sentinel nodes per patient) versus 100% in group B (mean 2.6 sentinel nodes per patient). Visualization scores (p=0.008), total counts (p=0.001) and maximum counts per pixel (p=0.034) in the sentinel nodes were significantly better in group B. This also led to more efficient intraoperative detection of the sentinel nodes with the portable gamma camera (84% in group A versus 100% in group B). CONCLUSION: Enhancement of the particle concentration may lead to significant improvement in sentinel node visualization and intraoperative localization in patients with prostate cancer. Further research regarding optimization of radiotracer labelling by changing the particle concentration is warranted

Curettage of the epithelium of the vas deferens might be a safe and effective method of male sterilization. We conducted a pilot study of vasectomy by epithelial curettage with a novel microcurette called the Vas-X in 12 normal men requesting elective sterilization. Seminal fluid analysis was obtained monthly after the procedure for 6 months. Pain was assessed by questionnaire. Three months after the procedure, all men attained sperm concentrations of less than 0.2 million sperm per mL, and seven were azoospermic. Post-procedural pain was minimal. Nine men ultimately achieved and maintained azoospermia; however, 4 to 6 months after the procedure, sperm concentrations increased in three of the 12 subjects, necessitating repeat vasectomy. Microscopic examination of the vas deferens from these failures revealed re-canalization. Vasectomy by epithelial curettage can result in effective sterilization; however, 1/4 of the subjects were not effectively sterilized by the procedure due to re-canalization of the vas deferens. Epithelial curettage will require further refinement to determine if it is a viable form of vasectomy.

Purpose The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. Patients and Methods Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). Results Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P < .00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis ≤ 1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n = 43). Conclusion Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

CONCLUSION: Both the regularly used heat and moisture exchanger (R-HME) and the HME with both an antimicrobial and hygroscopic element (F-HME) are effective moisture exchangers. The antimicrobial filter of the F-HME acts as a heat exchanger. The external features of the F-HME were experienced as inconvenient, but decreased sputum production was reported as well. OBJECTIVES: Recently an HME with an integrated antimicrobial filter has become available for use in laryngectomized patients. The purpose of this study was to assess its short-term endotracheal climate changes and feasibility in daily practice. METHODS: Endotracheal temperature and humidity were successfully measured in 13 laryngectomized patients (2652 analysed full breaths), during 10 min rest-breathing with the R-HME, with an F-HME and without HME in a randomized sequence. Additionally, a 3 week prospective clinical feasibility trial was conducted in 17 laryngectomized patients. RESULTS: Both R-HME and F-HME increase endotracheal minimum humidity values (5.8 and 4.7 mgH(2)O/L, respectively; p

While almost half of women use complementary and alternative medicine (CAM) during their menopause, almost no literature explores why women choose CAM for menopausal symptoms. Clinician–patient conversations about CAM can be unsatisfactory, and exploration of women’s choices may benefit communication. The objective of this study was to describe women’s choices to use CAM for menopausal health issues. This is a qualitative study utilizing semi-structured interviews. Convenience sample of 44 menopausal women ages 45 to 60 recruited in two primary care clinics. Both users and non-users of CAM were included. Transcripts of semi-structured interviews were analyzed for themes that were refined through comparison of labeled text. Four themes emerged in decisions to use CAM: (1) valuing CAM as “natural”, although the meaning of “natural” varied greatly, (2) perceiving menopause as marking a change in life stage, (3) seeking information about menopause generated from personal intuition and other women’s experiences, and (4) describing experiences before menopause of using CAM and allopathic medication in patterns similar to current use (patterned responses). Women’s decisions about using CAM during menopause can be understood through their perspectives on menopause and overall health. Increased clinician awareness of these themes may promote supportive discussions about CAM during counseling for menopause.

OBJECTIVE. The aim of this study was to establish changes in contrast-enhanced MRI of breast cancer during neoadjuvant chemotherapy that are indicative of pathology outcome. MATERIALS AND METHODS. In 54 patients with breast cancer, dynamic contrast-enhanced MRI was performed before chemotherapy and after two chemotherapy cycles. Imaging was correlated with final histopathology. Multivariate analysis with cross-validation was performed on MRI features describing kinetics and morphology of contrast uptake in the early and late phases of enhancement. Receiver operating characteristic (ROC) analysis was used to develop a guideline that switches patients at high risk for incomplete remission to a different chemotherapy regimen while maintaining first-line therapy in 95% of patients who are not at risk (i.e., high specificity). RESULTS. Change in largest diameter of late enhancement during chemotherapy was the single most predictive MRI characteristic for tumor response in multivariate analysis (A(z) [area under the ROC curve] = 0.73, p

Mycophenolic acid (MPA) levels have demonstrated a good correlation with clinical outcomes, but with great pharmacokinetic variability between patients. Therapeutic drug monitoring (TDM) is recommended to include a 12-hour area under the concentration-time curve (AUC). Since full AUC estimates are not practical for routine monitoring, limited sampling strategies have been suggested. We evaluated MPA pharmacokinetics in 18 stable renal transplant patients receiving mycophenolate mofetil (MMF) as part of their immunosuppressive therapy. The correlation between measured and estimated AUC was assessed using 4 different sparse sampling algorithms. The mean values for C(0) and AUC(0-6h) were 1.8 +/- 1.2 mg/L and 31.1 +/- 14.8 mg*h/L, respectively. The dose-corrected AUC(0-6h) was 35.4 +/- 17.9 mg*h/L. Regarding the single time points, C(0) showed a low correlation with AUC(0-6h) (r(2) = .34); C(1.5), the best correlation (r(2) = .72); and C(3), the worst (r(2) = .07). Sparse sample algorithms used to estimate 12-hour AUC including C(0), C(1), C(2), C(3), C(4), and/or C(6) showed a good correlation with the calculated AUC(0-6) (r(2) = .81-.96). The algorithm that used C(0), C(1), C(2), and C(4) showed the best correlation, but we also found a good correlation (r(2) = .91) with C(0), C(1), and C(2). Based on these results, we have suggested using the 3-point algorithm (C(0), C(1), and C(2)) for MPA TDM in stable renal transplant patients due to the good correlation with drug exposure and better functionality than an algorithm using a 4-hour postdose measurement.

Background High-resistance heat and moisture exchangers (HMEs) have been reported to increase transcutaneous oxygenation (tcpO2) values in laryngectomized individuals and to negatively influence patient compliance. The goal of the present study was to validate earlier published results on short-term transcutaneous oxygenation changes by high-resistance HMEs. Methods We conducted a randomized crossover study, monitoring the influence of an HME on tcpO2 over a 2-hour time interval in 20 subjects. Results No evidence of an immediate HME effect (95% CI: −14.9–13.3 mm Hg, p = .91), or a time-dependent HME effect (95% CI: −.121 – .172 mm Hg/minute, p = .74), on tcpO2 was found. After fitting the statistical model without time dependency, again no evidence of HME presence was seen (95% CI: −.5 mm Hg – 3.6 mm Hg, p = .15). Conclusion In contrast to earlier suggestions, there is no evidence of increased tcpO2 levels by high-resistance HMEs in laryngectomized individuals. Thus, using such HMEs has no added clinical value in this respect. © 2007 Wiley Periodicals, Inc. Head Neck, 2007

The aim of this study was to assess whether the semiautomatic measurement of breast-tumor extent using contrast-enhanced magnetic resonance imaging (CE-MRI) decreases measurement variation compared with manual evaluation and increases precision with respect to tumor extent measured at histopathology. Forty-three patients who underwent breast-conserving therapy for 46 tumors were consecutively included. Extended histopathology analysis was performed on the excision specimens. Two experienced breast-MR radiologists independently manually assessed the largest diameter of the tumors at preoperative CE-MRI. Two observers used a semiautomatic segmentation technique to independently obtain the largest diameter and the volume of the tumors. Semiautomatic volumetric measurement of tumor volume was more accurately correlated with histopathology (adjusted R-square 0.84 and 0.81) compared with conventional measurement (adjusted R-square 0.56 and 0.70) and semiautomatic measurement (adjusted R-square 0.63 and 0.60) of the largest diameter of the tumor. The interobserver variability between the volumetric measurements was significantly smaller than the interobserver variability between the largest-diameter measurements of tumor extent obtained by the radiologists (P

Our objective was to identify predictors of improved postthaw semen quality in men with testicular cancer banking sperm for fertility preservation. We reviewed 173 individual semen samples provided by 67 men with testicular germ cell tumor (TGCT) who cryopreserved sperm before gonadotoxic treatment between 1994 and 2010 at our tertiary university medical center. Our main outcomes measures were independent predictors for the greater postthaw total motile count (TMC) in men with TGCT. Men with NSGCT were more likely to be younger (P < 0.01) and had high cancer stage (II or III, P < 0.01) compared with men with seminoma. In our multiple regression model, NSGCT histology, use of density gradient purification, and fresh TMC > median fresh TMC each had increased odds of a postthaw TMC greater than median postthaw TMC. Interestingly, age, advanced cancer stage (II or III), rapid freezing protocol, and motility enhancer did not show increased odds of improved postthaw TMC in our models. In conclusion, men with TGCT or poor fresh TMC should consider preserving additional vials (at least 15 vials) before oncologic treatment. Density gradient purification should be routinely used to optimize postthaw TMC in men with TGCT. Larger, randomized studies evaluating cancer stage and various cryopreservation techniques are needed to assist in counseling men with TGCT regarding fertility preservation and optimizing cryosurvival.

Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF MS) has been introduced in clinical routine microbiology laboratories. For the rapid diagnosis of urinary tract infections, culture-independent methods prior MALDI-mediated identification have been described. Here, we describe a comparison of three of these methods based on their performance of bacterial identification and their potential as a routine tool for microbiology labs : (i) differential centrifugation, (ii) urine filtration and (iii) a 5-h bacterial cultivation on solid culture media. For 19 urine samples, all methods were directly compared and correct bacterial species identification by MALDI was used as performance indicator. A higher percentage of correct MALDI identification was obtained after filtration (78.9 %) and the growth-based method (84.2 %) as compared to differential centrifugation (68.4 %). Additional testing of 76 mono-microbial specimens (bacteriuria 10(5) CFU/mL) confirmed the good performance of short growth with a 90.8 % correct MALDI score, with a potentially better fit to the routine workflow of microbiology labs.

Contains fulltext : 49322.pdf (Publisher’s version ) (Closed access) BACKGROUND: The MRISC study is a screening study, in which women with an increased risk of hereditary breast cancer are screened by a yearly mammography and MRI, and half-yearly clinical breast examination. The sensitivity found in this study was 40% for mammography and 71% for MRI and the specificity was 95 and 90%, respectively. In the current subsequent study we investigated whether these results are influenced by age, a BRCA1/2 mutation, menopausal status and breast density. PATIENTS AND METHODS: From November 1999 to October 2003, 1909 eligible women were screened and 50 breast cancers were detected. For the current analysis, data of 4134 screening rounds and 45 detected breast cancers were used. For both imaging modalities, screening parameters, receiver operating characteristic (ROC) curves and uni- and multivariate odds ratios (ORs) were calculated. All analyses were separately performed for age at entry (< 40, 40-49, >/=50), mutation status, menopausal status and breast density. RESULTS: Sensitivity of MRI was decreased in women with high breast density (adjusted OR 0.08). False-positive rates of both mammography (OR(adj) 1.67) and MRI (OR(adj) 1.21) were increased by high breast density, that of MRI by pre-menopausal status (OR(adj) 1.70), young age (OR(adj) 1.58 for women 40-49 years versus women >/=50 years) and decreased in BRCA1/2 mutation carriers (OR(adj) 0.74). In all investigated subgroups the discriminating capacity (measured by the area under the ROC-curve) was higher for MRI than for mammography, with the largest differences for BRCA1/2 mutation carriers (0.237), for women between 40 and 49 years (0.227) and for women with a low breast density (0.237). CONCLUSIONS: This report supports the earlier recommendation that MRI should be a standard screening method for breast cancer in BRCA1/2 mutation carriers.

In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to␣tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P = 0.02) and tended to be more often ≤1 cm (58 vs. 31%; P = 0.11). MRI was more sensitive than mammography for a wide spectrum of invasive tumor characteristics i.e., size, nodal status, histology, grade and ER status. Half of the breast cancers detected in this study were visible by MRI only and these tumors were smaller and significantly more often node-negative than other screen-detected tumors, suggesting that MRI makes an important contribution to the early detection of hereditary breast cancer.

Retinoic acid (RA), the active metabolite of vitamin A, is required for spermatogenesis and many other biological processes. RA formation requires irreversible oxidation of retinal to RA by aldehyde dehydrogenase enzymes of the 1A family (ALDH1A). While ALDH1A1, ALDH1A2, and ALDH1A3 all form RA, the expression pattern and relative contribution of these enzymes to RA formation in the testis is unknown. In this study, novel methods to measure ALDH1A protein levels and intrinsic RA formation were used to accurately predict RA formation velocities in individual human testis samples and an association between RA formation and intratesticular RA concentrations was observed. The distinct localization of ALDH1A in the testis suggests a specific role for each enzyme in controlling RA formation. ALDH1A1 was found in Sertoli cells, while only ALDH1A2 was found in spermatogonia, spermatids, and spermatocytes. In the absence of cellular retinol binding protein (CRBP)1, ALDH1A1 was predicted to be the main contributor to intratesticular RA formation, but when CRBP1 was present, ALDH1A2 was predicted to be equally important in RA formation as ALDH1A1. This study provides a comprehensive novel methodology to evaluate RA homeostasis in human tissues and provides insight to how the individual ALDH1A enzymes mediate RA concentrations in specific cell types.

This study was conducted to assess the incidence and impact of additional findings from magnetic resonance imaging (MRI) on the workup of patients eligible for breast-conserving therapy (BCT) and to optimise the specificity of further workup by combining radiological reading with computerised analysis. One hundred and sixteen patients eligible for BCT underwent preoperative MRI where the gold standard was histology or follow-up (median 35 months, range 23-48). The incidence of additional findings and impact on treatment (wider excision/conversion to mastectomy) were assessed. The specificity of referral to further workup was also assessed without and with computerised analysis. Additional findings from MRI occurred in 41% of patients, requiring workup in 78%. In 22% the findings were malignant, causing change in treatment. Specificity was 33% (10/30) for radiological reading alone, and 97% (29/30) combined with computer analysis. Our findings show that additional findings preoperative MRI required workup in approximately one-third of patients and we suggest that combining radiological reading with computer analysis has the potential to accurately exclude benign lesions from further workup.

To investigate if and how computerized analysis complements characterization of breast lesions with clinical reading at magnetic resonance imaging.The institutional review board approved the use of data obtained prospectively and analyzed either prospectively with informed patient consent or retrospectively with waiver of consent. An existing computerized analysis system was retrained with 100 breast lesions (in 78 patients with mean age of 46.5 years) and tested with 136 other lesions (in 113 patients with mean age of 48.9 years; P=.15 for age difference between groups). Seventy-five lesions in the training set were previously rated by one of three radiologists in daily clinical practice. Lesion rating (as benign, probably benign, indeterminate, suspicious, or highly suggestive of malignancy) and probability of malignancy calculated with computerized analysis were included as covariates in logistic regression analysis to obtain a combined model. The performance of the model was compared with that of clinical reading alone in a set of 72 clinically and mammographically occult lesions not used to train the computerized analysis system (in 60 patients with mean age of 43.5 years; P=.09 for age difference between training and testing groups). Receiver operating characteristic (ROC) curves were plotted, and areas under the ROC curves were calculated and compared.Performance of reading in the clinical setting, as indicated by area under the ROC curve (Az=0.86), was similar to that of computerized analysis (Az=0.85; P=.99). Significant overall improvement in performance was obtained with the combined model (Az=0.91; P=.03). Improvement was accomplished mostly in characterization of lesions rated indeterminate or suspicious by radiologists.Computerized analysis complements clinical reading and makes computer-aided diagnosis feasible. The complementary information has the potential to increase overall performance for clinically and mammographically occult lesions.

Antigen-specific vaccines are one of several molecularly targeted approaches under investigation as possible treatments for prostate cancer. Important to the development of vaccines is the identification of appropriate target antigens. We hypothesized that antigens of the prostate might be identified in patients with the chronic prostatitis/pelvic pain syndrome, a syndrome for which an autoimmune pathology has been proposed. Such antigens might represent naturally recognized target antigens of the prostate that could be investigated in the future as prostate tumor antigens. In this report, we used SEREX to identify proteins expressed in a prostate cDNA expression library recognized by IgG from the sera of patients with chronic prostatitis. Candidate proteins were evaluated using a panel of sera from 62 subjects with symptomatic prostatitis and 71 control male blood donors. We identified one protein that was recognized primarily in sera from subjects with prostatitis compared with controls. MAD-PRO-34, a nucleolar autoantigen, was recognized in 6/62 subjects and 0/71 controls (p = 0.00897). This protein had previously been identified as an autoantigen in patients with prostate cancer. In addition, the NY-CO-7 protein was recognized in 9/62 subjects and 3/71 controls (p = 0.0654). Two subjects had IgG specific for both the MAD-PRO-34 and NY-CO-7 gene products. Our results demonstrate that some patients with the chronic prostatitis/pelvic pain syndrome have autoantibodies to specific proteins. Proteins identified, and MAD-PRO-34 in particular, could be further investigated as potential prostate tumor antigens.