M inverted V glansplasty: an update on technique and outcomes 30 years later.

Distal hypospadias is a common congenital urology anomaly for which numerous corrective procedures have been described. Over the last 40 years, the gold-standard operative technique for distal hypospadias has switched from the meatal advancement and glanuloplasty (MAGPI) procedure to the tubularized incised plate (TIP) urethroplasty. A modification to the MAGPI procedure, first described 30 years ago, is the M inverted V (MIV) glansplasty, which improved upon the MAGPI procedure to reduce instances of meatal retraction. The MIV glansplasty is unique compared to many commonly used procedures as it does not require a formal urethroplasty or incorporation of a dartos flap, and it does not always necessitate as extensive mobilization of the glans wings. We describe our updated technique and outcomes of the MIV glansplasty and delineate situations where the MIV is best employed.

Retargeting azithromycin analogues to have dual-modality antimalarial activity.

BACKGROUND: Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing 'delayed-death' activity against the parasite's apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. RESULTS: Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on 'quick-killing' activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. CONCLUSION: We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.

A role for nitric oxide in serotonin neurons of the midbrain raphe nuclei.

Neuronal nitric oxide synthase (nNOS) catalyses the production of the neurotransmitter nitric oxide. nNOS is expressed in the dorsal raphe nucleus (DRN), a source of ascending serotonergic projections. In this study, we examined the distribution nNOS and the function of nitric oxide in the DRN and adjacent median raphe nucleus (MRN) of the rat. We hypothesized that nNOS is differentially expressed across the raphe nuclei and that nitric oxide influences the firing activity of a subgroup of 5-HT neurons. Immunohistochemistry revealed that, nNOS is present in around 40% of 5-HT neurons, throughout the DRN and MRN, as well as in some non-5-HT neurons immediately adjacent to the DRN and MRN. The nitric oxide receptor, soluble guanylyl cyclase, was present in all 5-HT neurons examined in the DRN and MRN. In vitro extracellular electrophysiology revealed that application of the nitric oxide donor, diethylamine NONOate (30-300 µM) inhibited 60%-70% of putative 5-HT neurons, excited approximately 10% of putative 5-HT neurons and had no effect on the rest. The inhibitory response to nitric oxide was blocked by [1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 30 or 100 µM), indicating mediation by soluble guanylyl cyclase. Juxtacellular labelling revealed that nitric oxide inhibits firing in both putative 5-HT neurons which express nNOS and those which do not express nNOS. Our data are consistent with the notion that nitric oxide acts as both a trans-synaptic and autocrine signaller in 5-HT neurons in the DRN and MRN and that its effects are widespread and primarily inhibitory.

The Mechanism of Vesicle Solubilization by the Detergent Sodium Dodecyl Sulfate.

Membrane solubilization by sodium dodecyl sulfate (SDS) is indispensable for many established biotechnological applications, including viral inactivation and protein extraction. Although the ensemble thermodynamics have been thoroughly explored, the underlying molecular dynamics have remained inaccessible, owing to major limitations of traditional measurement tools. Here, we integrate multiple advanced biophysical approaches to gain multiangle insight into the time-dependence and fundamental kinetic steps associated with the solubilization of single submicron sized vesicles in response to SDS. We find that the accumulation of SDS molecules on intact vesicles triggers biphasic solubilization kinetics comprising an initial vesicle expansion event followed by rapid lipid loss and micellization. Our findings support a general mechanism of detergent-induced membrane solubilization, and we expect that the framework of correlative biophysical technologies presented here will form a general platform for elucidating the complex kinetics of membrane perturbation induced by a wide variety of surfactants and disrupting agents.

Ectopic ACTH-secreting neuroendocrine tumor: a rare etiology of a pediatric solid renal mass.

Neuroendocrine tumors (NETs) are rare tumors with varying clinical presentations. We describe the case of an 11-year-old female presenting with Cushingoid features in the setting of a left-sided flank mass. Her presentation and evaluation suggested a paraneoplastic ectopic ACTH syndrome. She underwent open left radical nephrectomy and final pathology confirming a high-grade NET with nodal metastasis. Although exceedingly rare, ACTH-secreting tumors of the kidney can cause significant morbidity and mortality and so we recommend it be included in the differential diagnosis of pediatric renal masses.

Autism spectrum disorder and other neurobehavioural comorbidities in rare disorders of the Ras/MAPK pathway.

AIM: To investigate the cognitive and behavioural phenotype in rare disorders of the Ras/MAPK pathway, namely Noonan, cardiofaciocutaneous (CFC), and Costello syndromes, particularly prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD). METHOD: Fifty children were recruited over 10 months through the regional genetics service and advertisements. A range of parent, child, and observational measures were administered including Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Scale. RESULTS: Using the Collaborative Programme for Excellence in Autism criteria, 12 out of 40 children with Noonan syndrome (30%) showed ASD, and 12 out of 40 (30%) with partial ASD features and 16 out of 40 (40%) showed non-ASD. The Noonan syndrome ASD group showed male dominance in a ratio of 5:1. In the CFC group, eight out of nine children met the criteria for ASD, with equal sex distribution. Additionally 19 out of 40 (48%) of the Noonan syndrome group and eight out of nine (88.9%) of the CFC group scored met clinical criteria for ADHD. Only one child was in the Costello syndrome group. INTERPRETATION: This is the first systematic study to suggest a high prevalence of ASD in Noonan and CFC syndromes, and thus offers crucial evidence to support the importance of the Ras/MAPK pathway in the aetiology of ASD. Limitations include the inevitable possibility of a sampling bias in a rare disorder study of this kind.

Notes from the field: Adverse events associated with administration of simulation intravenous fluids to patients--United States, 2014.

On December 23, 2014, the New York State Department of Health (NYSDOH) was notified of adverse health events in two patients who had been inadvertently administered nonsterile, simulation 0.9% sodium chloride intravenous (IV) fluids at an urgent care facility. Simulation saline is a nonsterile product not meant for human or animal use; it is intended for use by medical trainees practicing IV administration of saline on mannequins or other training devices. Both patients experienced a febrile illness during product administration and were hospitalized; one patient developed sepsis and disseminated intravascular coagulation. Neither patient died. Staff members at the clinic reported having ordered the product through their normal medical supply distributor and not recognizing during administration that it was not intended for human use.

Dying to remember, remembering to survive: mortality salience and survival processing.

Processing items for their relevance to survival improves recall for those items relative to numerous other deep processing encoding techniques. Perhaps related, placing individuals in a mortality salient state has also been shown to enhance retention of items encoded after the morality salience manipulation (e.g., in a pleasantness rating task), a phenomenon we dubbed the "dying-to-remember" (DTR) effect. The experiments reported here further explored the effect and tested the possibility that the DTR effect is related to survival processing. Experiment 1 replicated the effect using different encoding tasks, demonstrating that the effect is not dependent on the pleasantness task. In Experiment 2 the DTR effect was associated with increases in item-specific processing, not relational processing, according to several indices. Experiment 3 replicated the main results of Experiment 2, and tested the effects of mortality salience and survival processing within the same experiment. The DTR effect and its associated difference in item-specific processing were completely eliminated when the encoding task required survival processing. These results are consistent with the interpretation that the mechanisms responsible for survival processing and DTR effects are overlapping.

Training Program Factors Most Important to Women When Selecting an Otolaryngology Residency.

OBJECTIVES: The aim of the study was to determine factors that female resident physicians find most influential when choosing an otolaryngology residency program. METHODS: A three-part survey was sent to current female otolaryngology residents via email evaluating the importance of 19 characteristics impacting program choice. The 19 factors were scored from 1 (least important) to 5 (most important). The participants also ranked their personal top five most influential factors. Data were analyzed using descriptive statistics. RESULTS: One-hundred and fifty of 339 contacted residents participated. Most were aged 30-39 (63%), white (70%), and married (43%). Eighty-five percent had no children, and 52% did not plan to have children during residency. The highest scoring factors derived from Likert scale ratings included resident camaraderie (4.5 ± 0.8), resident happiness (4.4 ± 0.8), and case variety/number (4.4 ± 0.8). The lowest scoring factors were number of fellows (2.9 ± 1.1), attitudes toward maternity leave (2.7 ± 1.3), and maternity leave policies (2.4 ± 1.2). The top five most influential factors and the percentage selecting this were resident camaraderie (57%), resident happiness (57%), academic reputation (51%), case variety/number (47%), and early surgical/clinical experience (44%). Gender-specific factors were infrequently selected. However, 51 (34%) ranked at least one gender-specific factor within their top five list. CONCLUSION: Non-gender-related factors, like resident camaraderie and surgical experiences, were most valued by women. Conversely, gender-specific factors were less critical and infrequently ranked. Ninety-nine residents (64%) rated exclusively gender-neutral characteristics in their top five list of most influential factors. Our data offer insight into program characteristics most important to female otolaryngology residents, which may assist residency programs hoping to match female applicants. LEVEL OF EVIDENCE: NA Laryngoscope, 134:600-606, 2024.

Urology Match: Important Factors Women Consider When Choosing a Residency Training Program.

OBJECTIVE: To determine factors that women urology resident physicians rate as most influential when selecting residency programs. METHODS: Surveys were emailed to female urology residents during the 2021-2022 academic year. Residents scored 19 factors influencing residency program choice from 1 "least" to 5 "most" important and ranked their top 5 most influential factors. Data were analyzed via descriptive statistics and quantile regression. RESULTS: One hundred thirty-six (37%) of 367 female urology residents who received the survey participated. Eighty-two percent had no children and 57% did not plan to have children during residency. The three highest scoring factors derived from Likert scale ratings were resident camaraderie (4.6 ±â€¯0.5 [mean ±â€¯SD]), resident happiness (4.6 ±â€¯0.6), and case variety/number (4.4 ±â€¯0.8). As a whole, the lowest scoring characteristics were attitudes toward maternity leave (2.6 ±â€¯1.2) and maternity leave policies (2.5 ±â€¯1.2). Married residents were more likely than those who were single and engaged/in a committed relationship to rank attitudes and policies toward maternity leave as more important (3 vs 2 vs 2, P <.0001). Residents with children were more likely than those without children to rank maternity leave policies as more important (3 vs 2, P <.0001). CONCLUSION: As a whole, women urology residents prioritized non-gender-related factors. However, gender-specific factors were rated highly by married residents and those with children or planning to have children. Urology training programs may use these results to highlight desirable characteristics to aid recruitment of female residents.

Overlap between individual differences in cognition and symptoms of schizophrenia.

BACKGROUND: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified. STUDY DESIGN: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). RESULTS: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment. CONCLUSIONS: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods.

Adaptive memory: the survival scenario enhances item-specific processing relative to a moving scenario.

Nairne, Thompson, and Pandeirada (2007) found that retention of words rated for their relevance to survival is superior to that of words encoded under numerous other deep processing conditions. They suggested that our memory systems might have evolved to confer an advantage for survival-relevant information. Burns, Burns, and Hwang (2011) suggested a two-process explanation of the proximate mechanisms responsible for the survival advantage. Whereas most control tasks encourage only one type of processing, the survival task encourages both item-specific and relational processing. They found that when control tasks encouraged both types of processing, the survival processing advantage was eliminated. However, none of their control conditions included non-survival scenarios (e.g., moving, vacation, etc.), so it is not clear how this two-process explanation would explain the survival advantage when scenarios are used as control conditions. The present experiments replicated the finding that the survival scenario improves recall relative to a moving scenario in both a between-lists and within-list design and also provided evidence that this difference was accompanied by an item-specific processing difference, not a difference in relational processing. The implications of these results for several existing accounts of the survival processing effect are discussed.

Adding Cognitive Remediation to Employment Support Services: A Randomized Controlled Trial.

OBJECTIVE: Individual placement and support (IPS) is an evidence-based strategy that helps individuals with mental illness obtain and maintain competitive employment. Despite the approach's overall success, almost half of IPS clients do not find work. Impairment in cognitive abilities may hamper employment and limit the benefits from rehabilitation services such as IPS. This randomized controlled trial aimed to assess the effects of adding cognitive remediation therapy (CRT) for IPS clients who had difficulties finding employment. METHODS: At 14 mental health centers in Canada, 97 clients who had not found work after 3 months of receiving IPS services were recruited. Consenting clients were randomly assigned to either continue IPS alone or receive CRT added to IPS. The CRT used the Thinking Skills for Work protocol, a 12-week program that included computerized cognitive exercises along with coping strategies for managing cognitive challenges. RESULTS: Participants completed on average 10 of 12 individual training sessions in coping strategies and 12 of 24 computerized training sessions. The addition of CRT to IPS resulted in significantly more participants working at the 3-month (odds ratio [OR]=2.83, 95% confidence interval [CI]=1.22-6.60) and 9-month follow-ups (OR=2.91, 95% CI=1.27-6.65). Participants who received CRT worked more hours and earned more in wages than those receiving IPS alone over the 9-month follow-up period. Both groups showed significantly improved cognitive outcomes at the 3-month follow-up, with no time × group interaction. CONCLUSIONS: Cognitive remediation, especially skills training in coping and compensatory strategies, improves employment outcomes among individuals who do not show an early benefit of using IPS services.

Career satisfaction in women surgeons: A systematic review and meta-analysis.

BACKGROUND: Career satisfaction among women surgeons have been well-reported in literature. This study provides a comprehensive review to understand career satisfaction and its contributory factors among female surgeons. METHODS: PRISMA guidelines were utilized to extract studies for systematic review and meta-analysis. Outcomes assessed included surgical career satisfaction, career reconsideration, work-life balance, and gender bias and discrimination (GBD). Odds ratios were calculated comparing women to men for each outcome. RESULTS: This study demonstrated that female surgeons were less likely to endorse overall career satisfaction (OR, 0.68; 95% CI, 0.55-0.85) and work-life balance satisfaction (OR, 0.61; 95% CI, 0.40-0.92) compared to male surgeons. It also revealed that women surgeons were more likely to report workplace GBD (OR, 13.82; 95% CI, 4.37-43.65). CONCLUSIONS: Future interventions may be necessary to increase career and work-life balance satisfaction among women surgeons while reconciling the need to ensure they are adequately informed of the obligations of a surgical career.

A Case of Potential Pharmacokinetic Kratom-drug Interactions Resulting in Toxicity and Subsequent Treatment of Kratom Use Disorder With Buprenorphine/Naloxone.

The botanical product kratom produces opioid-like effects at high doses and is sometimes used for opioid replacement by individuals with opioid use disorder. Mitragynine, a major alkaloid contained in kratom leaves, has been shown to inhibit multiple cytochromes P450 (CYPs) in vitro, including CYP2D6 and CYP3A. As such, kratom may precipitate pharmacokinetic drug interactions when co-consumed with certain medications. We present a case of a patient taking 150 mg venlafaxine (CYP2D6/3A substrate), 300 mg quetiapine (CYP3A substrate), and a high amount of kratom (~90 g) daily. The patient presented to the emergency department with serotonin syndrome and corrected electrocardiogram abnormalities that may have been secondary to supratherapeutic exposure to venlafaxine and/or quetiapine. The patient's symptoms resolved after discontinuation of venlafaxine and quetiapine. He was amenable to medication therapy for kratom discontinuation and successfully completed an at-home induction with buprenorphine/naloxone. This case report adds to the literature about potential pharmacokinetic kratom-drug interactions and suggests that buprenorphine/naloxone can facilitate recovery from kratom use disorder.

Targeting malaria parasites with novel derivatives of azithromycin.

Introduction: The spread of artemisinin resistant Plasmodium falciparum parasites is of global concern and highlights the need to identify new antimalarials for future treatments. Azithromycin, a macrolide antibiotic used clinically against malaria, kills parasites via two mechanisms: 'delayed death' by inhibiting the bacterium-like ribosomes of the apicoplast, and 'quick-killing' that kills rapidly across the entire blood stage development. Methods: Here, 22 azithromycin analogues were explored for delayed death and quick-killing activities against P. falciparum (the most virulent human malaria) and P. knowlesi (a monkey parasite that frequently infects humans). Results: Seventeen analogues showed improved quick-killing against both Plasmodium species, with up to 38 to 20-fold higher potency over azithromycin after less than 48 or 28 hours of treatment for P. falciparum and P. knowlesi, respectively. Quick-killing analogues maintained activity throughout the blood stage lifecycle, including ring stages of P. falciparum parasites (<12 hrs treatment) and were >5-fold more selective against P. falciparum than human cells. Isopentenyl pyrophosphate supplemented parasites that lacked an apicoplast were equally sensitive to quick-killing analogues, confirming that the quick killing activity of these drugs was not directed at the apicoplast. Further, activity against the related apicoplast containing parasite Toxoplasma gondii and the gram-positive bacterium Streptococcus pneumoniae did not show improvement over azithromycin, highlighting the specific improvement in antimalarial quick-killing activity. Metabolomic profiling of parasites subjected to the most potent compound showed a build-up of non-haemoglobin derived peptides that was similar to chloroquine, while also exhibiting accumulation of haemoglobin-derived peptides that was absent for chloroquine treatment. Discussion: The azithromycin analogues characterised in this study expand the structural diversity over previously reported quick-killing compounds and provide new starting points to develop azithromycin analogues with quick-killing antimalarial activity.

Optimizing the Impact of Pragmatic Clinical Trials for Veteran and Military Populations: Lessons From the Pain Management Collaboratory.

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings.

"Individual Placement and Support" boosts employment for early psychosis clients, even when baseline rates are high.

AIM: Individual Placement and Support is an effective vocational intervention for increasing competitive employment for people with severe mental illness. Little is known, however, about its effectiveness in the context of early psychosis. This study assesses improvements in clients' employment in a phase of illness during which functional abilities often decline. METHODS: The trial design is an assessor-blinded randomized clinical trial, set in the context of a population-based Early Psychosis Intervention program in British Columbia, Canada. Participants were randomized either to 1 year of employment support added to treatment-as-usual, or the latter alone. Interviews at intake captured data regarding demographics, symptom severity, and employment; assessments at 6 and 12 months repeated queries about employment activities. RESULTS: A total of 109 clients were recruited. Employment rates in the Individual Placement and Support group increased over time, unlike the control group. Further, the number of days worked over the 12-month intervention period, compared to the 6 months prior to the study, improved for both groups, but the increase was greater among clients receiving IPS. Sensitivity analysis indicated the advantage in days worked was evident in the second half of the intervention period (6-12 months), but not the first half. CONCLUSIONS: Employment rates, for younger clients in both early-psychosis groups, were high compared to older clients in later stages of illness. In this study, use of the Individual Placement and Support strategy further increased employment, despite the high baseline rates. Further research is needed to identify the optimal timing of employment support for these clients.

Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention.

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.

Self-Focused Attention and Depressive Symptoms in Adults with Autistic Spectrum Disorder (ASD).

Adults with autistic spectrum disorder (ASD) are at high risk of developing comorbid depressive symptoms and in the general population self-focused attention has been associated with depression. Here, we aimed to examine the relationships between aspects of self-focused attention and symptoms of depression in individuals with a diagnosis of ASD. 113 adults with a diagnosis of ASD completed self-report questionnaires. Results found that higher levels of brooding, and to a lesser degree, reflection predicted increased depressive symptoms. However, higher levels of private self-consciousness actually predicted decreased depressive symptoms. Differential relationships were observed for males and females. The current study highlights the importance of using a multidimensional approach to examining self-focused attention in ASD, and its important relationship with depression.