Opioid analgesic use among patients with kidney disease: a systematic review.

INTRODUCTION: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. METHODS: We searched eight electronic databases from inception to 26th January 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091). RESULTS: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine. CONCLUSION: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.

Assessing Planetary Health Curricular Needs Across Health Professions Programs.

With growing recognition that climate change is a significant threat to human health, allied health professionals are increasingly recognized as critical allies in addressing this threat. This article describes the approach that Rush University's College of Sciences is pursuing to better prepare health sciences students for this reality. Faculty and students enrolled across all programs of the College were surveyed regarding their levels of concern about global warming using items from the Six Americas Survey, as well as perceived importance of planetary health curricular elements adapted from the Planetary Health Report Card. Faculty were additionally asked about perceived opportunities to bring planetary health education into each of the degree programs offered by the university. A total of 37 faculty and 43 students completed the survey, collectively representing all programs in the college. Responses reflected widespread interest in expanding planetary health education, but topic priorities and optimal methods for implementation differed between programs. Although the survey process had limitations, it demonstrated the need for greater attention to planetary health across curricula and offered more efficient approaches implementing this essential content across programs.

A child with unilateral abducens nerve palsy and neurovascular compression in Chiari malformation type 1 resolved with posterior fossa decompression: illustrative case.

BACKGROUND: Unilateral cranial nerve (CN) VI, or abducens nerve, palsy is rare in children and has not been reported in association with Chiari malformation type 1 (CM1) in the absence of other classic CM1 symptoms. OBSERVATIONS: A 3-year-old male presented with acute incomitant esotropia consistent with a unilateral, left CN VI palsy and no additional neurological symptoms. Imaging demonstrated CM1 without hydrocephalus or papilledema, as well as an anterior inferior cerebellar artery (AICA) vessel loop in the immediate vicinity of the left abducens nerve. Given the high risk of a skull base approach for direct microvascular decompression of the abducens nerve and the absence of other classic Chiari symptoms, the patient was initially observed. However, as his palsy progressed, he underwent posterior fossa decompression with duraplasty (PFDD), with the aim of restoring global cerebrospinal fluid dynamics and decreasing possible AICA compression of the left abducens nerve. Postoperatively, his symptoms completely resolved. LESSONS: In this first reported case of CM1 presenting as a unilateral abducens palsy in a young child, possibly caused by neurovascular compression, the patient's symptoms resolved after indirect surgical decompression via PFDD.

Psychological Impact and Posttraumatic Stress Disorder Symptomatology After Ulnar Collateral Ligament Injuries in Baseball Players.

Background: Significant psychological impact and prevalence of posttraumatic stress disorder (PTSD) have been well documented in patients sustaining anterior cruciate ligament injury. Purpose: To examine PTSD symptomatology in baseball players after sustaining elbow ulnar collateral ligament (UCL) injury. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Male baseball players of various competition levels (high school through Minor League Baseball [MiLB]) who underwent surgery for a UCL injury between April 2019 and June 2022 participated in the study. Before surgery, patients completed the Impact of Event Scale-Revised (IES-R) to assess PTSD symptomatology. Subgroup analysis was conducted according to level of play and player position. Results: A total of 104 male baseball players with a mean age of 19.4 years (range, 15-29 years) were included in the study; 32 players (30.8%) were in high school, 65 (62.5%) were in college, and 7 (6.7%) were in MiLB. There were 64 (61.5%) pitchers, 18 (17.3%) position players, and 22 (21.2%) 2-way players (both pitching and playing on the field). A total of 30 (28.8%) patients scored high enough on the IES-R to support PTSD as a probable diagnosis, and another 22 patients (21.2%) scored high enough to support PTSD as a clinical concern. Nineteen patients (18.3%) had potentially severe PTSD. Only 4 players (3.8%) were completely asymptomatic. Subgroup analysis revealed college players as significantly more symptomatic than high school players (P = .02), and 2-way players were found to be significantly less susceptible to developing symptoms of PTSD compared with pitchers (P = .04). Conclusion: Nearly 30% of baseball players who sustained a UCL injury qualified for a probable diagnosis of PTSD based on the IES-R. Pitchers and college athletes were at increased risk for PTSD after UCL injury compared with 2-way players and high school athletes, respectively.

Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension is defined by headaches and a decline in visual acuity due to increased intracranial pressure. Treatment options historically included weight loss, acetazolamide, and/or cerebrospinal fluid diversion surgery. Recent understanding of the contributions of dural venous sinus hypertension and stenosis has led to venous sinus stenting as a treatment option.

Persistent headache without neurologic deficit from a spontaneous vertebral artery dissection.

INTRODUCTION: Non-traumatic headache is a common complaint seen in the emergency department (ED), accounting for 2.3% of ED visits per year in the United States (Munoz-Ceron et al., 2019). When approaching the workup and management of headache, an emergency medicine physician is tasked with generating a deadly differential by means of a thorough history and physical exam to determine the next best steps. CASE: A 21-year-old male presented to the emergency department with a debilitating new-onset headache, preceded by an isolated vertiginous event 3 days prior. He was found to have a normal neurologic examination. A non-contrast CT scan of the head revealed a large hypodensity within the left cerebellum with a subsequent MRA of the brain and neck notable for a left vertebral artery dissection, complicated by an ischemic cerebellar stroke. DISCUSSION: With an estimated incidence of 1-5 per 100,000, vertebral artery dissection is a rare cause of stroke within the general population and carries with it a high degree of morbidity and mortality (Rodallec et al., 2008). Vertebral artery dissection is a result of blood penetrating the intimal wall of the artery to form an intramural hematoma. Diagnosis can be difficult in cases presenting subacutely but a thorough history evaluating for red flags and using simple but highly sensitive exams such as the bedside HINTS exam can increase pretest probability of stroke. Clinical syndromes, red flags, and time from onset of symptoms should guide imaging modalities such as CT, CTA, MRI, and MRA in detection of small ischemic changes, intimal flaps, and luminal thromboses. CONCLUSION: Vertebral artery dissection should remain high on the differential for an emergency medicine physician when history is suggestive of a new onset headache, preceded by vertiginous symptoms. An absence of recent trauma and a normal neurologic examination does not eliminate the diagnosis.

Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Strain background of Candida albicans interacts with SIR2 to alter phenotypic switching.

The genetic background between strains of a single species and within a single strain lineage can significantly impact the expression of biological traits. This genetic variation may also reshape epigenetic mechanisms of cell identity and environmental responses that are controlled by interconnected transcriptional networks and chromatin-modifying enzymes. Histone deacetylases, including sirtuins, are critical regulators of chromatin state and have been directly implicated in governing the phenotypic transition between the 'sterile' white state and the mating-competent opaque state in Candida albicans, a common fungal commensal and pathogen of humans. Here, we found that a previously ambiguous role for the sirtuin SIR2 in C. albicans phenotypic switching is likely linked to the genetic background of mutant strains produced in the RM lineage of SC5314. SIR2 mutants in a specific lineage of BWP17 displayed increased frequencies of switching to the opaque state compared to the wild-type. Loss of SIR2 in other SC5314-derived backgrounds, including newly constructed BWP17 sir2Δ/Δ mutants, failed to recapitulate the increased white-opaque switching frequencies observed in the original BWP17 sir2Δ/Δ mutant background. Whole-genome sequencing revealed the presence of multiple imbalanced chromosomes and large loss of heterozygosity tracts that likely interact with SIR2 to increase phenotypic switching in this BWP17 sir2Δ/Δ mutant lineage. These genomic changes are not found in other SC5314-derived sir2Δ/Δ mutants that do not display increased opaque cell formation. Thus, complex karyotypes can emerge during strain construction that modify mutant phenotypes and highlight the importance of validating strain background when interpreting phenotypes.

Perception and Representation of LGBTQ+ Individuals in U.S. Neurosurgical Training.

OBJECTIVE: The aim of this study is to gauge the current social climate in neurosurgical residency training and attitudes regarding sexual orientation and gender identity. METHODS: We conducted a cross-sectional study through a 35-question questionnaire distributed to roughly 1700 residents at all U.S. neurosurgical residency programs. RESULTS: A total of 107 responses were obtained. Seventeen residents (16%) identified as being an LGBTQ+ individual. The majority (76%) of LGBTQ+ residents were concerned about how their sexual orientation would be perceived while applying to programs, and 47% endorsed purposefully concealing sexual orientation at work for fear of rejection or reprisal. More than half (56%) of those surveyed have witnessed homophobic/transphobic remarks by patients. While at work, 29% of LGBTQ+ individuals stated they are uncomfortable being open with their sexual orientation, and 3 LGBTQ+ individuals admitted being the target of direct homophobic/transphobic comments. CONCLUSIONS: This is the first study to our knowledge that has been conducted assessing the presence, perception, and treatment of LGBTQ+ trainees in neurosurgical residency. Our study outlines the challenges LGBTQ+ individuals face when applying to neurosurgical programs, which involves the perception of their sexual orientation, their witnessed instances of homophobic and transphobic comments by coworkers and patients, and their hesitation with discussing their social lives compared with their non-LGBTQ+ peers at work for fear of judgment or reprisal. Ongoing research is needed to address these issues to obtain workplace respect and fairness in this population and thus create an accepting atmosphere and achieve social justice in neurosurgery training.

Postoperative Length of Stay in Patients With Stress Hyperglycemia Compared to Patients With Diabetic Hyperglycemia: A Retrospective Cohort Study.

BACKGROUND: Postoperative hospital length of stay (LOS) is longer in patients with diabetes than in patients without diabetes. Stress hyperglycemia (SH) in patients without a history of diabetes has been associated with adverse postoperative outcomes. The effect of SH on postoperative LOS is uncertain. The aim of this study is to compare postoperative LOS in patients with SH to patients with diabetic hyperglycemia (DH) following noncardiac surgery. METHODS: We carried out a retrospective cohort study of inpatients with at least two glucose measurements ≥180 mg/dL. Two groups were compared. Patients with SH had no preoperative history of diabetes. Patients were considered to have DH if they had an established preoperative diagnosis of diabetes mellitus or a preoperative hemoglobin A1c (HbA1c) ≥6.5%. The primary outcome measure was hospital LOS. RESULTS: We included 270 patients with postoperative hyperglycemia-82 in the SH group and 188 in the DH group. In a linear regression analysis, hospital LOS was longer in the SH group than in the DH group (10.4 vs 7.3 days; P = .03). Within the SH group, we found no association between LOS and prompt treatment of hyperglycemia within 12 hours (P = .43), insulin dose per day (P = .89), or overall mean glucose (P = .13). CONCLUSIONS: Postoperative LOS was even longer in patients with SH than in patients with DH, representing a potential target for quality improvement efforts. We did not, however, find evidence that improved treatment of SH was associated with reduction in LOS.

Candida albicans' inorganic phosphate transport and evolutionary adaptation to phosphate scarcity.

Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. In this process, initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity were eventually lost as populations presumably gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while that of others like membrane stress responses diverged from these fitness phenotypes. C. albicans therefore has diverse options to reconfigure Pi management during prolonged scarcity. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth and virulence.

Understanding Factors Influencing Nursing Faculty Departure and Intentions.

BACKGROUND: There is a known shortage of nursing faculty in academia. Understanding factors influencing the shortage will help to develop strategies to reduce it. PURPOSE: The purpose was to identify the underlying factors influencing the decisions of current and former nursing faculty to leave or consider leaving their teaching roles. METHODS: A cross-sectional state-level survey was distributed to licensed registered nurses and advanced practice registered nurses. The survey covered demographics, employment status, compensation, tenure, mentorship experiences, and significant factors affecting their decision-making. RESULTS: Of 496 nursing faculty responses (221 current, 275 former), low compensation, unrealistic workload, retirement, lack of appreciation, and personal/family issues were noted as significant reasons for leaving or considering departure. CONCLUSIONS: The study gives voice to various factors influencing nursing faculty's intention to leave and emphasizes the need to address issues of compensation, workload, and mentorship to mitigate faculty shortages.

Targeting CCNE1 amplified ovarian and endometrial cancers by combined inhibition of PKMYT1 and ATR.

Ovarian cancers (OVCAs) and endometrial cancers (EMCAs) with CCNE1-amplification are often resistant to standard of care treatment and represent an unmet clinical need. Previously, synthetic-lethal screening identified loss of the CDK1 regulator, PKMYT1, as synthetically lethal with CCNE1-amplification. We hypothesized that CCNE1-amplification associated replication stress will be more effectively targeted by combining the PKMYT1 inhibitor, lunresertib (RP-6306), with the ATR inhibitor, camonsertib (RP-3500/RG6526). Low dose combination RP-6306 with RP-3500 synergistically increased cytotoxicity more in CCNE1 amplified compared to non-amplified cells. Combination treatment produced durable antitumor activity and increased survival in CCNE1 amplified patient-derived and cell line-derived xenografts. Mechanistically, low doses of RP-6306 with RP-3500 increase CDK1 activation more so than monotherapy, triggering rapid and robust induction of premature mitosis, DNA damage and apoptosis in a CCNE1-dependent manner. These findings suggest that targeting CDK1 activity by combining RP-6306 with RP-3500 is a novel therapeutic approach to treat CCNE1-amplifed OVCAs and EMCAs.

Micelle-Promoted Reductive Amination of DNA-Conjugated Amines for DNA-Encoded Library Synthesis.

DNA-encoded libraries (DELs) have become a leading technology for hit identification in drug discovery projects as large, diverse libraries can be generated. DELs are commonly synthesised via split-and-pool methodology; thus, chemical transformations utilised must be highly efficient, proceeding with high conversions. Reactions performed in DEL synthesis also require a broad substrate scope to produce diverse, drug-like libraries. Many pharmaceutical compounds incorporate multiple C-N bonds, over a quarter of which are synthesised via reductive aminations. However, few on-DNA reductive amination procedures have been developed. Herein is reported the application of the micelle-forming surfactant, TPGS-750-M, to the on-DNA reductive amination of DNA-conjugated amines, yielding highly efficient conversions with a broad range of aldehydes, including medicinally relevant heterocyclic and aliphatic substrates. The procedure is compatible with DNA amplification and sequencing, demonstrating its applicability to DEL synthesis.

Natural reversion promotes LPS elongation in an attenuated Coxiella burnetii strain.

Lipopolysaccharide (LPS) phase variation is a critical aspect of virulence in many Gram-negative bacteria. It is of particular importance to Coxiella burnetii, the biothreat pathogen that causes Q fever, as in vitro propagation of this organism leads to LPS truncation, which is associated with an attenuated and exempted from select agent status (Nine Mile II, NMII). Here, we demonstrate that NMII was recovered from the spleens of infected guinea pigs. Moreover, these strains exhibit a previously unrecognized form of elongated LPS and display increased virulence in comparison with the initial NMII strain. The reversion of a 3-bp mutation in the gene cbu0533 directly leads to LPS elongation. To address potential safety concerns, we introduce a modified NMII strain unable to produce elongated LPS.

Self-Sampling for Human Papillomavirus Testing: Acceptability in a U.S. Safety Net Health System.

INTRODUCTION: Self-sampling for human papillomavirus testing is increasingly recognized as a strategy to expand cervical cancer screening access and utilization. Acceptability is a key determinant of uptake. This study assesses the acceptability of and experiences with mailed self-sampling kits for human papillomavirus testing among underscreened patients in a safety net health system. METHODS: A nested telephone survey was administered between 2021 and 2023 to a sample (n=272) of the 2,268 participants enrolled in the Prospective Evaluation of Self-Testing to Increase Screening trial. Trial participants include patients of a safety net health system aged 30-65 years who were not up to date on screening. Participants were asked about barriers to provider-performed screening. Kit users and nonusers were asked about their experiences. RESULTS: Prevalent barriers to provider-performed screening included perceived discomfort of pelvic examination (69.4%), being uncomfortable with male providers (65.4%), and embarrassment (57.0%). Among participants who reported using the mailed kit (n=164), most reported good experiences (84.8%). Most reported self-sampling as more/equally convenient (89.0%), less/equally embarrassing (99.4%), and less/equally stressful (95.7%) than provider-performed screening. Among kit nonusers (n=43), reasons for not using the kit included forgetting about it (76.7%), preferring provider-performed screening (76.7%), and fearing cancer (67.4%). CONCLUSIONS: Prospective Evaluation of Self-Testing to Increase Screening trial participants generally had a positive experience with self-sampling for human papillomavirus testing. Increased comfort and reduced embarrassment/anxiety with self-sampling are relevant attributes because these were the most prevalent reported barriers to provider-performed screening. High acceptability suggests potentially high uptake when self-sampling for human papillomavirus testing receives regulatory approval and is available in safety net health systems.

Deletion of the Candida albicans TLO gene family using CRISPR-Cas9 mutagenesis allows characterisation of functional differences in α-, ß- and γ- TLO gene function.

The Candida albicans genome contains between ten and fifteen distinct TLO genes that all encode a Med2 subunit of Mediator. In order to investigate the biological role of Med2/Tlo in C. albicans we deleted all fourteen TLO genes using CRISPR-Cas9 mutagenesis. ChIP-seq analysis showed that RNAP II localized to 55% fewer genes in the tloΔ mutant strain compared to the parent, while RNA-seq analysis showed that the tloΔ mutant exhibited differential expression of genes required for carbohydrate metabolism, stress responses, white-opaque switching and filamentous growth. Consequently, the tloΔ mutant grows poorly in glucose- and galactose-containing media, is unable to grow as true hyphae, is more sensitive to oxidative stress and is less virulent in the wax worm infection model. Reintegration of genes representative of the α-, ß- and γ-TLO clades resulted in the complementation of the mutant phenotypes, but to different degrees. TLOα1 could restore phenotypes and gene expression patterns similar to wild-type and was the strongest activator of glycolytic and Tye7-regulated gene expression. In contrast, the two γ-TLO genes examined (i.e., TLOγ5 and TLOγ11) had a far lower impact on complementing phenotypic and transcriptomic changes. Uniquely, expression of TLOß2 in the tloΔ mutant stimulated filamentous growth in YEPD medium and this phenotype was enhanced when Tloß2 expression was increased to levels far in excess of Med3. In contrast, expression of reintegrated TLO genes in a tloΔ/med3Δ double mutant background failed to restore any of the phenotypes tested, suggesting that complementation of these Tlo-regulated processes requires a functional Mediator tail module. Together, these data confirm the importance of Med2/Tlo in a wide range of C. albicans cellular activities and demonstrate functional diversity within the gene family which may contribute to the success of this yeast as a coloniser and pathogen of humans.