Assessment of respiratory rate monitoring in the emergency department.

Objectives: This study aimed to compare the different respiratory rate (RR) monitoring methods used in the emergency department (ED): manual documentation, telemetry, and capnography. Methods: This is a retrospective study using recorded patient monitoring data. The study population includes patients who presented to a tertiary care ED between January 2020 and December 2022. Inclusion and exclusion criteria were patients with simultaneous recorded RR data from all three methods and less than 10 min of recording, respectively. Linear regression and Bland-Altman analysis were performed between different methods. Results: A total of 351 patient encounters met study criteria. Linear regression yielded an R-value of 0.06 (95% confidence interval [CI] 0.00-0.12) between manual documentation and telemetry, 0.07 (95% CI 0.01-0.13) between manual documentation and capnography, and 0.82 (95% CI 0.79-0.85) between telemetry and capnography. The Bland-Altman analysis yielded a bias of -0.8 (95% limits of agreement [LOA] -12.2 to 10.6) between manual documentation and telemetry, bias of -0.6 (95% LOA -13.5 to 12.3) between manual documentation and capnography, and bias of 0.2 (95% LOA -6.2 to 6.6) between telemetry and capnography. Conclusion: There is a poor correlation between manual documentation and both automated methods, while there is relatively good agreement between the automated methods. This finding highlights the need to further investigate the methodology used by the ED staff in monitoring and documenting RR and ways to improve its reliability given that many important clinical decisions are made based on these assessments.

The gap year for college students interested in medicine: Can they contribute to your mission?

Gap years taken between undergraduate completion and entrance into medical school have become increasingly popular. We examine the role of gap years among college graduates interested in medicine and how they might contribute to academic research productivity within clinical environments. Recently, academic faculty have struggled to balance increasing clinical responsibilities with their scholarly endeavors. Academic medical departments may have incentives to hire pre-medical students to help ease the research burden on faculty. Properly motivated pre-medical students may view research positions in academic medical departments as ideal opportunities to learn in areas that will broaden their scientific knowledge and help prepare them for medical school, while greatly enhancing their medical school applications through distinguishing themselves as co-authors published in medical journals. Our experience, with two co-authors working as research associates while preparing for their medical school applications and careers, suggests that pre-medical students can strengthen their medical school applications during their gap year(s) while proving instrumental in enhancing research output thus alleviating the workload of clinical faculty.

Characterizing cell type specific transcriptional differences between the living and postmortem human brain.

Single-nucleus RNA sequencing (snRNA-seq) is often used to define gene expression patterns characteristic of brain cell types as well as to identify cell type specific gene expression signatures of neurological and mental illnesses in postmortem human brains. As methods to obtain brain tissue from living individuals emerge, it is essential to characterize gene expression differences associated with tissue originating from either living or postmortem subjects using snRNA-seq, and to assess whether and how such differences may impact snRNA-seq studies of brain tissue. To address this, human prefrontal cortex single nuclei gene expression was generated and compared between 31 samples from living individuals and 21 postmortem samples. The same cell types were consistently identified in living and postmortem nuclei, though for each cell type, a large proportion of genes were differentially expressed between samples from postmortem and living individuals. Notably, estimation of cell type proportions by cell type deconvolution of pseudo-bulk data was found to be more accurate in samples from living individuals. To allow for future integration of living and postmortem brain gene expression, a model was developed that quantifies from gene expression data the probability a human brain tissue sample was obtained postmortem. These probabilities are established as a means to statistically account for the gene expression differences between samples from living and postmortem individuals. Together, the results presented here provide a deep characterization of both differences between snRNA-seq derived from samples from living and postmortem individuals, as well as qualify and account for their effect on common analyses performed on this type of data.

Self-Assembled Block Copolymers as a Facile Pathway to Create Functional Nanobiosensor and Nanobiomaterial Surfaces.

Block copolymer (BCP) surfaces permit an exquisite level of nanoscale control in biomolecular assemblies solely based on self-assembly. Owing to this, BCP-based biomolecular assembly represents a much-needed, new paradigm for creating nanobiosensors and nanobiomaterials without the need for costly and time-consuming fabrication steps. Research endeavors in the BCP nanobiotechnology field have led to stimulating results that can promote our current understanding of biomolecular interactions at a solid interface to the never-explored size regimes comparable to individual biomolecules. Encouraging research outcomes have also been reported for the stability and activity of biomolecules bound on BCP thin film surfaces. A wide range of single and multicomponent biomolecules and BCP systems has been assessed to substantiate the potential utility in practical applications as next-generation nanobiosensors, nanobiodevices, and biomaterials. To this end, this Review highlights pioneering research efforts made in the BCP nanobiotechnology area. The discussions will be focused on those works particularly pertaining to nanoscale surface assembly of functional biomolecules, biomolecular interaction properties unique to nanoscale polymer interfaces, functionality of nanoscale surface-bound biomolecules, and specific examples in biosensing. Systems involving the incorporation of biomolecules as one of the blocks in BCPs, i.e., DNA-BCP hybrids, protein-BCP conjugates, and isolated BCP micelles of bioligand carriers used in drug delivery, are outside of the scope of this Review. Looking ahead, there awaits plenty of exciting research opportunities to advance the research field of BCP nanobiotechnology by capitalizing on the fundamental groundwork laid so far for the biomolecular interactions on BCP surfaces. In order to better guide the path forward, key fundamental questions yet to be addressed by the field are identified. In addition, future research directions of BCP nanobiotechnology are contemplated in the concluding section of this Review.

Memory-like differentiation enhances NK cell responses against colorectal cancer.

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB.

Psychotropic Medication Usage in Pediatric CKD: Reporting from the Chronic Kidney Disease in Children Cohort.

BACKGROUND: Mental health disorders (MHD) within the pediatric chronic kidney disease (CKD) population are prevalent. The frequency is unknown with which psychotropic medications that commonly treat these conditions are used in this population. METHODS: Data from the Chronic Kidney Disease in Children (CKiD) cohort study were utilized to describe the use of psychotropic medications and patient-related characteristics of use. Medications were classified into 3 groups: antidepressants, CNS stimulants, and antipsychotic/mood stabilizing medications. Participant age, sex, CKD severity, and duration of medication use were ascertained. Medication use was evaluated in parallel with CKD disease type, presence of urological comorbidity, and hypertension. Chi-square tests compared subgroup medication use. RESULTS: Among 1074 CKiD participants (median baseline age 9.8 years), 6% (n=60) of participants used psychotropic medications at study entry with 11% reporting incident use of any medication category (n=120). CNS stimulants were most common at baseline. Antidepressants were more frequent among incident users at 7%. Use of two or more medications was rare (3%). Median eGFR at medication initiation was 45 ml/min|1.73m2. CNS stimulants were reported at a higher rate in males compared to females (p<0.05). CONCLUSIONS: 11% of CKiD patients report incident use of any psychotropic medication, with 7% reporting incident use of antidepressants. Future work is warranted to better ascertain the frequency, safety, and efficacy of psychotropic medication usage in relationship to formal MHD diagnoses in the pediatric CKD population.

Sonographic Appearance of the Ischiocondylar Origin of the Adductor Magnus.

The adductor magnus ischiocondylar origin (AM-IO) tendon has often been described as a third proximal hamstring tendon due to its common origin on the ischial tuberosity as well as similar function. Prior studies have described the magnetic resonance imaging characteristics of the AM-IO; however, its appearance on ultrasound has not been well-detailed. The purpose of our study is to describe the sonographic appearance of the AM-IO and provide a structured scanning protocol for complete evaluation of the tendon.

An incidental large adrenal schwannoma: A case report.

Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the head, neck, and limbs. However, schwannomas can also rarely occur rarely in the adrenal gland within the retroperitoneal cavity. In the adrenal gland, these tumors arise from the medulla and are difficult to diagnose, often misdiagnosed as other benign or malignant entities. In this article, we report the case of a 43-year-old female with a large left adrenal mass revealed by biopsy to be a schwannoma. We focus on the use of radiological imaging modalities and immunohistochemical analysis to optimize diagnosis and treatment intervention of this rare tumor.

CellMag-CARWash: A High Throughput Droplet Microfluidic Device for Live Cell Isolation and Single Cell Applications.

The recent push toward understanding an individual cell's behavior and identifying cellular heterogeneity has created an unmet need for technologies that can probe live cells at the single-cell level. Cells within a population are known to exhibit heterogeneous responses to environmental cues. These differences can lead to varied cellular states, behavior, and responses to therapeutics. Techniques are needed that are not only capable of processing and analyzing cellular populations at the single cell level, but also have the ability to isolate specific cell populations from a complex sample at high throughputs. The new CellMag-Coalesce-Attract-Resegment Wash (CellMag-CARWash) system combines positive magnetic selection with droplet microfluidic devices to isolate cells of interest from a mixture with >93% purity and incorporate treatments within individual droplets to observe single cell biological responses. This workflow is shown to be capable of probing the single cell extracellular vesicle (EV) secretion of MCF7 GFP cells. This article reports the first measurement of ß-Estradiol's effect on EV secretion from MCF7 cells at the single cell level. Single cell processing revealed that MCF7 GFP cells possess a heterogeneous response to ß-Estradiol stimulation with a 1.8-fold increase relative to the control.

Divergent landscapes of A-to-I editing in postmortem and living human brain.

Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

Structural basis for Rab6 activation by the Ric1-Rgp1 complex.

Rab GTPases act as molecular switches to regulate organelle homeostasis and membrane trafficking. Rab6 plays a central role in regulating cargo flux through the Golgi and is activated via nucleotide exchange by the Ric1-Rgp1 protein complex. Ric1-Rgp1 is conserved throughout eukaryotes but the structural and mechanistic basis for its function has not been established. Here we report the cryoEM structure of a Ric1-Rgp1-Rab6 complex representing a key intermediate of the nucleotide exchange reaction. This structure reveals the overall architecture of the complex and enabled us to identify interactions critical for proper recognition and activation of Rab6 on the Golgi membrane surface. Ric1-Rgp1 interacts with the nucleotide-binding domain of Rab6 using an uncharacterized helical domain, which we establish as a novel RabGEF domain by identifying residues required for Rab6 nucleotide exchange. Unexpectedly, the complex uses an arrestin fold to interact with the Rab6 hypervariable domain, indicating that interactions with the unstructured C-terminal regions of Rab GTPases may be a common specificity mechanism used by their activators. Collectively, our findings provide a detailed mechanistic understanding of regulated Rab6 activation at the Golgi.

Navigating the layers of concern for safe dry needling of the rectus abdominis: a cadaveric study.

OBJECTIVES: To assess needle placement accuracy in the rectus abdominis (RA) muscle during dry needling (DN) without entering the peritoneum. METHODS: Two physical therapists performed DN on a cadaver, making 10 attempts each to needle the RA without entering the peritoneum. Techniques followed two common DN approaches. Ultrasound verified needle depth and safety. RESULTS: Seventy percent of attempts were recorded as safe needle placement, while 30% were unsafe. Accurate RA needle placement without peritoneal entry occurred in 55% of attempts. DISCUSSION/CONCLUSION: Inadvertent peritoneal needle placement during RA DN poses risks regardless of experience. Ultrasound guidance may enhance safety and precision in clinical practice.

Investigating Microbial Biosignatures in Aeolian Environments Using Micro-X-Ray: Simulation of PIXL Instrument Analyses at Jezero Crater Onboard the Perseverance Mars 2020 Rover.

Assessing the past habitability of Mars and searching for evidence of ancient life at Jezero crater via the Perseverance rover are the key objectives of NASA's Mars 2020 mission. Onboard the rover, PIXL (Planetary Instrument for X-ray Lithochemistry) is one of the best suited instruments to search for microbial biosignatures due to its ability to characterize chemical composition of fine scale textures in geological targets using a nondestructive technique. PIXL is also the first micro-X-ray fluorescence (XRF) spectrometer onboard a Mars rover. Here, we present guidelines for identifying and investigating a microbial biosignature in an aeolian environment using PIXL-analogous micro-XRF (µXRF) analyses. We collected samples from a modern wet aeolian environment at Padre Island, Texas, that contain buried microbial mats, and we analyzed them using µXRF techniques analogous to how PIXL is being operated on Mars. We show via µXRF technique and microscope images the geochemical and textural variations from the surface to ∼40 cm depth. Microbial mats are associated with heavy-mineral lags and show specific textural and geochemical characteristics that make them a distinct biosignature for this environment. Upon burial, they acquire a diffuse texture due to the expansion and contraction of gas-filled voids, and they present a geochemical signature rich in iron and titanium, which is due to the trapping of heavy minerals. We show that these intrinsic characteristics can be detected via µXRF analyses, and that they are distinct from buried abiotic facies such as cross-stratification and adhesion ripple laminations. We also designed and conducted an interactive survey using the Padre Island µXRF data to explore how different users chose to investigate a biosignature-bearing dataset via PIXL-like sampling strategies. We show that investigating biosignatures via PIXL-like analyses is heavily influenced by technical constraints (e.g., the XRF measurement characteristics) and by the variety of approaches chosen by different scientists. Lessons learned for accurately identifying and characterizing this biosignature in the context of rover-mission constraints include defining relative priorities among measurements, favoring a multidisciplinary approach to the decision-making process of XRF measurements selection, and considering abiotic results to support or discard a biosignature interpretation. Our results provide guidelines for PIXL analyses of potential biosignature on Mars.

Electrospun composite-coated endotracheal tubes with controlled siRNA and drug delivery to lubricate and minimize upper airway injury.

Endotracheal Tubes (ETTs) maintain and secure a patent airway; however, prolonged intubation often results in unintended injury to the mucosal epithelium and inflammatory sequelae which complicate recovery. ETT design and materials used have yet to adapt to address intubation associated complications. In this study, a composite coating of electrospun polycaprolactone (PCL) fibers embedded in a four-arm polyethylene glycol acrylate matrix (4APEGA) is developed to transform the ETT from a mechanical device to a dual-purpose device capable of delivering multiple therapeutics while preserving coating integrity. Further, the composite coating system (PCL-4APEGA) is capable of sustained delivery of dexamethasone from the PCL phase and small interfering RNA (siRNA) containing polyplexes from the 4APEGA phase. The siRNA is released rapidly and targets smad3 for immediate reduction in pro-fibrotic transforming growth factor-beta 1 (TGFϐ1) signaling in the upper airway mucosa as well as suppressing long-term sequelae in inflammation from prolonged intubation. A bioreactor was used to study mucosal adhesion to the composite PCL-4APEGA coated ETTs and investigate continued mucus secretory function in ex vivo epithelial samples. The addition of the 4APEGA coating and siRNA delivery to the dexamethasone delivery was then evaluated in a swine model of intubation injury and observed to restore mechanical function of the vocal folds and maintain epithelial thickness when observed over 14 days of intubation. This study demonstrated that increase in surface lubrication paired with surface stiffness reduction significantly decreased fibrotic behavior while reducing epithelial adhesion and abrasion.

A warm Neptune's methane reveals core mass and vigorous atmospheric mixing.

Observations of transiting gas giant exoplanets have revealed a pervasive depletion of methane1,2,3,4, which has only recently been identified atmospherically5,6. The depletion is thought to be maintained by disequilibrium processes such as photochemistry or mixing from a hotter interior7,8,9. However, the interiors are largely unconstrained along with the vertical mixing strength and only upper limits on the CH4 depletion have been available. The warm Neptune WASP-107 b stands out among exoplanets with an unusually low density, reported low core mass10, and temperatures amenable to CH4 though previous observations have yet to find the molecule2,4. Here we present a JWST NIRSpec transmission spectrum of WASP-107 b which shows features from both SO2 and CH4 along with H2O, CO2, and CO. We detect methane with 4.2σ significance at an abundance of 1.0±0.5 ppm, which is depleted by 3 orders of magnitude relative to equilibrium expectations. Our results are highly constraining for the atmosphere and interior, which indicate the envelope has a super-solar metallicity of 43±8× solar, a hot interior with an intrinsic temperature of Tint=460±40 K, and vigorous vertical mixing which depletes CH4 with a diffusion coefficient of Kzz = 1011.6±0.1 cm2/s. Photochemistry has a negligible effect on the CH4 abundance, but is needed to account for the SO2. We infer a core mass of 11.5 - 3.6 + 3.0 M⊕, which is much higher than previous upper limits10, releasing a tension with core-accretion models11.

Effects of Alcohol Use and Minority Stress on Intimate Partner Violence Perpetration among Transgender and Gender Diverse People.

OBJECTIVE: Intimate partner violence (IPV) is highly prevalent among transgender and gender diverse (TGD) adults. Integrated theories of minority stress and alcohol-related IPV suggest minority stress risk and protective factors should interact with alcohol use to predict IPV, although this has never been examined in TGD adults. Thus, we examined the synergistic influence of alcohol use, minority stress, and TGD community connectedness on IPV perpetration among TGD adults. METHOD: A sample of 137 TGD adults completed a cross-sectional survey assessing minority stressors (i.e., internalized transnegativity, identity outness), TGD community connectedness, alcohol use/problems, and IPV perpetration (i.e., psychological, physical, and gender minority identity-specific abuse). We regressed each form of IPV perpetration on alcohol use/problems and tested the moderating effect of internalized transnegativity, identity outness, and community connectedness on the association between alcohol use/problems and IPV perpetration. RESULTS: The association between alcohol use/problems and all forms of IPV perpetration were moderated by internalized transnegativity and identity outness, but not TGD community connectedness. Alcohol use/problems related to each form of IPV perpetration at low and medium, but not high levels, of identity outness and internalized transnegativity. CONCLUSIONS: Alcohol use/problems is an important risk factor for IPV perpetration among TGD adults and this association may be exacerbated by less identity outness. Further, internalized transnegativity might not influence IPV risk at high levels of alcohol use. TGD-affirming IPV prevention programs might focus on reducing alcohol use and related problems while providing a safe and accessible space for TGD individuals at various levels of identity outness.

Anterior-posterior Wnt signaling network conservation between indirect developing sea urchin and hemichordate embryos.

How animal body plans evolved and diversified is a major question in evolutionary developmental biology. To address this question, it is important to characterize the exact molecular mechanisms that establish the major embryonic axes which give rise to the adult animal body plan. The anterior-posterior (AP) axis is the first axis to be established in most animal embryos, and in echinoderm sea urchin embryos its formation is governed by an integrated network of three different Wnt signaling pathways: Wnt/ß-catenin, Wnt/JNK, and Wnt/PKC pathway. The extent to which this embryonic patterning mechanism is conserved among deuterostomes, or more broadly in metazoans, is an important open question whose answers could lead to a deeper appreciation of the evolution of the AP axis. Because Ambulacrarians (echinoderms and hemichordates) reside in a key phylogenetic position as the sister group to chordates, studies in these animals can help inform on how chordate body plans may have evolved. Here, we assayed the spatiotemporal gene expression of a subset of sea urchin AP Wnt patterning gene orthologs in the hemichordate, Schizocardium californicum. Our results show that positioning of the anterior neuroectoderm (ANE) to a territory around the anterior pole during early AP formation is spatially and temporally similar between indirect developing hemichordates and sea urchins. Furthermore, we show that the expression of wnt8 and frizzled5/8, two known drivers of ANE patterning in sea urchins, is similar in hemichordate embryos. Lastly, our results highlight divergence in embryonic expression of several early expressed Wnt genes (wnt1, wnt2 and wnt4). These results suggest that expression of the sea urchin AP Wnt signaling network is largely conserved in indirect developing hemichordates setting the foundation for future functional studies in S. californicum.

TNF signaling mediates cellular immune function and promotes malaria parasite killing in the mosquito Anopheles gambiae.

Tumor Necrosis Factor-α (TNF-α) is a proinflammatory cytokine and a master regulator of immune cell function in vertebrates. While previous studies have implicated TNF signaling in invertebrate immunity, the roles of TNF in mosquito innate immunity and vector competence have yet to be explored. Herein, we confirm the identification of a conserved TNF-α pathway in Anopheles gambiae consisting of the TNF-α ligand, Eiger, and its cognate receptors Wengen and Grindelwald. Through gene expression analysis, RNAi, and in vivo injection of recombinant TNF-α, we provide direct evidence for the requirement of TNF signaling in regulating mosquito immune cell function by promoting granulocyte midgut attachment, increased granulocyte abundance, and oenocytoid rupture. Moreover, our data demonstrate that TNF signaling is an integral component of anti-Plasmodium immunity that limits malaria parasite survival. Together, our data support the existence of a highly conserved TNF signaling pathway in mosquitoes that mediates cellular immunity and influences Plasmodium infection outcomes, offering potential new approaches to interfere with malaria transmission by targeting the mosquito host.

Adverse childhood experiences, gender, and suicidality among Florida high school students: Examining intervening mechanisms.

BACKGROUND: Adverse childhood experiences (ACEs) represent a key risk factor for suicidal thoughts and behaviors among adolescents. However, the intervening mechanisms linking ACEs and suicidality, and whether such processes vary by gender, remain underexplored. OBJECTIVE: The present study examines whether the relationships between ACEs and the likelihood of experiencing suicidal thoughts and attempting suicide are indirect through depressive symptoms and low self-control. This study also investigates whether these direct and indirect paths might be moderated by gender. PARTICIPANTS AND SETTING: The analyses make use of data on a statewide representative sample of students enrolled in public high schools in Florida (N = 23,078) from the 2022 Florida Youth Substance Abuse Survey (FYSAS). METHODS: Generalized structural equation modeling (GSEM) was used to estimate the direct and indirect effects of ACEs on the likelihood of suicidal thoughts and attempting suicide. The indirect effects were assessed using bootstrapping, and between-gender differences in the coefficients were tested. RESULTS: ACEs has direct associations with depressive symptoms, low self-control, and both suicidality outcomes. The effects of ACEs on suicidal thoughts are indirect through both depressive symptoms and low self-control, and the effects of ACEs on suicide attempts are indirect through depressive symptoms. Limited gender differences in these pathways emerge. CONCLUSIONS: For male and female youth, ACEs are associated with heightened depression symptoms and reduced self-control, and both of these factors partially explain the previously established relationship between ACEs and suicidality.

Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma.

Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.