The Democratization of Hematology-Oncology Medical Education during the COVID-19 Pandemic.

Like many other aspects of hematology-oncology training, medical education experienced rapid changes throughout the COVID-19 pandemic that continue until today. We discuss some of the most transformative areas within medical education, including, but not limited to, educational philosophy; use of virtual resources; inter-institutional connections, shifts in clinical training; changes in recruitment practice; and attention to equity and diversity. Moreover, we add our own experiences to complement the limited literature addressing these topics. We conclude by highlighting some of the benefits of this unprecedented transformation in democratizing medical education that we hope endure beyond the pandemic.

Digital marketing of commercial breastmilk substitutes and baby foods: strategies, and recommendations for its regulation in Mexico.

BACKGROUND: Parents are exposed to breastmilk substitutes and baby foods marketing on the internet and social media, which hinders adequate breastfeeding and complementary feeding. This study identifies digital marketing strategies for breastmilk substitutes, specifically commercial milk formula and baby foods used by the industry to influence infant and young children's feeding practices in Mexico and proposes regulatory recommendations that can be useful for similar countries. METHODS: Qualitative study based on the CLICK monitoring framework developed by the World Health Organization, adapted for digital marketing of commercial milk formula and baby foods. Semi-structured interviews (n = 53) with key actors were conducted between November 2020 and March 2021, and used grounded theory for the analysis and interpretation with the MAXQDA 20 software. RESULTS: Commercial milk formula and baby food companies use digital media to contact and persuade parents to use their products by sending electronic newsletters with advertising. Companies hire influencers to market their products because there is no regulation prohibiting the advertisement of breastmilk substitutes on social media, and promote formula among health professionals inviting them to participate in sponsored webinars on infant nutrition, ignoring conflict of interest and the International Code of Marketing of Breastmilk Substitutes. Parents trust formula and baby food advertisements, which use emotional messages and health and nutrition claims to encourage their consumption. Health professionals consider that claims contribute to the indiscriminate use of formula, and some actors propose the use of plain packaging for these products. CONCLUSIONS: Breastmilk substitutes companies promote their products in digital media using unethical strategies that fail to comply with the International Code of Marketing of Breastmilk Substitutes. They generate strong conflicts of interest with health professionals, taking advantage of legal framework gaps and the lack of monitoring and effective sanctions for non-compliers. Updating the legal framework and monitoring compliance, including digital media, is urgently needed to protect children's right to breastfeeding, healthy nutrition and life, and the rights of women to health and informed decision-making.

[E-VAC therapy as treatment of complications in gastrointestinal surgery in a gastroenterology reference center in Colombia: Case series]. / Terapia E-VAC como tratamiento de complicaciones en cirugía gastrointestinal en centro de referencia de gastroenterología en Colombia: Serie de casos.

Gastrointestinal postoperative anastomotic leaks and fistulas occur frequently and many are managed surgically; however, endoscopic interventions have shown to improve healing outcomes and length of hospital stay. The experience of vacuum-assisted closure therapy (E-VAC) is described, in complications such as fistulas and postoperative anastomotic leaks, in a gastrointestinal reference center in Colombia. A case series study was carried out in patients with anastomotic leaks and fistulas at different levels of the digestive tract, treated by E-VAC, by the Gastroenterology Service in Colombia, during a period from February 2019 to November 2021. Sociodemographic, clinical and surgical variables were described. 6 cases are described, 4 from lower digestive tract and 2 from upper digestive tract. 83% were men; the mean age was 51.8 years (+/-17.5). The indication for E-VAC was colorectal anastomotic fistula in 66%; the most frequent anatomical location was near the anal region (66%), less frequently at the level of the cardia (16%) and esophagus (16%). The size of the defect was described between 20 and 80% in patients undergoing E-VAC therapy, with an average hospitalization length of stay of 22.5 days, with an average number of exchanges of seven per patient. Anastomotic leaks and fistulas are potentially fatal complications in gastrointestinal surgery. E-VAC therapy has shown to be effective and safe, promoting defect closure and drainage of collections present, also decreasing the length of hospital stay.

Minocycline prevents chronic restraint stress-induced vulnerability to developing cocaine self-administration and associated glutamatergic mechanisms: a potential role of microglia.

Stressful experience-induced cocaine-related behaviors are associated with a significant impairment of glutamatergic mechanisms in the Nucleus Accumbens core (NAcore). The hallmarks of disrupted glutamate homeostasis following restraint stress are the enduring imbalance of glutamate efflux after a cocaine stimulus and increased basal concentrations of extracellular glutamate attributed to GLT-1 downregulation in the NAcore. Glutamate transmission is tightly linked to microglia functioning. However, the role of microglia in the biological basis of stress-induced addictive behaviors is still unknown. By using minocycline, a potent inhibitor of microglia activation with anti-inflammatory properties, we determined whether microglia could aid chronic restraint stress (CRS)-induced glutamate homeostasis disruption in the NAcore, underpinning stress-induced cocaine self-administration. In this study, adult male rats were restrained for 2 h/day for seven days (day 1-7). From day 16 until completing the experimental protocol, animals received a vehicle or minocycline treatment (30 mg/Kg/12h i.p.). On day 21, animals were assigned to microscopic, biochemical, neurochemical or behavioral studies. We confirm that the CRS-induced facilitation of cocaine self-administration is associated with enduring GLT-1 downregulation, an increase of basal extracellular glutamate and postsynaptic structural plasticity in the NAcore. These alterations were strongly related to the CRS-induced reactive microglia and increased TNF-α mRNA and protein expression, since by administering minocycline, the impaired glutamate homeostasis and the facilitation of cocaine self-administration were prevented. Our findings are the first to demonstrate that minocycline suppresses the CRS-induced facilitation of cocaine self-administration and glutamate homeostasis disruption in the NAcore. A role of microglia is proposed for the development of glutamatergic mechanisms underpinning stress-induced vulnerability to cocaine addiction.

Chronic wound healing by controlled release of chitosan hydrogels loaded with silver nanoparticles and calendula extract.

As the skin is the main protective organ of the body, it is exposed to wounds or injuries which carry out a healing process during a period of approximately 15 days depending on the severity of the injury. In the present research, the development of chitosan-based hydrogels loaded with silver nanoparticles and calendula extract (Ch-AgNPs-Ce) was proposed. This can be used to fulfill the hemostatic, anti-infective, antibacterial, healing and anti-inflammatory functions through controlled release of the nanoparticles and calendula extract in substitution of commonly used drugs. The physical properties of the silver nanoparticles were analyzed by UV-visible spectroscopy, scanning and transmission electron microscopy, showing a size between 50 and 100 nm. The antibacterial properties were evaluated by the agar well diffusion method. Antimicrobial testing of the hydrogels showed that the inclusion of silver nanoparticles provides concentration-dependent antibacterial behavior against E. coli and S. aureus. The healing properties of the system were tested in two diabetic patients to whom said hydrogels were placed, obtaining a positive curative result after a few weeks. Therefore, it can be concluded that Ch-AgNPs-Ce hydrogels can achieve healing in chronic or exposed wounds after a period of time which can be used in alternative treatments in patients with poor healing capacity.

Endogenous enkephalin is necessary for cocaine-induced alteration in glutamate transmission within the nucleus accumbens.

Altered glutamate transmission within the nucleus accumbens (NAc) has been proposed as a central mechanism underlying behavioural sensitisation associated with repeated cocaine exposure. In addition to glutamate, enkephalin, an endogenous opioid peptide derived from proenkephalin, is necessary for the neuroadaptations associated with chronic cocaine. However, the influence of enkephalin on long-term changes in glutamate transmission within the NAc associated with cocaine-induced sensitisation has not been described. This study used knockout proenkephalin mice (KO) to study the influence of endogenous enkephalin on the adaptations in glutamate neurotransmission associated with repeated cocaine treatment. Wild-type (WT) and KO mice were treated with daily cocaine injections for 9 days to induce sensitisation. On days 15 and 21, the animals received a cocaine challenge and locomotor sensitisation was evaluated, and microdialysis was performed to determine accumbens glutamate content on day 21. No expression of behavioural sensitisation to cocaine was evidenced in the KO mice. Consistently, these showed no changes in glutamate transmission in the NAc associated with repeated cocaine. This study reveals the central role of enkephalin in regulating the glutamate mechanisms associated with cocaine sensitisation.

The Matilda Effect: Underrecognition of Women in Hematology and Oncology Awards.

BACKGROUND: The proportion of women in the field of hematology and oncology (H&O) has increased over recent decades, but the representation of women in leadership positions remains poor. In an effort to close the gender gap in academia, it is important to report on such inequities in hopes to close these gaps and improve career development. MATERIALS AND METHODS: We conducted a retrospective, observational study of published award recipients from 1994 to 2019 from the seven major H&O societies in the world. Gender was determined based on publicly available data. The χ2 and Cochran-Armitage tests were used for data analysis. RESULTS: Of the 1,642 awardees over the past 26 years, 915 met inclusion criteria. Award recipients were overwhelmingly men (77.9%) and non-Hispanic White (84.7%). Women awardees received 30.3% of the humanistic and education-related awards, whereas only receiving 16.0% of basic science awards (p < .01). Women represent 35.6% of all hematologists and oncologists but only received 24.0% of awards given to these physicians (p = .004). Black, Hispanic, and Asian awardees represented 3.7%, 3.3%, and 6.8% of the total awardees, respectively. CONCLUSION: From 1994 to 2019, women were less likely to receive recognition awards from the seven major H&O societies studied compared with men. We also observed a considerably low proportion of minority awardees across all oncology subspecialties. Further studies examining how selection criteria favor either gender would be warranted in order to achieve equal representation in academic awards. IMPLICATIONS FOR PRACTICE: In this study, women and minority groups were found to be underrepresented amongst award recipients. Significant disparities were seen in disciplines that have been historically male predominant, such as basic sciences. As awards on an international level enhance academic resumes and assist with career advancement, it is important that awards are being given in an equitable manner. First steps to promote diversity and inclusion in academic medicine is reporting of gender and racial disparities in various areas of academia.

Development of fluorinated naphthofluoresceins for Cerenkov imaging.

In this paper, we report the synthesis and characterization of fluorinated derivatives of naphthofluorescein (NF), a fluorescent pH-sensitive probe that can be used for functional Cerenkov imaging. The compounds were prepared using electrophilic fluorination with dilute fluorine gas under acidic conditions. The fluorination of the NF molecule occurred in the ortho positions to the hydroxyl moiety, producing mono-, di-, and tri-substituted derivatives. The properties of the fluorinated naphthofluoresceins were similar to the parent compound, retaining pH sensitivity and fluorescence capability, but showed a more acidic pKa with increasing fluorination degree and a bathochromic shift in both absorbance and fluorescence. NF and its two major fluorinated derivatives were shown to attenuate Cerenkov radiation in the basic form; the greatest attenuation was observed at wavelengths coinciding with the absorption maxima. NF also showed potential as a Cerenkov Radiation Energy Transfer (CRET) probe. Fluorinated naphthofluoresceins provide a new family of molecular imaging probes for the detection of pH in tissue and organs by using a combination of PET and Cerenkov imaging.

Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring.

Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain's resident immune-cells, are now known to be critically involved in normal brain development, shaping connections between neurons by pruning superfluous synaptic spines. Our aim was to investigate whether maternal infection during critical stages of gestation compromises the role of microglia in sculpting neuronal circuits. Using a mouse model of maternal immune activation (MIA) induced by bacterial Lipopolysaccharide (LPS), we assayed the offspring's behavior during postnatal development. Additionally, we quantified spines within the offspring's brain and assessed alterations in some molecular signals involved in pruning. LPS-induced MIA led to behavioral changes relevant to ASD in the offspring in the absence of gross neurological problems. Prenatal LPS resulted in a significant increase in the number of spines in the granule cells of the dentate gyrus, as well as a reduction in hippocampal expression of the fractalkine microglial receptor (CX3CR1), involved in mediating the pruning process in the offspring. Interestingly, these changes were only noted in the male progeny of the LPS challenged dams. These results provide an early indicator that microglial function is altered in the brain of offspring from immune challenged mothers and that the effects in the brain appear to be specific along sex lines.

Modification of Blair Approach With a Modified Endaural Component to Access the Parotid Region.

OBJECTIVE: The aim of this study is to present our experience with a modification of the Blair approach to the parotid area, by means of a modified endaural component, which provides both excellent exposure and optimal functional and esthetic results, mainly over the preauricular area. PATIENTS AND METHODS: A retrospective case series study was performed. It included surgical cases of patients who were operated on the parotid region in which the mentioned approach was indicated. The information was collected from the database available at the Universidad El Bosque Oral and Maxillofacial Surgery Department in Bogota, Colombia from 2008 to 2013. RESULTS: The sample consisted of 12 patients, with ages ranging from 23 to 56 years and a mean age of 38 years. A total of 8 patients were women and 4 patients were men. Parotid pathologies included salivary gland tumor (10 patients) and cranial base tumor (2 patients). Procedures executed were: superficial lobe and total parotidectomy resection, pharynx extended and cranial base tumor resections. CONCLUSIONS: This investigation presents our experience with a modified approach to the parotid region. This approach gives an extended and safe exposure to the region with excellent cosmetic outcomes.

Online description of services provided in adult survivorship programs across U.S. accredited cancer centers.

PURPOSE: The American College of Surgeons Standard 4.8 requires an institution to implement a survivorship program to become a Commission on Cancer (CoC)-accredited cancer center. The online information offered by these cancer centers can help educate patients and their caregivers about available services. We assessed the content of survivorship program websites of CoC-accredited cancer centers in the United States. METHODS: Of the 1245 CoC-accredited centers for adults, we sampled 325 institutions (26%) based proportionately on the 2019 new cancer cases by state. Website pages of the institutions' survivorship programs were assessed for information and services offered using the COC Standard 4.8. We included programs for adult survivors of adult- and childhood-onset cancers. RESULTS: 54.5% of the cancer centers did not have a survivorship program website. Of the 189 included programs, most were aimed at adult survivors in general, rather than those with specific cancer types. On average, five essential CoC-recommended services were described, most commonly nutrition, care plans, and psychology services. The least mentioned services were genetic counseling, fertility, and smoking cessation. Most programs described services offered to patients who had completed treatment, while 7.4% of described services for those with metastatic disease. CONCLUSION: More than half of CoC-accredited programs did have information about cancer survivorship programs on their websites and when included, had variable and limited description of services. IMPLICATIONS FOR CANCER SURVIVORS: Our study provides an overview of online cancer survivorship services and offers a methodology that may be used by cancer centers to review, expand, and improve the information described on their websites.

Multimodal Endoscopic Management of Esophageal Perforations as a Complication of Peroral Endoscopic Myotomy for a Zenker's Diverticulum.

Zenker's diverticulum develops because of a weakness in Killian's triangle, leading to a mucosal and submucosal herniation. Its treatment has evolved from morbid surgical interventions to safer endoscopic techniques such as peroral endoscopic myotomy (Z-POEM). Despite being a safe technique, Z-POEM is not free of complications such as perforations, bleeding, pneumoperitoneum, and pneumothorax, for which new endoscopic techniques have been developed. We present the case of a 53-year-old man taken to a Z-POEM who postoperatively presented dehiscence of the mucosotomy and a mediastinal collection, managed with a vacuum-assisted endoscopic closure device.

Health Disparities Experienced by Hispanic Americans with Multiple Myeloma: A Systematic Review.

Health disparities in multiple myeloma (MM) disproportionately affect minorities. Characterization of health disparities encountered by Hispanic Americans with MM is necessary to identify gaps and inform future strategies to eliminate them. We performed a systematic review of publications that described health disparities relevant to Hispanic Americans with MM through December 2021. We included all original studies which compared incidence, treatment, and/or outcomes of Hispanic Americans with other ethnic groups. Eight hundred and sixty-eight articles were identified of which 22 original study articles were included in our systematic review. The number of publications varied over time with the highest number of studies (32%) published in 2021. Most of the published studies (59%) reported worse outcomes for Hispanic Americans with MM compared to other ethnic groups. There is growing evidence that Hispanic Americans with MM are facing a multitude of disparities that require immediate attention and solutions.

Carfilzomib combined with rituximab, ifosfamide, carboplatin, and etoposide for relapsed or refractory DLBCL.

The CORAL study highlighted the need to develop novel salvage regimens in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) previously treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Carfilzomib (CFZ) can overcome rituximab chemotherapy resistance in lymphoma preclinical models by targeting the ubiquitin-proteasome system. We conducted an investigator initiated, single-center, open-label, prospective phase 1 study evaluating the safety and efficacy of CFZ in combination with rituximab, ifosfamide, carboplatin, and etoposide (C-R-ICE) in high-dose chemotherapy with autologous stem cell transplant (HDC-ASCT) eligible patients with R/R DLBCL (NCT01959698). In the dose-escalation phase, 18 patients were enrolled at 6 dose levels with no dose-limiting toxicities noted. CFZ 45 mg/m2 was selected as the recommended dose for expansion. Eleven additional patients were enrolled in the dose-expansion phase. Overall response rate (ORR) was 66% (48% CR; 17% PR); 52% patients underwent HDC-ASCT. An ORR of 85% was observed in patients with nongerminal center B-cell-like (non-GCB) DLBCL compared with only 13% in those with GCB DLBCL. Median progression-free survival (PFS) was 15.2 months (5.1 months, not reached [NR]), and median overall survival (OS) was 22.6 months (6.8 months, NR). Patients with non-GCB subtype had a significantly longer PFS (NR vs 6.6 months; P = .0001) and OS (NR vs 6.6 months; P = .001) than those with GCB subtype. C-R-ICE is well tolerated in patients with R/R DLBCL with toxicities comparable to rituximab, ifosfamide, carboplatin, and etoposide therapy. Our data show that patients with non-GCB DLBCL benefit significantly from incorporating CFZ into second-line therapy and HDC-ASCT.

Impact of detectable monoclonal protein at diagnosis on outcomes in marginal zone lymphoma: a multicenter cohort study.

Given the paucity of data surrounding the prognostic relevance of monoclonal paraprotein (M-protein) in marginal zone lymphoma (MZL), we sought to evaluate the impact of detecting M-protein at diagnosis on outcomes in patients with MZL in a large retrospective cohort. The study included 547 patients receiving first-line therapy for MZL. M-protein was detectable at diagnosis in 173 (32%) patients. There was no significant difference in the time from diagnosis to initiation of any therapy (systemic and local) between the M-protein and no M-protein groups. Patients with M-protein at diagnosis had significantly inferior progression-free survival (PFS) compared with those without M-protein at diagnosis. After adjusting for factors associated with inferior PFS in univariate models, presence of M-protein remained significantly associated with inferior PFS (hazard ratio, 1.74; 95% confidence interval, 1.20-2.54; P = .004). We observed no significant difference in the PFS based on the type or quantity of M-protein at diagnosis. There were differential outcomes in PFS based on the first-line therapy in patients with M-protein at diagnosis, in that, those receiving immunochemotherapy had better outcomes compared with those receiving rituximab monotherapy. The cumulative incidence of relapse in stage 1 disease among the recipients of local therapy was higher in the presence of M-protein; however, this did not reach statistical significance. We found that M-protein at diagnosis was associated with a higher risk of histologic transformation. Because the PFS difference related to presence of M-protein was not observed in patients receiving bendamustine and rituximab, immunochemotherapy may be a preferred approach over rituximab monotherapy in this group and needs to be explored further.

Impact of early relapse within 24 months after first-line systemic therapy (POD24) on outcomes in patients with marginal zone lymphoma: A US multisite study.

Progression of disease within 24 months (POD24) from diagnosis in marginal zone lymphoma (MZL) was shown to portend poor outcomes in prior studies. However, many patients with MZL do not require immediate therapy, and the time from diagnosis-to-treatment interval can be highly variable with no universal criteria to initiate systemic therapy. Hence, we sought to evaluate the prognostic relevance of early relapse or progression within 24 months from systemic therapy initiation in a large US cohort. The primary objective was to evaluate the overall survival (OS) in the two groups. The secondary objective included the evaluation of factors predictive of POD24 and the assessment of cumulative incidence of histologic transformation (HT) in POD24 versus non-POD24 groups. The study included 524 patients with 143 (27%) in POD24 and 381 (73%) in non-POD24 groups. Patients with POD24 had inferior OS compared to those without POD24, regardless of the type of systemic therapy received (rituximab monotherapy or immunochemotherapy) at diagnosis. After adjusting for factors associated with inferior OS in the univariate Cox model, POD24 remained associated with significantly inferior OS (HR = 2.50, 95% CI = 1.53-4.09, p = 0.0003) in multivariable analysis. The presence of monoclonal protein at diagnosis and those who received first-line rituximab monotherapy had higher odds of POD24 on logistic regression analysis. Patients with POD24 had a significantly higher risk for HT compared to those without POD24. POD24 in MZL might be associated with adverse biology and could be used as an additional information point in clinical trials and investigated as a marker for worse prognosis.

Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase.

Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl-coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.

Integrative analysis of clinicopathological features defines novel prognostic models for mantle cell lymphoma in the immunochemotherapy era: a report from The North American Mantle Cell Lymphoma Consortium.

BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.

Critical review of the toxicity mechanisms of bisphenol F in zebrafish (Danio rerio): Knowledge gaps and future directions.

Replacement chemicals for bisphenol A, such as bisphenol F (BPF), are detected in aquatic environments worldwide and can potentially exert negative effects on aquatic organisms. We synthesized peer-reviewed literature reporting molecular and physiological responses in zebrafish following exposure to BPF, as BPF is closely related to BPA structure and is a dominant replacement chemical in the marketplace. Global concentrations of BPF in aquatic environments were compiled and compared to physiological and behavioral impacts reported in zebrafish (e.g., developmental abnormalities, oxidative stress, immunotoxicity, endocrine disruption, and neurotoxicity). Using computational approaches, we elucidate BPF-mediated molecular networks and reveal novel biomarkers associated with BPF exposure. Functional classes of proteins including inflammatory cytokines, ATPases, peroxidases, and aromatic l-amino decarboxylases represent novel, underexplored targets of toxicity. Most revealing of this critical review is that few studies report biological responses to BPF at levels present in aquatic environments. Recommendations for future investigations based on knowledge gaps include: (1) Mechanistic studies in the central nervous system of zebrafish to address neurotoxicity; (2) Behavioral assays in zebrafish that assess the effects of BPF on anxiolytic, social, and fear-related behaviors; (3) Studies that broaden understanding of potential endocrine disrupting effects of BPF, for example insulin signaling is predicted to be sensitive to BPF exposure; (4) Studies into metabolic disruption with a focus on glutathione and aromatic amino acids, based upon pathway analysis data; (5) Studies utilizing mixture exposures with other BPA analogs to reflect environmental conditions more accurately.