Peripheral nerve block adjuncts: which medication to choose? A narrative review of the current literature.

Enhancing the effect of peripheral nerve blockade by adding other classes of medications has long history of trial and error. Studies have identified multiple potentially beneficial adjuncts that work to either speed the onset of analgesia or prolong its duration. The benefits of these adjuncts must be weighed against the risks of systemic negative side effects. To date, the most commonly used adjuncts, and ones with the most robust scientific efficacy are, dexamethasone, dexmedetomidine and buprenorphine. This narrative review will discuss several classes of local anesthetic adjuncts and provide evidence for the clinical efficacy and side effect profile of the most commonly studied medications.

Prevalence of fentanyl in methamphetamine and cocaine samples collected by community-based drug checking services.

BACKGROUND: Overdose deaths involving stimulants and opioids simultaneously have raised the specter of widespread contamination of the stimulant supply with fentanyl. METHODS: We quantified prevalence of fentanyl in street methamphetamine and cocaine, stratified by crystalline texture, analyzing samples sent voluntarily to a public mail-in drug checking service (May 2021-June 2023). Samples from 77 harm reduction programs and clinics originated in 25 US states. Sample donors reported expected drug and physical descriptions. Substances were identified by gas chromatography-mass spectrometry. Negative binomial models were used to calculate fentanyl prevalence, adjusting for potential confounders related to sample selection. We also examined if xylazine changed donors' accuracy of detecting fentanyl. RESULTS: We analyzed 718 lab-confirmed samples of methamphetamine (64%) and cocaine (36%). The adjusted prevalence of fentanyl was 12.5% (95% CI: 2.2%, 22.9%) in powder methamphetamine and 14.8% (2.3%, 27.2%) in powder cocaine, with notable geographic variation. Crystalline forms of both methamphetamine (Chisq=57, p<0.001) and cocaine (Chisq=18, p<0.001) were less likely to contain fentanyl: less than 1% of crystal methamphetamine (2/276) and no crack cocaine (0/53). Heroin was present in 6.6% of powder cocaine samples. Xylazine reduced donors' ability to detect fentanyl, with correct classification dropping from 92% to 42%. CONCLUSIONS: Fentanyl was detected primarily in powder forms of methamphetamine and cocaine. Recommended interventions include expanding community-based drug checking, naloxone and fentanyl test strip distribution for people who use stimulants , and supervised drug consumption sites. New strategies to dampen variability in street drug composition are needed to reduce inadvertent fentanyl exposure.

Tumor Cell-Specific Retention and Photodynamic Action of Erlotinib-Pyropheophorbide Conjugates.

To enhance uptake of photosensitizers by epithelial tumor cells by targeting these to EGFR, pyropheophorbide derivatives were synthesized that had erlotinib attached to different positions on the macrocycle. Although the addition of erlotinib reduced cellular uptake, several compounds showed prolonged cellular retention and maintained photodynamic efficacy. The aim of this study was to identify whether erlotinib moiety assists in tumor targeting through interaction with EGFR and whether this interaction inhibits EGFR kinase activity. The activity of the conjugates was analyzed in primary cultures of human head and neck tumor cells with high-level expression of EGFR, and in human carcinomas grown as xenografts in mice. Uptake of erlotinib conjugates did not correlate with cellular expression of EGFR and none of the compounds exerted EGFR-inhibitory activity. One derivative with erlotinib at position 3, PS-10, displayed enhanced tumor cell-specific retention in mitochondria/ER and improved PDT efficacy in a subset of tumor cases. Moreover, upon treatment of the conjugates with therapeutic light, EGFR-inhibitory activity was recovered that attenuated EGFR signal-dependent tumor cell proliferation. This finding suggests that tumor cell-specific deposition of erlotinib-pyropheophorbides, followed by light triggered release of EGFR-inhibitory activity, may improve photodynamic therapy by attenuating tumor growth that is dependent on EGFR-derived signals.

Regional anesthesia for breast cancer surgery: which block is best? A review of the current literature.

Breast cancer is the most common type of cancer worldwide. Fortunately, continual advances in diagnosis and treatment are resulting in increased survival rates. Earlier detection and treatment, to include surgical resection, can greatly improve patients outcomes. However, due to the complex innervation of the breast, management of postoperative pain has proven difficult in the past. Approximately, half of all women who undergo breast cancer surgery report postoperative pain syndrome. The paravertebral block has long been the anesthesiologist's choice for mitigating pain during and after the procedure. Newer techniques such as the pectoral nerve block and erector spinae plane block may prove to have some additional benefits. This literature review compares the risks, benefits and specific uses of these three regional nerve blocks in women undergoing breast cancer surgery. It aims to better inform anesthesiologists when they are choosing which technique is best for their patients.

Breast cancer is the most common type of cancer worldwide with 2 million new cases each year. Approximately 12% of women are diagnosed with breast cancer at some point in their lives. Part of breast cancer treatment often involves surgery to remove a mass. This can cause pain in both the short and long term. There are multiple different kinds of procedures a person can have done that may decrease the pain, they have from that surgery. These procedures are called nerve blocks. This article examines how well different nerve blocks decrease pain from breast cancer surgery. The nerve blocks we review in this article are called paravertebral blocks, pectoral nerve blocks and erector spinae plane blocks. They all block pain from breast surgery in slightly different ways. The decision of which block is best rests on the person performing the block.

Tumor cell-specific retention of photosensitizers determines the outcome of photodynamic therapy for head and neck cancer.

Pheophorbide-based photosensitizers have demonstrated tumor cell-specific retention. The lead compound 3-[1'-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) in a clinical trial for photodynamic therapy of head and neck cancer lesions indicated a complete response in 80% of patients. The question arises whether the partial response in 20% of patients is due to inefficient retention of photosensitizers by tumor cells and, if so, can the photosensitizer preference of individual cancer cases be identified prior to photodynamic therapy. This study determined the specificity of head and neck cancer cells and tumor tissues for the uptake and retention of diffusible pheophorbides differing in peripheral groups on the macrocycle that contribute to cellular binding. The relationship between photosensitizer level and light-mediated photoreaction was characterized to identify markers for predicting the effectiveness of photodynamic therapy in situ. The experimental models were stromal and epithelial cells isolated from head and neck tumor samples and integrated into monotypic tissue cultures, reconstituted three-dimensional co-cultures, and xenografts. Tumor cell-specific photosensitizer retention patterns were identified, and a procedure was developed to allow the diagnostic evaluation of HPPH binding by tumor cells in individual cancer cases. The findings of this study may assist in designing conditions for photosensitizer application and photodynamic therapy of head and neck cancer lesions optimized for each patient's case.

Charged groups on pyropheophorbide-based photosensitizers dictate uptake by tumor cells and photodynamic therapy efficacy.

This study investigated the impact of anionic and cationic substituents of the pyropheophorbide-based photosensitizers (PS) on uptake and retention by tumor epithelial cells and photodynamic therapy (PDT). A series of PSs were generated that bear carboxylic acid functionalities, alkyl amines with variable length of carbon units or as a quaternary ammonium salt introduced at position 172 of 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH). The nature of the functionalities in the macrocycle made a significant difference in overall lipophilicity (log D values at pH 7.4), and in binding to and retention by human and murine tumor cells. Depending on the presence of functional groups, the PSs showed a change in cellular uptake from diffusion to endocytosis and in the preference for subcellular localization to mitochondria/ER or lysosomes. Two and more carboxylic groups drastically reduced uptake by all cell types. In contrast, PSs with amine and quaternary amine salt showed higher cellular binding, uptake and in vitro PDT efficacy than HPPH. The enhanced cellular uptake of the cationic PSs was accompanied by a loss of tumor cell specificity and contributed to severe systemic toxicity in tumor-bearing mice intravenously injected with the PS and subjected to investigate their therapeutic potential.

The Impact of COVID-19 on Freshwater Fisheries Fieldwork and Data Collection.

COVID-19 has affected almost every aspect of society including freshwater fisheries fieldwork. Our study quantified the effects of the pandemic on fisheries fieldwork in the United States. We administered a survey to fisheries chiefs in all 50 states to assess the pandemic's impact on fisheries fieldwork. Of the 37 participants, 91% reported the pandemic affected their fieldwork and 92% adapted their sampling methods in response to the pandemic. Common adaptation strategies included using personal protective equipment (100%), practicing social distancing (97%), using smaller crews (82%), and developing contingency plans (51%). Based on the survey results, we identified potential challenges to adaptations and offered strategies to improve them. Strategies we identified include adopting novel data collection techniques, finding new positions for temporary employees, and publicly sharing contingency plans. Ultimately, this paper offers novel guidance on how fisheries professionals can best move forward with fieldwork during a time of crisis.

Interactions between semaphorins and plexin-neuropilin receptor complexes in the membranes of live cells.

Signaling of semaphorin ligands via their plexin-neuropilin receptors is involved in tissue patterning in the developing embryo. These proteins play roles in cell migration and adhesion but are also important in disease etiology, including in cancer angiogenesis and metastasis. While some structures of the soluble domains of these receptors have been determined, the conformations of the full-length receptor complexes are just beginning to be elucidated, especially within the context of the plasma membrane. Pulsed-interleaved excitation fluorescence cross-correlation spectroscopy allows direct insight into the formation of protein-protein interactions in the membranes of live cells. Here, we investigated the homodimerization of neuropilin-1 (Nrp1), plexin A2, plexin A4, and plexin D1 using pulsed-interleaved excitation fluorescence cross-correlation spectroscopy. Consistent with previous studies, we found that Nrp1, plexin A2, and plexin A4 are present as dimers in the absence of exogenous ligand. Plexin D1, on the other hand, was monomeric under similar conditions, which had not been previously reported. We also found that plexin A2 and A4 assemble into a heteromeric complex. Stimulation with semaphorin 3A or semaphorin 3C neither disrupts nor enhances the dimerization of the receptors when expressed alone, suggesting that activation involves a conformational change rather than a shift in the monomer-dimer equilibrium. However, upon stimulation with semaphorin 3C, plexin D1 and Nrp1 form a heteromeric complex. This analysis of interactions provides a complementary approach to the existing structural and biochemical data that will aid in the development of new therapeutic strategies to target these receptors in cancer.

Topical arginase inhibition decreases growth of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinomas (cSCC) are among the most commonly diagnosed malignancies, causing significant morbidity and mortality. Tumor-associated macrophage (TAM) expression of arginase is implicated in tumor progression, and therapeutic use of arginase inhibitors has been studied in various cancers. However, investigating potential cSCC immunotherapies including arginase inhibition in pre-clinical models is hampered by the lack of appropriate tumor models in immunocompetent mice. PDV is a cSCC cell line derived from chemical carcinogenesis of mouse keratinocytes. PDVC57 cells were derived from a PDV tumor in C57BL/6 (B6) mice. Unlike PDV, PDVC57 tumors grow consistently in B6 mice, and have increased TAMs, decreased dendritic and T cell intra-tumor infiltration. Arginase inhibition in cSCC tumors using Nω-hydroxy-nor-arginine (nor-NOHA) reduced tumor growth in B6 mice but not immunodeficient Rag1-deficient mice. nor-NOHA administration increased dendritic and T cell tumor-infiltration and PD-1 expression. The combination of nor-NOHA and anti-PD-1 therapy with nivolumab enhanced anti-PD-1 therapeutic efficacy. This study demonstrates the therapeutic potential of transcutaneous arginase inhibition in cSCC. A competent immune microenvironment is required for tumor growth inhibition using this arginase inhibitor. Synergistic co-inhibition of tumor growth in these results, supports further examination of transcutaneous arginase inhibition as a therapeutic modality for cSCC.

Chiral Alkyl Groups at Position 3(1') of Pyropheophorbide-a Specify Uptake and Retention by Tumor Cells and Are Essential for Effective Photodynamic Therapy.

To investigate the importance of the chirality and precise structure at position 3(1') of pyropheophorbide-a for tumor cell specificity and photodynamic therapy (PDT), a series of photosensitizers (PSs) was synthesized: (a) with and without chirality at position 3(1'), (b) alkyl ether chain with a variable number of chiral centers, (c) hexyl ether versus thioether side chain, and (d) methyl ester versus carboxylic acid group at position 172. The cellular uptake and specificity were defined in human lung and head/neck cancer cells. PSs without a chiral center and with an alkyl chain or thioether functionalities showed limited uptake and PDT efficacy. Replacing the methyl group at the chiral center with a propyl group or introducing an additional chiral center improved cellular retention and tumor cell specificity. Replacing the carboxylic acid with methyl ester at position 172 lowered cellular uptake and PDT efficacy. A direct correlation between the PS uptake in vitro and in vivo was identified.

Synthesis, Tumor Specificity, and Photosensitizing Efficacy of Erlotinib-Conjugated Chlorins and Bacteriochlorins: Identification of a Highly Effective Candidate for Photodynamic Therapy of Cancer.

Erlotinib was covalently linked to 3-(1'-hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) and structurally related chlorins and bacteriochlorins at different positions of the tetrapyrrole ring. The functional consequence of each modification was determined by quantifying the uptake and subcellular deposition of the erlotinib conjugates, cellular response to therapeutic light treatment in tissue cultures, and in eliminating of corresponding tumors grown as a xenograft in SCID mice. The experimental human cancer models the established cell lines UMUC3 (bladder), FaDu (hypopharynx), and primary cultures of head and neck tumor cells. The effectiveness of the compounds was compared to that of HPPH. Furthermore, specific functional contribution of the carboxylic acid side group at position 172 and the chiral methyl group at 3(1') to the overall activity of the chimeric compounds was assessed. Among the conjugates investigated, the PS 10 was identified as the most effective candidate for achieving tumor cell-specific accumulation and yielding improved long-term tumor control.

Telemedicine Companies Providing Prescription-Only Medications: Pros, Cons, and Proposed Guidelines.

In the past few years, there has been a significant increase in the number of direct-to-consumer telehealth companies offering prescription medications to women. Leveraging technology, these companies have the potential to improve access to care and ensure that women have access to prescription-only medications in a convenient fashion. However, it is important to ensure that they are doing so in a safe, patient-centered way that observes evidence-based prescribing guidelines. In this article, we discuss the pros and cons of direct-to-consumer telehealth companies offering prescription medicine and suggest several guidelines to ensure that women are being cared for in an appropriate way.

Fetal alcohol spectrum disorder prevention program: SBIRT's role in averting fetal alcohol spectrum disorders.

Empowering obstetricians to assess and improve their own practices of screening brief intervention and referral to treatment (SBIRT) in treating alcohol use disorders (AUDs) and preventing fetal alcohol spectrum disorder (FASD) is the goal of the American College of Obstetricians and Gynecologist (ACOG) FASD Prevention Program. The FASD Prevention Program is a CDC funded initiative of the ACOG which is the largest specialty professional membership organization in the United States. Obstetrics and gynecology as a specialty is dedicated to the broad, integrated medical and surgical care of women's health throughout their lifespan. Understanding of reproductive physiology, including the physiologic, social, cultural, environmental, and genetic factors that influence disease in women, is a major priority for ACOG. Preventive counseling and health education are essential and integral parts of the practice of obstetricians and gynecologists as they advance the individual and community-based health of women of all ages. The FASD Prevention Program aims to provide obstetrician-gynecologists with the resources and tools needed to communicate with patients and the communities they serve about alcohol use during pregnancy. This review describes activities to empower and educate providers to address alcohol use disorder in pregnancy and the effect of FASD.

Cell-specific Retention and Action of Pheophorbide-based Photosensitizers in Human Lung Cancer Cells.

This study determined in primary cultures of human lung cancer cells the cell specificity of chlorin-based photosensitizers. Epithelial cells (ECs) preferentially retained 3-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) and related structural variants. Tumor-associated fibroblasts (Fb) differ from EC by a higher efflux rate of HPPH. Immunoblot analyses indicated dimerization of STAT3 as a reliable biomarker of the photoreaction. Compared to mitochondria/ER-localized photoreaction by HPPH, the photoreaction by lysosomally targeted HPPH-lactose showed a trend toward lower STAT3 cross-linking. Lethal consequence of the photoreaction differed between EC and Fb with the latter cells being more resistant. A survey of lung tumor cases indicated a large quantitative range by which EC retains HPPH. The specificity of HPPH retention defined in vitro could be confirmed in vivo in selected cases grown as xenografts. HPPH retention as a function of the tetrapyrrole structure was evaluated by altering side groups on the porphyrin macrocycle. The presence or absence of a carboxylic acid at position 172 proved to be critical. A benzyl group at position 20 enhanced retention in a subset of cancer cells with low HPPH binding. This study indicated experimental tools that are potentially effective in defining the photosensitizer preference and application for individual patient's cancer lesions.

Parental consent: an unnecessary barrier to adolescent obstetrical care.

When adolescents in the United States become pregnant, these young mothers experience differential access to obstetrical services, including prenatal, intrapartum, and postpartum care. As of 2018, 13 states in the United States do not afford a pregnant minor rights to prenatal care without parental consent, and 13 states do not ensure confidentiality from parental disclosure. Because of this, young mothers may avoid seeking timely and medically necessary care, not to mention counseling regarding preventive health services and monitoring of underlying chronic conditions. Lack of access during these critical months leads to missed essential opportunities for intervention and increased pregnancy-related risks to the mother and infant. It is imperative for obstetricians and gynecologists to value, support, and advocate for adolescents' emerging autonomy and personal agency to make informed decisions about their own bodies during their pregnancies, but also in making the choice to prevent future pregnancies through contraception.

Identifying and Assisting Sexually Exploited and Trafficked Patients Seeking Women's Health Care Services.

It is estimated that 21 million people are trafficked worldwide, including 11.4 million women and girls. Approximately 4.5 million are forced to do sexual labor. The exact prevalence of human trafficking is difficult to ascertain, however, given the limitations of data collection in an illegal industry. Obstetrician-gynecologists should not only be aware of the widespread nature of human trafficking, but also have the tools to assess patients for trafficking and respond to victim identifications. Patients may present with signs of physical abuse, depression, anxiety, posttraumatic stress disorder, substance use, sexually transmitted infections, pregnancy, and nonspecific somatic complaints. As with intimate partner violence, clinicians should be suspicious if the patient is accompanied by an individual who refuses to leave her side. Other potential red flags include patients with wounds in various stages of healing, patients appearing fearful or unable to answer specific questions, and patients who do not have any personal identification. Health care providers should speak with the patient privately, using professional interpreters when indicated. Although there are no validated screening questions for the health care setting, in this article, we provide sample questions such as, "Is anyone forcing you to do anything physically or sexually that you do not want to do?" The physical examination should be thorough with appropriate workup, sexually transmitted infection prophylaxis, and emergency contraception. Physicians and patients should be aware of their state's mandatory reporting requirements and careful documentation is essential. Finally, to ensure a comprehensive, interdisciplinary response to trafficked patients, practitioners should engage hospital-based and community-based services when appropriate.

Contraception: Menarche to Menopause.

Contraception services should be part of routine health care maintenance in reproductive-aged women, especially in light of the fact that approximately 50% of pregnancies in the United States remain unplanned. Barrier methods, especially condoms, may play a role in sexually transmitted disease prevention but are less efficacious for pregnancy avoidance. There are several available hormonal contraceptive options, including the combination hormonal pill, progestin-only pill, combination hormonal patches and rings, injectable progestins, implantable progestins, intrauterine devices (copper or progestin), and permanent sterilization. These methods have varying efficacy, often related to patient compliance or tolerance of side effects.

Stress-induced dynamic regulation of mitochondrial STAT3 and its association with cyclophilin D reduce mitochondrial ROS production.

Signal transducer and activator of transcription 3 (STAT3) is associated with various physiological and pathological functions, mainly as a transcription factor that translocates to the nucleus upon tyrosine phosphorylation induced by cytokine stimulation. In addition, a small pool of STAT3 resides in the mitochondria, where it serves as a sensor for various metabolic stressors including reactive oxygen species (ROS). Mitochondrially localized STAT3 largely exerts its effects through direct or indirect regulation of the activity of the electron transport chain (ETC). It has been assumed that the amounts of STAT3 in the mitochondria are static. We showed that various stimuli, including oxidative stress and cytokines, triggered a signaling cascade that resulted in a rapid loss of mitochondrially localized STAT3. Recovery of the mitochondrial pool of STAT3 over time depended on phosphorylation of Ser727 in STAT3 and new protein synthesis. Under these conditions, mitochondrially localized STAT3 also became competent to bind to cyclophilin D (CypD). Binding of STAT3 to CypD was mediated by the amino terminus of STAT3, which was also important for reducing mitochondrial ROS production after oxidative stress. These results outline a role for mitochondrially localized STAT3 in sensing and responding to external stimuli.

Structural and Epimeric Isomers of HPPH [3-Devinyl 3-{1-(1-hexyloxy) ethyl}pyropheophorbide-a]: Effects on Uptake and Photodynamic Therapy of Cancer.

The tetrapyrrole structure of porphyrins used as photosentizing agents is thought to determine uptake and retention by malignant epithelial cancer cells. To assess the contribution of the oxidized state of individual rings to these cellular processes, bacteriochlorophyll a was converted into the ring "D" reduced 3-devinyl-3-[1-(1-hexyloxy)ethyl]pyropheophorbide-a (HPPH) and the corresponding ring "B" reduced isomer (iso-HPPH). The carboxylic acid analogs of both ring "B" and ring "D" reduced isomers showed several-fold higher accumulation into the mitochondria and endoplasmic reticulum by primary culture of human lung and head and neck cancer cells than the corresponding methyl ester analogs that localize primarily to granular vesicles and to a lesser extent to mitochondria. However, long-term cellular retention of these compounds exhibited an inverse relationship with tumor cells generally retaining better the methyl-ester derivatives. In vivo distribution and tumor uptake was evaluated in the isogenic model of BALB/c mice bearing Colon26 tumors using the respective 14C-labeled analogs. Both carboxylic acid derivatives demonstrated similar intracellular localization and long-term tumor cure with no significant skin phototoxicity. PDT-mediated tumor action involved vascular damage, which was confirmed by a reduction in blood flow and immunohistochemical assessment of damage to the vascular endothelium. The HPPH stereoisomers (epimers) showed identical uptake (in vitro & in vivo), intracellular retention and photoreaction.