Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Empowering Voices: Inspiring Women in Medicinal Chemistry.

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

Analyte and matrix method extension of per- and polyfluoroalkyl substances in food and feed.

The development and expansion of analytical methods for per- and polyfluoroalkyl substances (PFAS) in food are essential for the continued monitoring of the United States (US) food supply and assessments of dietary exposure. In March 2022, the European Union Reference Laboratory for Halogenated Persistent Organic Pollutants in Feed and Food (EURL POPs) released a guidance document covering priority PFAS of interest, including analytical method parameters and limits of quantification (LOQs). As a result, the Food and Drug Administration (FDA) began method extension work to incorporate ten new additional analytes to method C-010.02 including long-chain perfluorosulfonic acids, fluorotelomer sulfonates, and perfluorooctane sulfonamide. Four long-chain carboxylic acids were also validated across all foods, which were previously added to C-010.02 but only validated in seafood. In December 2022, the European Union published Commission Regulation 2022/2388, establishing maximum levels for perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) in certain foodstuffs, primarily fish, molluscs, crustaceans, and eggs. As a result, the FDA method was evaluated for performance in reaching LOQs defined in Commission Regulation (EU) 2022/1431. The FDA method was found to be able to reach all required LOQs for analytes in matrices with established maximum levels. Currently, method detection limits (MDLs), which are used by the FDA as the lower limit for reporting PFAS in surveillance samples, were in the same range as defined indicative levels. With further method modifications, required LOQs could be met in fruits, vegetables, and milk. Reaching the lower targeted LOQs for these food matrices will require moving the method to an instrument that can provide increased signal:noise gains at the lower limits of quantification.

"It was like a bad dream": Making sense of violent hand amputation and replantation in South Africa.

BACKGROUND: South Africa is faced with one of the highest rates of violent crime in the world. Accordingly, therapists treat high numbers of deliberate hand injuries. There is, however, a paucity of literature exploring the lived experiences of these survivors. PURPOSE: The aim of this study was to describe and interpret the meaning of living through a violent hand amputation and replantation, the impact on occupational adaptation and to reflect on therapeutic intervention, within the context of South Africa. STUDY DESIGN: An exploratory embedded single case study using a qualitative approach. METHODS: Interpretative phenomenological analysis was used to analyze data from: 8 interviews with the primary participant, over a period of 33 months; an interview with his work colleague; interviews with 5 health professionals; a review of the occupational therapy rehabilitation file and a review of the audio-visuals, recorded over 2-years. RESULTS: This narrative reveals a man who understood his terrifying assault to be part of a southern African ritual of spiritual origin - using human body parts for traditional medicine (muti crime) or witchcraft. He perceived his expensive hand replantation and therapy as surreal and violence as normal. Challenges highlighted the importance of being attentive to the psychosocial sequelae of violence; and the most valuable part of therapy was perceived as occupational engagement. CONCLUSIONS: The perception of attempted muti murder situates this extreme and unusual case study as a novel contribution to the medical and rehabilitation literature. South African therapists are urged to be actively involved in changing the culture of violence, and hand therapists are reminded of the importance of applying holistic and occupation-based intervention.

Plasma and Skin Per- and Polyfluoroalkyl Substance (PFAS) Levels in Dairy Cattle with Lifetime Exposures to PFAS-Contaminated Drinking Water and Feed.

Plasma and ear notch samples were removed from 164 Holstein cows and heifers, which had lifetime exposures to per- and polyfluoroalkyl substances (PFAS) through consumption of contaminated feed and water sources. A suite of nine PFAS including five perfluoroalkyl carboxylic acids (PFCA) and four perfluoroalkyl sulfonic acids (PFSA) was quantified in plasma and ear notch samples by liquid chromatography-mass spectrometry. Bioaccumulation of four- to nine-carbon PFCAs did not occur in plasma or skin, but PFSAs longer than four carbons accumulated in both plasma and skin. Exposure periods of at least 1 year were necessary for PFSAs to reach steady-state concentrations in plasma. Neither parity (P = 0.76) nor lactation status (P = 0.30) affected total PFSA concentrations in mature cow plasma. In contrast, lactation status greatly affected (P < 0.0001) total PFSA concentrations in ear notch samples. Skin samples could be used for biomonitoring purposes in instances when on-farm blood collection and plasma preparation are not practical.

Analysis of Per- and Poly(fluoroalkyl) Substances (PFASs) in Highly Consumed Seafood Products from U.S. Markets.

Seafood consumption has been identified as one of the major contributors of per- and poly(fluoroalkyl) substances (PFASs) to the human diet. To assess dietary exposure, highly consumed seafood products in the United States were selected for analysis. The analytical method previously used for processed food was extended to include four additional long-chain perflurocarboxylic acids (PFCAs), which have been reported in seafood samples. This method was single-lab-validated, and method detection limits were reported at 345 ng kg-1 for perfluorobutanoic acid (PFBA) and 207 ng kg-1 for perfluoropentanoic acid (PFPeA) and below 100 ng kg-1 for the rest of the PFAS analytes. The 81 seafood samples (clams, crab, tuna, shrimp, tilapia, cod, salmon, pollock) were analyzed for 20 PFASs using the updated analytical method. Most of the seafood packaging was also analyzed by Fourier transform infrared-attenuated total reflectance (FTIR-ATR) to identify packaging potentially coated with PFASs. None of the packaging samples in this study were identified as having PFASs. A wide range of concentrations was observed among the seafood samples, ranging from below the method detection limit to the highest concentration of 23 µg kg-1 for the sum of PFASs in one of the canned clam samples. Such a wide range is consistent with those reported in previous studies. The highest concentrations were reported in clams and crabs, followed by cod, tuna, pollock, tilapia, salmon, and shrimp. Technical perfluorooctanoic acid (PFOA) dominated the profile of the clam samples, which has been consistently found in other clam samples, especially in Asia. Long-chain PFCAs, specifically perfluoroundecanoic (PFUdA) and perfluorododecanoic (PFDoA), were the most frequently detected analytes across all seafood samples. The trends observed are comparable with those in the literature where benthic organisms tend to have the highest PFAS concentrations, followed by lean fish, fatty fish, and aquaculture. The results from this study will be used to prioritize future studies and to inform steps to reduce consumer exposure to PFASs.

Analysis of per- and poly-fluoroalkyl substances (PFAS) in processed foods from FDA's Total Diet Study.

Additional occurrence data are needed to better understand human exposure to per- and poly-fluoroalkyl substances (PFAS) from commercially available foods in the United States. The Food and Drug Administration's (FDA) Total Diet Study (TDS) collects foods that are both nationally and regionally distributed. In 2018, 172 processed foods were collected from grocery stores around Lenexa, KS, as part of the TDS national collection. A previously developed method for the analysis of PFAS in foods as part of the TDS regional collection was modified and optimized for these samples. This method was single lab validated using 5 different matrices and method detection limits were calculated. During the analysis of these samples, challenges arose with method blanks and further investigation into statistical methods to distinguish between blank and sample concentrations were done. The confirmation of two short chain PFAS, perfluorobutanoic acid (PFBA) and perfluoropentanoic acid (PFPeA), was not possible using triple quadrupole mass spectrometry and a confirmation method was developed using high-resolution mass spectrometry. This technique was also used to investigate potential detections and interferents that fell within the retention time criteria for positive detections. In the national collection, positive detections of perfluorooctanesulfonic acid (PFOS) and perfluorononanoic acid (PFNA) were found in frozen fish sticks/patties, PFOS and perfluorodecanoic acid (PFDA) in canned tuna, and PFOS in protein powder. Concentrations were all below 150 ppt, and no other detects were confirmed above the method detection limits in any other foods.

Method Development and Validation of Per- and Polyfluoroalkyl Substances in Foods from FDA's Total Diet Study Program.

Human exposure to per- and polyfluoroalkyl substances (PFAS) through the US diet has not been well-characterized. Highly consumed foods are routinely monitored through FDA's Total Diet Study program. Portions of these samples were used to develop and validate a method for PFAS in a wide variety of foods. The extraction of 16 PFAS was performed using the quick, easy, cheap, effective, rugged, and safe (QuEChERS) method and analyzed by liquid chromatography/mass spectrometry. Method optimizations are described including investigations into the QuEChERS sorbents, matrix effects, and solid-phase extraction (SPE) cartridges. The use of a custom push-through SPE cartridge showed promising results as a rapid cleanup option for food samples. Challenges in ion confirmation are discussed, and the use of enhanced product ion (EPI) full-scan MS/MS spectra is presented as a potential option for verifying false positives. The validated method was then used for the analysis of 179 total diet study samples, and positive detects for perfluorooctanesulfonic acid (PFOS) were found in two fish and one meat sample.

Stereochemical Differences in Fluorocyclopropyl Amides Enable Tuning of Btk Inhibition and Off-Target Activity.

Bruton's tyrosine kinase (Btk) is thought to play a pathogenic role in chronic immune diseases such as rheumatoid arthritis and lupus. While covalent, irreversible Btk inhibitors are approved for treatment of hematologic malignancies, they are not approved for autoimmune indications. In efforts to develop additional series of reversible Btk inhibitors for chronic immune diseases, we sought to differentiate from our clinical stage inhibitor fenebrutinib using cyclopropyl amide isosteres of the 2-aminopyridyl group to occupy the flat, lipophilic H2 pocket. While drug-like properties were retained-and in some cases improved-a safety liability in the form of hERG inhibition was observed. When a fluorocyclopropyl amide was incorporated, Btk and off-target activity was found to be stereodependent and a lead compound was identified in the form of the (R,R)- stereoisomer.

Strategies to Mitigate the Bioactivation of Aryl Amines.

The bioactivation of xenobiotics to yield reactive metabolites can lead to tolerability and toxicity concerns within a drug discovery program. Development of strategies for mitigating the metabolic liability of commonly encountered toxicophores, such as anilines, relies on an understanding of the relative tendency of these functionalities to undergo bioactivation. In this report, we present the first systematic study of the structure-activity relationships of the bioactivation of aryl amine fragments (molecular weight < 250 Da) using a glutathione (GSH) trapping assay in the presence of human liver microsomes and the reduced form of nicotinamide adenine dinucleotide phosphate. This study demonstrates that conversion of anilines to nitrogen-containing heteroarylamines results in a lower abundance of GSH conjugates in the order phenyl > pyrimidine ≈ pyridine > pyridazine. Introduction of electron-withdrawing functionality on the aromatic ring had a less pronounced effect on the extent of GSH conjugation. Examination of more drug-like compounds sourced from in-house drug discovery programs revealed similar trends in bioactivation between matched pairs containing (hetero)aryl amines. This study provides medicinal chemists with insights and qualitative guidance for the minimization of risks related to aryl amine metabolism.

The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells.

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.

Congenital Absence of Tibial Sesamoids, With Alternate Insertions of the Flexor Hallucis Brevis Tendon.

There have been a dozen case reports of congenital absence of pedal sesamoid absence. We present the first documented case of congenital bilateral absence of tibial sesamoids with use of magnetic resonance imaging to identify a naturally occurring compensatory aberration of the flexor hallucis brevis. The right foot had bifurcation of the flexor hallucis brevis with one slip blending into the abductor hallucis tendon and capsule and the other slip traversing laterally and attaching to lateral flexor hallucis brevis tendon and fibular sesamoid. On the left foot, the entire flexor hallucis brevis traversed laterally and attached onto the fibular sesamoid and lateral flexor hallucis brevis. The present findings of this patient's anatomical variation could help provide valuable information to prevent known deformities that are the sequalae of a tibial sesamoidectomy.

It Takes a Village: Mentors, Colleagues, Family, and Friends.

Technical expertise is only the starting point to achieve a successful and rewarding career in medicinal chemistry. Just as important are characteristics such as insatiable curiosity, passion, risk-taking, life-long learning, being a team player, and perseverance in the face of obstacles and setbacks. Rounding out this list is creating and making the most of a network of mentors, colleagues, family, and friends from whom one can learn and grow, gain confidence, and celebrate successes.

Functional outcome using early controlled active motion in rehabilitation of a replanted hand: A case report.

STUDY DESIGN: Case report. INTRODUCTION: This case report details the postsurgical rehabilitation and outcome of a young maintenance man who sustained a complete amputation of his dominant upper limb at the level of the distal forearm. The patient underwent replantation surgery with 2-centimeter bone shortening, followed by early controlled active motion commencing on day 6. PURPOSE OF THE STUDY: To illustrate the use of early motion after replantation. RESULTS: The patient achieved almost full active range of motion of the digits, intrinsic function, 30 seconds on Nine-Hole Peg Test and early return to work without any additional reconstructive procedures. DISCUSSION: Several fairly recently published protocols advocate initiating active range of motion at only 3 or 4 weeks after upper limb replantation. The following therapeutic interventions were considered important contributors to our favorable functional outcome; early controlled active motion, occupation-based therapy in combination with therapeutic exercises and many custom molded orthoses. CONCLUSION: Future research is required to determine if bone shortening, which is an integral part of replantation surgery, reduces tendon repair tension, allowing for early active motion and thereby contributing to a favorable outcome.

Analysis of diglycolic acid in food packaging, over the counter products, direct additive carboxymethyl cellulose, and retail foods.

Carboxymethyl cellulose (i.e. CMC or cellulose gum) is used as a direct additive for foods and drugs to change texture and act as a binder. CMC can also be a fluid absorbent used in food packaging and food contact materials. CMC and other carboxymethyl starches are synthesised by condensing glycolic acid with monochloroacetic acid. Diglycolic acid (DGA) is a byproduct produced by this condensation which cannot be completely removed. Currently, there are no analytical methods to accurately detect and quantify DGA in foods and food packaging materials. A method using a methanol/water extraction coupled with weak anion exchange solid phase extraction cleanup for more complex matrices was developed. A novel LC-MS/MS method was used to determine the DGA concentration in food contact materials, food grade direct additive CMC, and foods containing CMC. This paper will discuss the development of a new method for the preparation and cleanup of various food matrices and LC-MS/MS analysis for the presence of DGA.